JP2008529674A - System and method for detecting specimen by reducing sample volume - Google Patents

Abstract

A method for collecting body fluid from a patient is disclosed. The method includes providing a liquid processing system that includes one or more liquid pathways (20), and injecting an infusate into the patient via the one or more liquid pathways by the liquid processing system. The method further includes obtaining a sample of bodily fluid from the patient via the one or more pathways by the liquid processing system. The sample to be obtained is 400 μl or less in volume. The method further includes analyzing at least an analytical portion of the sample obtained by the analyte detection system (324) operatively associated with the liquid processing system and measuring the concentration of at least one analyte. A corresponding system is also disclosed.
[Selection] Figure 7E

Description

  Individual embodiments disclosed herein relate to a method and apparatus for measuring the concentration of an analyte in a sample, such as an analyte in a body fluid sample, and to a method and apparatus used to support such measurements.

  It is common practice to measure specific analyte levels such as glucose in body fluids such as blood. This is done in hospitals or clinical treatments when there is a risk of compromising patient health if a particular specimen level exceeds a predetermined range.

  Various deficiencies have been pointed out in currently known systems for monitoring specimens in hospitals or clinical treatments.

  A particular embodiment is a method of collecting body fluid. The method includes providing a liquid processing system having one or more liquid paths. The method further includes injecting the infusate into the extracorporeal fluid conduit via the one or more liquid pathways using the liquid processing system. The method further includes obtaining a sample of bodily fluid from the conduit via the one or more liquid pathways using the liquid processing system. The sample thus obtained has a volume of 400 μl or less. The method further includes analyzing at least an analytical portion of the acquired sample and measuring the concentration of at least one analyte using an analyte detection system operatively associated with the liquid processing system.

  In certain embodiments, the method further includes separating the acquired sample into a first portion and a second portion that is returned to the patient without analysis. In one embodiment, the first portion is no greater than 60 μl by volume. In other embodiments, the first portion has a volume of 40 μl or less. In certain embodiments, the method further includes the step of separating the first portion into a plurality of portions, one of the plurality of portions being the analysis portion. In one embodiment, the analysis portion is no greater than 10 μl by volume.

  A particular embodiment is a bodily fluid treatment system that includes a liquid treatment network configured to access a patient's bodily fluid and having a patient end. The main body liquid treatment system is further a pump system coupled to the liquid treatment network, the pump system operating in a first mode that operates to infuse the infusate toward the patient via the liquid treatment network; A pump system having a second mode that operates to withdraw a sample of bodily fluid from the fluid processing network. The main body fluid treatment system further comprises an analyte detection system that is accessible to the fluid treatment network and configured to measure at least a portion of the analyte of the extracted body fluid sample. The liquid processing network has a maximum extraction area corresponding to the maximum extraction state of the liquid processing system. The maximum extraction area is 400 μl or less in volume.

  In certain embodiments, the bodily fluid processing system further includes a sample preparation section that separates the extracted sample into a first portion and a second portion that is returned to the patient without analysis. In one embodiment, the first portion is no greater than 60 μl by volume. In other embodiments, the first portion is no greater than 40 μl by volume. In certain embodiments, the bodily fluid processing system further comprises a sample preparation portion configured to separate the first portion into a plurality of portions, one of the plurality of portions including an analysis portion. In one embodiment, the analysis portion is no greater than 10 μl by volume.

  A particular embodiment is a body fluid analysis system with a fluid pathway. The liquid analysis system further includes an analyzer that is accessible to the liquid path and configured to deliver information related to the analyte measurement of the sample. The liquid analysis system further includes a processor in conjunction with the analyzer. The liquid analysis system further comprises stored program instructions, the stored program instructions comprising: (a) injecting infusate toward the patient end of the liquid path; and (b) sample. Extracting 400 μl or less from the patient side end toward the analyzer through the liquid path, and (c) analyzing at least a part of the extracted sample and measuring the concentration of at least one specimen And can be executed by the processor to operate.

  In one embodiment, the body fluid analysis system further includes a sample preparation section that separates the extracted sample into a first portion and a second portion that is returned to the patient without analysis. In one embodiment, the first portion is no greater than 60 μl by volume. In other embodiments, the first portion is no greater than 40 μl by volume. In certain embodiments, the main body fluid analysis system further comprises a sample preparation portion configured to separate the first portion into a plurality of portions, one of the plurality of portions including the analysis portion. Yes. In one embodiment, the analysis portion is no greater than 10 μl by volume.

  In certain embodiments, the liquid processing module can be used with a body fluid analyzer having a pump system and an analyte detection system. The liquid treatment module includes a liquid delivery network having a patient end and a boundary portion spaced from the patient end and engaged with the pump system and configured to obtain body fluid from the patient. The liquid processing module further includes a sample analysis cell that is accessible to the liquid delivery network and configured to interface with the analyte detection system. The liquid delivery network has a maximum extraction area corresponding to the maximum extraction state of the network. The maximum extraction area is 400 μl or less in volume.

  In certain embodiments, the liquid processing module further comprises a sample preparation unit that separates bodily fluid obtained from the patient into a first part and a second part that is returned to the patient without analysis. In one embodiment, the first portion is no greater than 60 μl by volume. In other embodiments, the first portion is no greater than 40 μl by volume. In certain embodiments, the liquid processing module further comprises a sample preparation portion configured to separate the first portion into a plurality of portions, one of the plurality of portions including an analysis portion. In one embodiment, the analysis portion is no greater than 10 μl by volume.

  The objects and advantages of the present invention are described here. It should be understood that not all such objects and advantages may be realized in separate embodiments. Thus, for example, those skilled in the art will recognize other advantages or teachings herein to achieve or optimize one or more of the advantages or advantages taught herein when implementing or implementing the present invention. Obviously, an objective or advantage may not necessarily be achieved.

  The summary of the specific embodiment has been described above. However, while specific embodiments have been described, the invention is defined solely by the appended claims (not the abstract). Summary embodiments and other embodiments will be readily apparent to those skilled in the art from the detailed description of the invention that follows, using preferred embodiments and with reference to the drawings. However, the present invention is not limited to the individual embodiments disclosed herein.

  In order to show a component, an aspect, or a feature, the reference symbol is attached | subjected in drawing, However, The common reference symbol is used in several drawing about the same component, aspect, or feature.

Hereinafter, preferred embodiments and examples will be individually described, but the content of the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or uses of the present invention. Those skilled in the art will appreciate that obvious modifications and equivalents are covered. Therefore, the scope of the present invention disclosed in this specification is not limited by the embodiments described below. For example, in the methods or steps disclosed herein, the acts or actions making up the methods / steps may be performed by any suitable procedure and need not be limited to those disclosed herein. In order to compare the various embodiments with the prior art, certain aspects and advantages of these embodiments are described in appropriate places in the specification. Of course, it will be understood that not all such aspects or advantages may be achieved from any embodiment. For example, various embodiments may be implemented to achieve or optimize a particular advantage or group of advantages taught herein, but may not achieve the other aspects or advantages taught herein. Please understand that. Although the systems and methods described herein can be used in invasive procedures, these systems and methods are also used in non-invasive procedures or other suitable techniques, or hospitals, clinics, ICUs, or homes. be able to.

Outline of liquid processing system of embodiment

  Disclosed are liquid processing systems and various types of sample fluid analysis methods. With reference to FIG. 1, an embodiment of a liquid processing system 10 that can measure the concentration of one or more substances in a sample fluid such as whole blood collected from a patient P will be described. The liquid treatment system 10 is also adapted to inject an infusion fluid 14 into the patient.

  The illustrated liquid processing system 10 is disposed on the bed side of a patient and generally includes a container 15 that holds an infusion solution 14 and a person collection system 100 that communicates with the container 15 and the patient P. In some embodiments, the liquid treatment system 10 may be in communication with an extracorporeal fluid line that contains an amount of bodily fluid. A tube 13 extends from the container 15 to the collection system 100. The tube 12 extends from the collection system 100 to the patient P. In some embodiments, instead of the illustrated tube 12, a suitable extracorporeal fluid tube, such as a catheter, PV tube, or IV network, is connected to the collection system 100 using a connector, such as the illustrated junction 110. Can connect. The extracorporeal fluid pipe does not need to be attached to the patient P. For example, the extracorporeal fluid pipe may communicate with a body fluid (for example, blood) or a container intended for the extracorporeal fluid pipe, or may be a body fluid container intended alone. Also good. In some embodiments, one or more components that make up the liquid treatment system 10 can be located in other facilities, rooms, or suitable remote locations. The one or more components constituting the liquid processing system 10 include one or more other components (or devices) constituting the liquid processing system 10, an optical interface, an electrical interface, and a wireless interface. The communication can be performed by an appropriate communication means without limitation. These interfaces can consist of a local network, the Internet, a wireless network, or other suitable network.

  Infusion solution 14 may contain water, saline, dextrose, lactated Ringer's solution, drug, insulin, or mixtures thereof, or other suitable materials. The illustrated collection system 100 can inject an infusate into the patient P and / or use the infusate for analysis, and in some embodiments, the bodily fluid treatment system 10 can use no infusion. Good. Thus, the body fluid treatment system 10 may extract the sample without administering the liquid to the patient P.

  The collection system 100 can be detachably or permanently joined to the tube 13 and the tube 12 via the joints 110 and 120. The patient junction 110 can selectively control the flow of liquid through the tube bundle 130 including the patient junction path 112 and the collection path 113, as shown in FIG. 1B. The collection system 100 can also extract one or more samples from the patient P using suitable means. The collection system 100 can perform one or more analyzes on the sample and then return the sample to the patient or discard it in a waste container. In some embodiments, the harvesting system 100 is a modular unit that can be removed and replaced as needed. The collection system 100 includes liquid processing and analysis devices, junctions, pathways, catheters, tubing, liquid controllers, valves, pumps, liquid sensors, pressure sensors, temperature sensors, hematocrit sensors, hemoglobin sensors, colorimetric sensors and gases (or “Bubble”) sensors, fluid regulators, gas injectors, gas filters, plasma separators and / or communicators (eg, wireless) that communicate information within collection system 100 or between collection system 100 and a network. Communication device). The illustrated collection system 100 includes a patient junction 110 and a liquid processing and analysis device 140 that analyzes a sample collected from a patient P. The liquid processing and analysis device 140 and the patient junction 110 jointly control the infusate to the patient P and / or the sample flow drawn from the patient P. Samples can also be transferred by other suitable methods after collection.

  FIG. 1A is an enlarged view of a liquid processing and analysis apparatus 140 including a partial cutaway view for illustrating some internal components. The liquid processing and analysis device 140 preferably includes a pump 203 that controls the flow of liquid from the container 15 to the patient P and / or the flow of liquid collected from the patient P. The pump 203 can selectively control the flow rate, direction, and other flow parameters of the liquid flow as needed. As used herein, the term “pump” is broad and refers to, but is not limited to, a pressure / pressurization device, a vacuum device, or any other suitable means for generating a fluid flow. Pump 203 may be, but is not limited to, a reversible peristaltic pump, a two-way pump that generates flow in two directions in conjunction with a valve, a one-way pump, a variable pump, a syringe, a membrane pump, a roller pump, or other suitable Pressure pumps can be included.

  The illustrated liquid processing and analysis apparatus 140 includes a display unit 141 and an input unit 143. The illustrated liquid processing and analysis device 140 can include a collection unit 200 configured to analyze an incorporated liquid sample. The collection unit 200 can receive the sample, prepare the sample, and / or have the (prepared or unprepared) sample undergo one or more tests. Next, the collection unit 200 can receive the sample and analyze the result of the test. The collection unit 200 may include, but is not limited to, a separator, a filter, a centrifuge, a centrifuge, a sample element, and / or a detection system described in detail below. The collection unit 200 (FIG. 3) can include a sample detection system that detects one or more sample concentrations in the body fluid sample. In some embodiments, the collection unit 200 can prepare a sample for analysis. When the liquid processing and analysis device 140 analyzes plasma in whole blood collected from the patient P, the plasma is removed from other blood in the blood using a filter, separator, centrifuge or other type of sample preparation device. Can be separated from the components. After the separation step, the collection unit 200 can analyze the plasma to measure the glucose level of the patient P, for example. The sampling unit 200 can use a spectroscopic method, a colorimetric method, an electrochemical method, or other suitable methods to analyze the sample.

  The description will be continued with reference to FIGS. 1 and 1A again. The liquid 14 in the container 15 flows to the liquid source path 111 through the pipe 13. The liquid further flows to the pump 203 via the path 111, and the pump 203 pressurizes the liquid. The liquid 14 then flows from the catheter 11 into the patient P via the patient joint path 112 from the pump 203. In order to analyze the body fluid of the patient P (for example, whole blood, plasma, interstitial fluid, bile, sweat, excretion, etc.), the liquid processing and analysis device 140 sends a sample from the patient P via the catheter 11 to the patient junction. Extract to 110. The patient junction 110 guides the liquid sample to the collection path 113 that continues to the collection unit 200. The sampling unit 200 can perform one or more analyzes on the sample. The liquid processing and analysis apparatus 140 can output the result obtained from the collection unit 200 on the display unit 141.

  In some embodiments, the liquid processing system 10 can extract a body fluid sample from the patient P for analysis and measure glucose levels in real time or near real time. Body fluid samples can be taken from patient P continuously, at regular intervals (eg, 5, 10, 15, 20, 30, 60 minutes), at irregular intervals, or for any desired measurement at any time or procedure Can be extracted. These measured values can be comfortably displayed by the display unit 141 on the bed side of the patient.

  The illustrated liquid processing system 10 is attached to a stand 16 and can be used in hospitals, ICUs, houses, clinics, and the like. In some embodiments, the liquid treatment system 10 is transportable or portable for outpatients. In order to make it possible to connect the outpatient liquid processing system 10 to a patient (for example, by tying or attaching the outpatient liquid processing system 10), it may be smaller than the clinical liquid processing system 10 shown in FIG. 1. In some embodiments, the liquid treatment system 10 is an implantation system sized to be implanted subcutaneously so that it can be used for continuous monitoring. In some embodiments, the liquid processing system 10 is further miniaturized so that the entire liquid processing system can be embedded. In other embodiments, only a portion of the liquid processing system 10 can be embedded.

  In some embodiments, the liquid processing system 10 includes a disposable liquid processing system and / or one or more disposable parts. In this specification, “disposable” applied to a system or a component (or a combination of components) such as a cassette or a sample element is a broad meaning, and is discarded after a target component is used a finite number of times. It is meant to be, but is not limited to this. Some disposable components are discarded after a single use. Other disposable components are discarded after more than one use. For example, the liquid processing and analysis device 140 may include a central instrument section and a disposable cassette attached to the central instrument section, as described below. The disposable cassette can be used for a predetermined amount of time to analyze a predetermined amount of sample fluid. In some embodiments, a cassette is used to prepare multiple samples for subsequent analysis at the central instrument section. A reusable central instrument section with the desired number of cassettes is used. Additionally or alternatively, the cassette can be portable or hand-held for convenient transportation. In these embodiments, the cassette can be manually attached to or removed from the central instrument section. In some embodiments, the cassette may be a non-disposable cassette that is permanently attached to the central instrument section, as described below.

In the present specification, a liquid processing system, a collection system, a liquid processing and analysis apparatus, a specimen system, and methods of using them according to a plurality of embodiments will be described. Part I discloses various embodiments of liquid processing systems that can be used in transporting liquid extracted from a patient for analysis. In Part II below, various embodiments of liquid treatment methods that can be used with the Part I apparatus are disclosed. In Part III below, various embodiments of the collection system that can be used with the Part I apparatus or Part II method are disclosed. Part IV below discloses various embodiments of sample analysis systems that can be used to detect one or more analyte concentrations in a material sample. Part V below discloses a method for measuring analyte concentration from a sample spectrum.

Part I Liquid treatment system

  FIG. 1 is a schematic view of a liquid processing system 10 that is supported by a stand 16 and includes a container 15 that can be filled with liquid, a catheter 11, and a collection system 100. The liquid processing system 10 includes one or more pathways 20 that form a conduit connecting the container, collection system, and catheter. In general, the collection system 100 is adapted to receive a liquid such as the liquid 14 and is connected to the patient using a catheter 11 inserted into the patient P, although not limited thereto. Although the liquid 14 is not limited to this, it is a liquid for inject | pouring into patients, such as a salt solution, lactated Ringer's solution, or water. When the collection system is connected to the patient, the liquid can be injected into the patient. Further, the collection system 100 can extract a sample such as blood from a patient via the catheter 11 and the path 20 and analyze at least a part of the extracted sample. The collection system measures one or more properties of the extracted sample such as, but not limited to, plasma glucose, blood urea nitrogen (BUN), hematocrit, hemoglobin or lactic acid levels. If necessary, the collection system 100 may include other devices or sensors, including but not limited to information about other patients or devices such as patient blood pressure, pressure fluctuations within the collection system, sampling rate, etc. taking measurement.

  More specifically, as shown in FIG. 1, the collection system 100 includes a patient joint 110, a liquid processing and analysis device 140, and a joint 120. The collection system 100 combines a path, a liquid control and measurement device, and an analyzer, and guides a sample to analyze the liquid. Path 20 of collection system 100 includes a liquid source path 111 from junction 120 to liquid treatment and analysis device 140, a patient junction path 112 from liquid treatment and analysis device 140 to patient junction 110, and patient junction 110. To a liquid processing and analysis device 140. For ease of description of the system, path 20 is shown to include one or more paths, such as paths 111, 112, 113, but the path is not limited to this, but includes pumps, valves, manifolds, and It should be understood that one or more individual components, such as analytical instruments, and many other intervening components may be included.

  As used herein, “path” is broadly defined and is used in its ordinary sense and is not limited thereto, but unless explicitly indicated, an opening in a member that functions as a conduit through which a fluid, such as a liquid or gas, can pass. Part. The pathway can be, but is not limited to, any flexible, inflexible, or partially flexible tube, laminated structure with openings, holes through the member, and other conduits. Includes structures or combinations thereof. The inner surface of the pathway for delivering fluid to the patient or transporting blood is preferably formed of a biocompatible material including, but not limited to, silicon, polyetheretherketone (PEEK) or polyethylene (PE). . One type of preferred path is a flexible tube with a fluid contact surface formed of a biocompatible material. As used herein, a path also includes individual portions that form the path when joined.

  The inner surface of the passage may have various types of coatings, such as coatings that affect blood coagulation and coatings that reduce friction caused by flow to enhance the inherent properties of the conduit. The film may include, but is not limited to, a molecular processed product or an ion processed product.

  In this specification, the term “joined” is used in its broad sense and is used in its ordinary sense, but is not limited thereto, but two or more things (eg, parts, devices, patients, etc.) unless explicitly indicated. Direct, indirect (eg, via inclusions), continuous, selective, or intermittently in physical contact or attachment, and / or direct, indirect, continuous, ( For example, including a state of selective or intermittent fluid communication (using one or more intervening valves, liquid processing units, switches, loads, etc.), a communication state by electrical or optical signals. A fluid communication state is considered to exist whether or not there is a fluid column or liquid column extending continuously or in contact between two or more objects of interest. Various types of joints can connect the components of the liquid processing system described herein. In this specification, the term “junction” has a broad meaning and is used in its ordinary sense, and is not limited to this. Means a device that joins or communicates on either side of the joint (whether continuous, selective or intermittent). In this specification, the junction includes an apparatus that connects an opening through which fluid can pass. These joints may include those that affect the flow rate, such as intervening valves, switches, and liquid processing equipment. In some embodiments, the junction may also contain equipment such as a meter, controller, and liquid dispenser, as described in the above embodiments.

  As described above, the liquid processing and analysis apparatus 140 controls the flow of the fluid flowing through the path 20 and analyzes the sample extracted from the patient. The liquid processing and analysis apparatus 140 includes an input unit such as a display unit 141 and a button 143. The display unit 141 provides information on the operation or analysis result executed by the liquid processing and analysis device 140. In one embodiment, the display 141 displays the function of the button 143 used to input information to the liquid processing and analysis device 140. Information input to the liquid processing and analysis device 140 or information obtained by the liquid processing and analysis device 140 is not limited to, but is not limited to, an injection ratio, a dose ratio, a sampling ratio, or the like. Includes patient-specific information such as patient identification number or medical information. In other alternative embodiments, the liquid processing and analysis device 140 may provide information regarding the patient P, such as, but not limited to, a medical condition, a drug being administered, a blood report at the time of a clinical test, gender, weight Through a communication network such as a hospital communication network having patient specific information. Although the scope of the present invention is not limited, FIG. 1 shows a case where the catheter 11 is joined to the patient P as an example of the use of the liquid processing system 10.

  As described below, the liquid treatment system 10 may insert a catheter into a patient's vein or artery. The collection system 100 is removably joined to the container 15 and the catheter 11. Thus, for example, as shown in FIG. 1, the container 15 has a tube 13 that forms a path for liquid to or from the container, and the catheter 11 has a catheter having a tube 12 outside the patient. ing. The joint portion 120 joins the pipe 13 and the path 111. The patient joint 110 is connected to the tube 12 and joins the path 112 and the path 113.

  Patient junction 110 may also include one or more devices that control, direct, process, or affect the flow through path 112 and path 113. In some embodiments, one or more lines 1114 are provided for exchanging signals between the patient junction 110 and the liquid processing and analysis device 140. The line 114 may be an electrical line, an optical communication line, a wireless communication line, or other communication means. As shown in FIG. 1, the collection system 100 may include a route 112, a route 113, and a line 114. The path and electrical line between the device 140 and the patient junction 110 shall be referred to as, but not limited to, the tube bundle 130.

  In various embodiments, the liquid processing and analysis device 140 and / or the patient interface 110 includes other components (not shown in FIG. 1), such as, but not limited to, valves, pumps, etc. Fluid control unit, pressure sensor, temperature sensor, hematocrit sensor, hemoglobin sensor, colorimetric sensor, liquid sensor including gas (or “bubble”) sensor, fluid injector including gas injector, gas filter, and plasma separator 1 includes components other than those shown in FIG. 1, such as a wireless communication unit that transmits information within the collection system or between the collection system 100 and the wireless network.

  In one embodiment, the patient junction 110 is equipped with a device that detects that blood has flowed into the liquid liquid 14 and informs that the collected sample has been extracted through the path 113. Providing such a device at the patient junction 110 allows the liquid processing system 10 for analyzing the sample to operate without being affected by the actual length of the tube 12. Thus, the tube bundle 130 is not limited to carrying fluids including air or communicating information between the patient junction 110 and the liquid processing and analysis device 140, for example one or more Components may be included, including other paths and / or wiring.

  In one embodiment of the collection system 100, the path and line of the tube bundle 130 is long enough to allow the patient junction 110 to be placed near the patient P, for example, the length of the tube 12 is 0.1-0. At 5 meters, preferably about 0.15 meters, the liquid processing and analysis device 140 is adapted to be located at a convenient distance, for example in the vicinity of the stand 16. Therefore, for example, the tube bundle 130 has a length of 0.3 to 3 meters, more preferably 1.5 to 2.0 meters. Although not required, it is preferred that the patient joint 110 and the joint 120 have removable joints so that the tubes 12, 13 can be attached respectively. In one embodiment, container 15 / tube 13 and catheter 11 / tube 12 are stands and medical parts, and collection system 100 can easily attach and remove containers and catheters to and from liquid processing system 10. It can be removed.

  In other embodiments of the collection system 100, the substantial portions of the tubes 12, 13 and the channels 111, 112 have substantially the same internal cross-sectional area. Although not essential, the internal cross-sectional area of the path 113 is preferably smaller than the internal cross-sectional areas of the paths 111 and 112 (see FIG. 1B). As described below, this area difference allows the liquid processing system 10 to transport a small amount of blood sample from the patient junction 110 to the liquid processing and analysis device 140.

  For example, in one embodiment, the paths 111, 112 are formed of tubes having an inner diameter of 0.3 mm to 1.50 mm, more preferably 0.60 mm to 1.2 mm. The passage 113 is formed by a tube having an inner diameter of 0.3 mm to 1.50 mm, more preferably 0.60 mm to 1.2 mm.

  Although the collection system 100 that joins the patient and the liquid source is shown in FIG. 1, the scope of the present disclosure is not limited to the present embodiment. Alternative embodiments may include, but are not limited to, a greater or lesser number of junctions or pathways, where the junctions are located at different locations within the liquid treatment system 10, alternative fluids. It may be arranged in the route. For example, the pathways 111, 112 may be formed of one tube, or may be two or more connected tubes including, for example, branches to other tubes in the collection system 100 and / or the patient. It may have a bifurcation for injecting into or extracting a sample from the patient. In addition, patient junction 110, junction 120, and collection system 100 include pumps and / or valves that control fluid flow, as described below.

  1A and 2 are diagrams illustrating a collection system 100 configured to analyze blood collected from a patient P. FIG. Although it is almost the same as the sampling system of the embodiment shown in FIG. 1, the differences will be described in detail below. The same components as those in the embodiment of FIGS. 1 and 2 will be described with the same reference numerals. FIG. 1 and FIG. 2 show a liquid treatment including a sampling element 220 and a junction 230, portions of paths 111 and 113, a patient junction 110 including a line 114, and a pump 203, a sampling unit 200, and a controller 210. And an analyzer 140. The pump 203, the collection unit 200, and the control unit are housed in the housing 209 of the liquid processing and analysis device 140. The path 111 extends from the joint 120 to the pump 203 via the housing 209. The tube bundle 130 extends from the pump 203, the sampling unit 200 and the control unit 210 to the patient joint 110.

  As shown in FIGS. 1A and 2, the path 111 provides fluid communication between the joint 120 and the pump 203, and the path 113 provides fluid communication between the pump 203 and the joint 110. The control unit 210 communicates with the pump 203, the sampling unit 200, and the sampling element unit 220 via the line 114. The control unit 210 can access the memory 212 and, if necessary, a medium reading unit 214 including, but not limited to, a DVD or CD-ROM reading unit, and a private line, an intranet, or the Internet. A communication link 216 having a wired or wireless communication network, including connections, can be accessed.

  As described below, in some embodiments, the collection unit 200 may include one or more pathways, pumps, and / or valves, and the collection element unit 220 may include pathways, sensors, valves, and / or valves. Alternatively, a sample detector may be provided. The control unit 210 collects information from the sensors and instruments in the sampling element unit 220 and from the sensors and analysis instruments in the sampling unit 200 and sends an adjustment signal to the pump 203 and, if present, the sampling element unit 220. Control the pumps and valves inside.

  The liquid processing and analysis device 140 has the function of driving the pump in the forward direction (patient direction) and in the opposite direction (direction away from the patient). For this reason, for example, the pump 203 guides the liquid 14 to the patient P, or pumps a sample such as a blood sample from the patient P to the collection element unit 220, and from there through the path 113 for further analysis. It can also lead to 200. Preferably, the pump 203 generates a forward flow rate that is at least sufficient to keep the patient's results open, and in one embodiment, the forward flow rate is 1-5 ml / hour. In some embodiments, the liquid flow rate is about 0.05 ml / hour, 0.1 ml / hour, 0.2 ml / hour, 0.4 ml / hour, 0.6 ml / hour, 0.8 ml / hour, 1 ml 0.0 ml / hour and ranges including these flow rates, and in some embodiments, for example, the liquid flow rate may be less than about 1.0 ml / hour. In certain embodiments, the liquid flow rate may be less than about 0.1 ml / hour. When operating in the opposite direction, the liquid processing and analysis device 140 has the function of driving the pump to pump the sample from the patient to the collection element 220 and to flow through the path 113. In one embodiment, the pump 203 causes the blood to flow back to the collection element portion 220, preferably backflow the blood to a sufficient distance beyond the collection portion to ensure that the collection portion contains an undiluted blood sample. Like to do. In one embodiment, the inner diameter of the path 113 is 25-200 microns, more preferably 50-100 microns. The collection unit 200 pumps a small amount of sample, eg, 10 to 100 microliters of blood, more preferably 40 microliters of blood, from the collection element unit 220.

  In one embodiment, pump 203 is a directionally controllable pump that acts on the flexible portion of path 111. Examples of directionally controllable pumps include, but are not limited to, reversible peristaltic pumps or two one-way pumps that operate in conjunction with a valve to generate bi-directional flow. In an alternative embodiment, pump 203 also includes a combination of pumps that control bi-directional flow in path 111, including but not limited to syringes and / or variable pumps such as valves.

  The controller 210 includes one or more processors that control the operation of the liquid processing system 10 and analyze sample measurements from the liquid processing and analysis device 140. The control unit 210 also receives an input from the button 143 and outputs information to the display unit 141. As necessary, the control unit 210 communicates with a hospital network in a wired or wireless communication system, for example, patient information. The one or more processors comprising the controller 210 may include one or more processors in the liquid processing and analysis device 140 or networked with the device.

  Control of the liquid processing system 10 by the controller 210 may include, but is not limited to, control of the flow rate to be injected into the patient, sample collection, preparation, and analysis. The analysis of the measurement values obtained by the liquid processing and analysis device 140 is not limited to this, but from the information obtained from the database regarding the patient-specific information or for the analysis of the measurement values by the liquid processing and analysis device 140 210 may include analysis of the sample based on patient-specific information input from information provided via the network to 210.

  The procedure for injecting the patient by the liquid processing system 10 and the procedure for collecting the blood of the patient are as follows. The liquid processing system 10 is connected to the bag 15 containing the liquid 14 and the patient P, and the control unit 210 operates the pump 203 to guide the liquid to the patient for injection. Thus, for example, in one embodiment, the controller operates to activate the pump 203 to draw and extract a sample from the patient. In one embodiment, the pump 203 draws a predetermined amount of sample sufficient to be sent to the collection element 220. In other embodiments, pump 203 draws the sample until the device in collection element 220 indicates that the sample has reached patient junction 110. As an example not intended to limit the scope of the present invention, this display is made by a sensor that detects the color change of the sample. Other examples include, but are not limited to, a decrease in the amount of liquid 14, a change in the amount of liquid over time, a measure of the amount of hemoglobin, or a sign of a change from fluid to blood in the pathway, A device that displays a change in the substance in the path 111 is used.

  When the sample reaches the sampling element 220, the controller 210 sends an operating signal to a valve and / or pump (not shown) in the sampling system 100 to pump the sample from the sampling element 220 to the sampling unit 200. . After the sample has been pumped into the collection unit 200, the control unit 210 sends a signal to the pump 203 to resume infusion into the patient. In one embodiment, the controller 210 sends a signal to the pump 203 and repeats the patient injection while the sample is being pumped from the collection element 220. In an alternative embodiment, the controller 210 sends a signal to the pump 203 and stops injecting the patient while pumping the sample from the collection element 220. In another alternative embodiment, the controller 210 sends a signal to the pump 203 to slow the rate at which blood is drawn from the patient while the sample is being pumped from the collection element 220.

  In another alternative embodiment, the controller 210 monitors for signs of occlusion in the vessel or the vessel into which the catheter was inserted while the pump is operating in the reverse direction, and the pump flow rate and / or the direction of the pump 203. To adjust. For example, when the flow is blocked due to blockage or bending of the path during operation of the pump, or an abnormality in the blood vessel into which the catheter is inserted, the flow pressure is lower than that in the non-blocked state. In one embodiment, the occlusion is monitored using a pressure sensor in the collection element 220 or along the path 20. When the pressure starts to decrease while the pump is operating or the pressure value falls below a predetermined value, the control unit 210 controls the pump 203 to reversely rotate the pump, stop the pump, or the pump is closed again. Operate the pump in a quasi-direction so that it operates in the absence.

  FIG. 3 is a schematic diagram showing details of the collection system 300. Although it is almost the same as the sampling system 100 of the embodiment shown in FIGS. 1 and 2, the differences will be described in detail below. The sampling system 300 includes a joint 230 that joins the pipe 12 along the path 112, a pressure sensor 317, a colorimetric sensor 311, a first bubble sensor 314a, a first valve 312, a second valve 313, and a second bubble sensor 314b. Is provided. The path 113 forms a “T” shape with the path 111 at a junction 318 located between the first valve 312 and the second valve 313, and includes a gas injection manifold 315 and a third valve 316. Line 114 is between colorimetric sensor 311, first, second and third valves (312, 313, 316), first and second bubble sensors (314a, 314b), gas injection manifold 315, and pressure sensor 317. With control and / or signal lines extending. The collection system 300 also includes a collection unit 200 having a bubble sensor 321, a sample analyzer 330, a first valve 323 a, a waste container 325, a second valve 323 b, and a pump 328. The path 113 forms a “T” shape and branches into a discard path 324 and a pump path 327.

  Although not essential, the sensor of the collection system 100 preferably accommodates a path through which the sample may pass and detects through the path wall. As will be described below, this configuration allows the sensor to be reused while the path is disposable. Further, although not essential, it is preferable that the path is smooth and that there is no sudden three-dimensional change that causes damage to the blood or hinders the smooth flow of blood. Furthermore, it is preferable that the path for transporting blood from the patient to the analyzer does not have a gap or dimensional change that causes fluid to stay and makes it difficult for blood to flow through the path.

  In one embodiment, each path in which the valves 312, 313, 316, 323 are located is a flexible tube, and the valves 312, 313, 316, 323 have one or more movable surfaces compressing the tube. A “pinch valve” that restricts or stops the flow through the tube. In one embodiment, the pinch valve has one or more moving surfaces that act to “pinch” the flexible path and stop the flow. In one embodiment, an example of a pinch valve is, for example, Model PV256 Low Power Pinch Valve (Intech Laboratories, Inc., Plymouth Meeting, PA). Alternatively, the one or more valves 312, 313, 316, and 323 may be other valves as long as the flow through each path can be controlled.

  The colorimetric sensor 311 accommodates or forms part of the path 111 to indicate whether blood is present in the path. In one embodiment, the colorimetric sensor 311 is configured such that the controller 210 discriminates between the liquid 14 and blood. Preferably, the colorimetric sensor 311 is adapted to detect blood by accommodating a tube or other path. This is done, for example, by inserting or attaching a disposable tube to a reusable colorimetric sensor. In an alternative embodiment, the colorimetric sensor 311 is placed near the bubble sensor 314b. Examples of colorimetric sensors include, for example, Optical Blood Leak / Blood vs. available from Introtek International (Edgewood, NJ). For example, Saline Dector.

  As will be described below, the collection system 300 injects gas (referred to herein as “bubbles”, but not limited to this) into the path 113. The collection system 300 includes a gas injection manifold 315 at or near the junction 318 and injects one or more bubbles, each separated from the liquid, into the path 113. By using bubbles, the liquid mixes back and forth as the fluid flows through the path, both when diluting the sample for analysis and when flowing the sample to clean the path between the samples. Help to prevent that. For example, in one embodiment of the present invention, the fluid of the path 113 includes two amounts of liquid such as the sample S and the liquid 14 separated by bubbles, or a plurality of amounts of liquid each separated by bubbles. It is done.

  Bubble sensors 314a, 314b, 321 contain or form a portion of path 112 or path 113, respectively, to indicate whether air is present in the path, or to indicate a change in the flow of liquid and air. It has become. Examples of bubble sensors include, but are not limited to, ultrasonic sensors or optical sensors that can detect small bubbles or bubble differences generated from liquid in the path. As such a bubble detector, there is a MEC Series Air Bubble / Liquid Detection Sensor (Introtek International, Edgewood, NY). Preferably, each of the bubble sensors 314a, 314b, 321 houses a tube or other path that detects the bubble. Thereby, for example, a disposable tube can be attached to a reusable bubble sensor.

  The pressure sensor 317 accommodates or forms a part of the path 111 and indicates the measured value of the fluid in the path. When all valves between the pressure sensor 317 and the catheter 11 are open, the pressure sensor 317 indicates a measurement of the pressure in the blood vessel into which the patient's catheter has been inserted. In one embodiment, the output of the pressure sensor 317 is sent to the control unit 210 and the operation of the pump 203 is adjusted. For example, if the pressure sensor 317 measures a pressure value above a predetermined value, it is interpreted that the system is operating properly, and if the pressure sensor 317 measures a pressure value below the predetermined value, For example, it is understood that the pump is over-operating due to a path or vessel occlusion. For example, in the pump 203 operating to pump blood from the patient P, if the pressure value measured by the pressure sensor 317 is within the normal blood pressure range, blood is being pumped from the patient and the pump It may be operating continuously. However, when the pressure value measured by the pressure sensor 317 falls below a certain level, the control unit 210 instructs the pump 203 to decelerate or operate in the forward direction so that the blood vessel opens again. Examples of such pressure sensors include Deltran IV part number DPT-412 (Utah Medical Products, Midvale, UT).

  When material analyzer 330 receives the sample, it performs an analysis. In some embodiments, the material analyzer 330 is configured to prepare a sample for analysis. For this reason, for example, the material analyzer 330 includes a sample preparation unit 332 and a sample detection system 334, and places the sample preparation unit between the patient and the sample detection system. In general, sample preparation takes place between collection and analysis. For this reason, for example, the sample preparation unit 332 may be arranged away from the specimen detection, for example, in the sampling element part 220, or in the vicinity of the specimen detection system 334 or in the specimen detection system 334. .

  As used herein, “analyte” is broadly defined and is used in its ordinary sense and includes, but is not limited to, a chemical species that detects the presence or concentration in a material sample by an analyte detection system. For example, the sample is not limited to this, but glucose, ethanol, insulin, water, carbon dioxide, blood, oxygen, cholesterol, bilirubin, ketone, fatty acid, lipoprotein, albumin, urea, creatinine, leukocyte, red blood cell, hemoglobin, oxidation Includes hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules, drugs, cytochromes, various proteins and chromophores, microcalcifications, electrolytes, sodium, potassium, chlorine compounds, bicarbonates, hormones. In the present specification, the term “material sample” (or “sample”) has a broad meaning and is used in its ordinary sense, and includes, but is not limited to, a collection of substances suitable for analysis. For example, the material sample includes whole blood, blood components (eg, plasma or serum), interstitial fluid, intercellular fluid, saliva, urine, sweat and / or other organic or inorganic substances, or derivatives of these substances. . In one embodiment, whole blood components or blood components may be collected from a patient's capillaries.

  In one embodiment, the sample preparation unit 332 separates plasma from a whole blood sample or removes contaminants from the blood sample, including but not limited to a filter, membrane, centrifuge, or One or more devices including those combinations are provided. In an alternative embodiment, the analyte detection system 334 directly analyzes the sample, eliminating the need for the sample preparation unit 332.

  Generally, a sampling element unit 220 and a sampling unit 200 that guides the liquid sampled from the sampling element unit 220 to the sample analyzer 330 via the path 113 are provided. FIG. 4 is a schematic diagram of the collection unit 400 according to the embodiment in which a part of the sample is bypassed to the sample analyzer 330. The collection unit 400 is substantially the same as the collection unit 200, but the differences will be described in detail below. The collection unit 400 includes a bubble sensor 321, a valve 323, a sample analyzer 330, a waste pipe 324, a waste container 325, a valve 326, a pump pipe 327, a pump 328, a valve 322, and a waste pipe 329. Waste tube 329 includes a valve 322 and forms a “T” shape with pump tube 337. Valves 316, 322, 323, and 326 guide the flow through path 113 to waste container 325 via sample analyzer 330 or to waste container 325 via waste tube 324.

  FIG. 5 is a schematic diagram of a collection system 500 of one embodiment. The collection unit 500 is substantially the same as the collection system 100 or 300 of the embodiment shown in FIGS. 1 to 4, but the differences will be described in detail below. The collection system 500 includes a collection unit 510 that is partially different from the collection system 300 in that the liquid sent from the path 111 returns to the path 111 at a junction 502 between the pump 203 and the junction 120. .

  As shown in FIG. 5, the sampling unit 510 includes a return pipe 503 that divides the path 111 into the opposite side of the pump 203 and the path 113, the bubble sensor 505 and the pressure sensor 507 controlled by the control unit 210. The bubble sensor 505 is substantially the same as the bubble sensors 314 a, 314 b, and 321, and the pressure sensor 507 is substantially the same as the pressure sensor 317. The pressure sensor 507 can be used to determine whether the sampling system 500 is operating correctly by monitoring the pressure in the path 111. For example, when the pressure sensor 507 is in fluid communication with the catheter 11 (ie, when the intervening valve is open), the pressure in the path 111 is related to the pressure of the catheter 11. Like the pressure sensor 317 already described, the output of the pressure sensor 507 can be used to control the pump of the sampling system 500.

  The sampling unit 510 includes valves 501, 326 a and 326 b controlled by the control unit 210. The valve 501 further controls the flow rate between the collection unit 200 and the collection unit 510. Pump 328 is preferably a bi-directional pump capable of pumping liquid from path 113 and pumping liquid to path 113. The liquid is pumped from the path 501, returned to the path 501, or led to the waste container 325. Valves 326a, 326b are located on either side of pump 328. Liquid is pumped through path 113 and sent to return pipe 503 by joint control of pump 328 and valves 326a, 326b. The flow from the return tube 503 can be directed to send liquid to the collection system 500. For example, when the valve 326a is open and the valve 326b is closed, the pump 328 is operated to pump the liquid from the path 113 and send it to the collection unit 510. If the valve 326a is closed and the valve 326b is open, the pump 328 is operated to push the liquid to the path 113 and return to the path 113.

  FIG. 6A is a schematic diagram of a gas injection manifold 315 according to one embodiment. Although it is almost the same as the gas injection manifold included in the embodiment shown in FIGS. 1 to 5, the differences will be described in detail below. The gas injection manifold 315 is a device that injects one or more bubbles into the liquid in the passage 113 by opening a valve to the atmosphere side, lowering the pressure of the fluid in the manifold, and sucking air. As described below, the gas injection manifold 315 facilitates the injection of air or other gas bubbles into the liquid in the path 113. The gas injection manifold 315 includes three gas injectors 610 including a first injector 610a, a second injector 610b, and a third injector 610c. Each injector 610 has a path 611 extending from one of a plurality of locations spaced laterally along path 113 to a corresponding valve 613 and terminating at an end 615 open to the atmosphere. . In an alternative embodiment, a filter is placed at the end 615 to filter atmospheric dust or particles. As described below, each injector 610 opens the corresponding valve 613, closes the valve at one end of the path 113, and activates the pump on the other side of the path to reduce the pressure and draw the atmosphere into the liquid. Thus, bubbles can be injected into the liquid in the path 113. In the gas injection manifold 315 of one embodiment, the passage 113 and the passage 611 are formed in an integral member (for example, as a hole formed in an integral plastic or metal housing or a hole penetrating the housing) (illustrated). Not) In alternative embodiments, the gas injection manifold 315 includes fewer than three, such as one or two injectors, or includes more than three injectors. In another alternative embodiment, the gas injection manifold 315 includes a controllable high pressure source for injecting liquid into the path 113. The valve 613 is preferably disposed in the vicinity of the path 113 in order to minimize the liquid remaining in the path 611.

  What is important is to prevent the gas injected into the path 20 from reaching the catheter 11. As a safety measure, in one embodiment, for example, the bubble sensor 314a of FIG. When bubble sensor 314a detects gas in path 111, one of several alternative embodiments prevents undesirable gas flow. In one embodiment, the flow near the collection element 220 is directed to the tube 113 or through the tube 113 to the waste container 325. As shown in FIG. 3, when gas is detected by bubble sensor 314a, valves 316 and 323a are opened, valves 313 and valves 613a, 613b and 613c of gas injection manifold 315 are closed, and pump 328 is activated to flow. A part of the path 111 between the collection element unit 220 and the patient P is guided to the path 113. The bubble sensor 321 performs monitoring and notifies when the route 113 is cleared. Valve 313 is then opened and valve 312 is closed, clearing the remainder of path 111. Alternatively, all flow in the direction of the catheter 11 is stopped, for example by closing all valves and stopping all pumps. In an alternative embodiment sampling element 220, an undesired gas is provided by placing a gas permeable membrane in the path 113 or in the gas inlet manifold 315 and allowing such gas to escape through the membrane to the atmosphere or a waste container. Is removed from the liquid processing system 10.

FIG. 6B is a schematic diagram of another embodiment of a gas injection manifold 315 ′. Although it is substantially the same as the gas injection manifold included in the embodiment shown in FIGS. 1 to 6A, the differences will be described in detail below. In the gas injection manifold 315 ′, the air pipe 615 and the path 113 intersect at the junction 318. Bubbles are injected by opening valves 316 and 613 while liquid is being pumped into path 113. Since the gas injection manifold 315 ′ is smaller than the gas injection manifold 315, the control and reliability of the gas generator is improved.

Part II-Liquid Processing Method

Schematic diagram of the fluid path of Table 1 and FIGS. 7A to 7J for a method using the liquid processing system 10 of the embodiment including the sampling element unit 220 and the sampling unit 200 illustrated in FIGS. 2, 3, and 6A. Will be described with reference to FIG. In general, the pump and valve are controlled to infuse the patient via path 111, the sample is extracted from the patient via path 113, and the sample is directed along path 113 to sample analyzer 330. In addition, the pump and valve are controlled to inject bubbles into the liquid and to clean the space between the tubes used for collection so that the liquid does not have a dilution effect with the previous liquid. The valve shown in FIGS. 7A to 7J is shown so that it can be seen whether the valve is open or closed. For example, a valve indicated as “x” is indicated as “xo” when the valve is open, and is indicated as “xc” when the valve is closed.

  With reference to FIG. 7A, the injection method to the patient of one Embodiment is demonstrated. In the step of FIG. 7A, the pump 203 operates in the forward direction (patient direction), the pump 328 is turned off or stopped, the valves 313, 312 are open, and the valves 613a, 613b, 613c, 316, 323a, 323b are closed. It is. Under these operating conditions, liquid 14 is delivered to patient P. In the preferred embodiment, all other pathways contain liquid 14 at the time of the step of FIG.

  With reference to the next seven figures (FIGS. 7B to 7J), the steps of the method of sampling from a patient will be described. The following steps do not include all steps taken from the patient, and alternative embodiments may include more steps, fewer steps, or different order of steps. . With reference to FIG. 7B, the first collection step of removing liquid from the patient junction path 112 and a portion of the collection path 113 will be described. In the step of FIG. 7B, pump 203 operates in the opposite direction (away from the patient), pump 328 is off, valve 313 is open, one or more valves 613a, 613b, 613c are open, Reference numerals 316, 323a, and 326b are closed. Under these operating conditions, air 701 is drawn into the collection path 113 and returns to the patient junction path 112 until the bubble sensor 314b detects the presence of air.

  With reference to FIG. 7C, the second collection step of pumping the sample from the patient P into the patient junction path 112 will be described. In the step of FIG. 7C, pump 203 operates in the opposite direction, pump 328 is off, valves 312 and 313 are open, and valves 316, 613a, 613b, 613c, 323a and 326b are closed. Under these operating conditions, the sample S is drawn into the path 112 and the air 701 is separated into air 701 a in the collection path 113 and air 701 b in the patient junction path 112. Preferably, this step is performed until the sample S just exceeds the junction point of the paths 112 and 113. In one embodiment, the steps of FIG. 7C continue until the presence of blood is signaled by a change in the output of colorimetric sensor 311 (eg, leveling off to a constant value), and then continuing for a further predetermined time. Thus, a sufficient amount of sample S is secured.

  With reference to FIG. 7D, the third collection step for pumping the sample into the collection path 113 will be described. In the step of FIG. 7D, the pump 203 is turned off or stopped, the pump 328 is activated, the valves 312, 316, 326b are open, and the valves 313, 613a, 613b, 613c, 323a are closed. Under these operating conditions, the sample S is sucked into the path 113. Preferably, pump 328 is activated to draw a sufficient amount of sample S into path 113. In one embodiment, pump 328 draws sample S in an amount of 30-50 microliters. In an alternative embodiment, the sample is drawn into both of the two paths 112,113. Pump 203 operates in the opposite direction, pump 328 operates, valves 312, 313, 316, 323 b are open, valves 613 a, 613 b, 613 c, 323 a are closed, ensuring fresh blood in sample S.

  With reference to FIG. 7E, the 4th collection | recovery step which inject | pours air into a sample is demonstrated. A valve that spans the cross-sectional area of the collection path 113 prevents the sample from being contaminated when the sample is withdrawn along the path 113. In the step of FIG. 7E, the pump 203 is turned off or stopped, the pump 328 is activated, the valves 316, 323b are opened, the valves 312, 313, 323a are closed, and the valves 613a, 613b are generated to generate three bubbles separately. , 613c are opened and closed successively. Under these operating conditions, the air in the path 113 is sucked into the path 113 because the pressure in the path 113 is below atmospheric pressure. Alternatively, the valves 613a, 613b, and 613c may be simultaneously opened for a short period and three bubbles may be generated separately. As shown in FIG. 7E, injectors 610a, 610b, and 610c inject bubbles 704, 703, and 702, respectively, and separate sample S into front sample S1, intermediate sample S2, and rear sample S3.

  With reference to FIG. 7F, a fifth collection step for removing bubbles from the patient junction path 112 will be described. In the step of FIG. 7F, the pump 203 is operated in the forward direction, the pump 328 is turned off, the valves 313, 316, 323a are opened, and the valves 312, 613a, 613b, 613c, 323b are closed. Under these operating conditions, the already injected air 701b exits the first path 111 and is sucked into the second path 113. This step continues until air 701b enters path 113.

  With reference to FIG. 7G, the sixth collection step for returning the blood in the path 112 to the patient will be described. In the step of FIG. 7G, the pump 203 is operated in the forward direction, the pump 328 is turned off, the valves 312 and 313 are opened, and the valves 316, 323a, 613a, 613b, 613c, and 323b are closed. Under these operating conditions, the already injected air remains in the path 113 and the path 111 is filled with the liquid 14.

  With reference to FIG. 7H and FIG. 7I, the 8th collection | recovery step which extrudes a sample partially to the path | route 113 and pushes out the liquid 14 and also a bubble is demonstrated. In the step of FIG. 7H, pump 203 operates in the forward direction, pump 328 is off, valves 313, 316, 323a are open, and valves 312, 613a, 613b, 613c, 323b are closed. Under these operating conditions, the sample S partially moves to the path 113, and bubbles are injected into the liquid 14 continuously or simultaneously from the injectors 610a, 610b, and 610c. In the step of FIG. 7I, the pump and valve operate similarly to the step of FIG. 7E, and the liquid is separated into the front solvent C1, the intermediate solvent C2, and the rear solvent C3 by the bubbles 705, 706, and 707.

The step of pushing the intermediate sample S2 to the sample analyzer 330 will be described with reference to FIG. In the step of FIG. 7J, the pump 203 operates in the forward direction, the pump 328 is off, the valves 313, 316, 323a are open, and the valves 312, 613a, 613b, 613c, 323b are closed. Under this operating condition, the sample is pushed out into the path 113. When bubble sensor 321 detects bubble 702, pump 203 continues to operate until sample S2 enters sample analyzer 330. Further activation of the pump using the step settings of FIG. 7J allows the bubble 113 and solvent to be pushed further into the waste container 325 after analysis of the sample S2 to clean the path 113 before receiving the next sample.

Part III-Collection system

  FIG. 8 is a front perspective view of a sampling system 800 according to the third embodiment. Although it is substantially the same as the sampling system 100, 300 or 500 of the embodiment shown in FIGS. 1 to 7, the differences will be described in detail below. The liquid processing and analysis device 140 of the collection system 800 includes a combination of an instrument unit 810 and a collection system cassette 820. The instrument unit 810 and the cassette 820 shown in FIG. 8 are partially removable. The instrument section 810 includes a control section 210 (not shown), a display section 141 and an input section 143, a cassette boundary section 811, and a line 114. The cassette 820 includes a path 111 and a path 113 extending from the joint 120 to the joint 230, a junction 829 of the paths 111 and 113, an instrument boundary 821, a front surface 823, an inlet 825 of the path 111, and paths 111 and 113. The inlet portion 827 is provided. Further, the sampling element portion 220 is formed from a sampling instrument element 813 having an opening 815 that receives the junction 829. The boundaries 811, 821 engage the components of the instrument 810 and cassette 820 to facilitate liquid pumping and analysis of the sample from the patient, and the collection instrument element 813 is within the opening 815. In response to the junction point 829, sampling is performed from the path 111.

  FIG. 9 and FIG. 10 are front views of the collection system cassette 820 and the instrument unit 810 constituting the collection system 800, respectively. The cassette 820 and instrument portion 810, when assembled, form a device comprising the sampling portion 510 of FIG. 5, the sampling element portion 220 of FIG. 3, and the gas injection manifold 315 ′ of FIG. 6B. Configure.

  Specifically, as shown in FIG. 9, the cassette 820 includes a path 111 including portions 111a, 112a, 112b, 112c, 112d, 112e, and 112f, and a path including portions 113a, 113b, 113c, 113d, 113e, and 113f. 113, a path 20 having a path 615, a waste container 325, for example, a sample preparation unit 332 that allows only plasma to flow through, a sample chamber 903 that retains plasma in the analyte detection system 334 to measure plasma characteristics. Including a disposable part of the sample analyzer 330 and a variable pump 905 having a piston controller 907.

  As shown in FIG. 10, the instrument unit 810 includes bubble sensor units 1001a, 1001b, and 100c, a colorimetric sensor that is a hemoglobin sensor unit 1003, a peristaltic pump roller 1005a, a roller support unit 1005b, and a pair of pincers 1007a, 1007b, 1007c, 1007d, 1007e, 1007f, 1007g, 1007h, an actuator 1009, and a pressure sensor unit 1011 are provided. Furthermore, the instrument unit 810 includes a sample analyzer 330 that measures a sample contained in the sample chamber 903 when positioned near or within the probe region 1002 of the optical analyte detection system 334.

  The path portion of the cassette 820 contacts the various components of the instrument section 810 to form the collection system 800. As shown in FIG. 5, for example, the pump 203 that moves the liquid through the path 111 when the roller is operated is formed of a portion 111 a disposed between the peristaltic pump roller 1005 a and the roller support portion 1005 b. 326a and 326b are formed by pincer sets 1007a, 1007b, 1007c, and 1007d that surround the portions 113a, 113c, 113d, and 113e, respectively, and allow or prevent the flow of liquid. Pump 328 is formed from an actuator 1009 arranged to move piston controller 907. The interconnection between the components of the cassette 820 and the components of the instrument section 810 described here is preferably performed in a single operation. For example, the boundaries 811, 821 are positioned so that the path is located with the stand on the back and / or between sensors, actuators, and other components.

  In addition to placing the boundary 811 relative to the boundary 821, assembly of the device 800 also includes assembly of the harvesting element portion 200. Specifically, the openings 815a and 815b receive the paths 111 and 113, respectively, and the junction 829 is accommodated in the sampling instrument element 813. Thus, for example, as shown in FIG. 3, the valves 313 and 312 are formed so that the portions 112a and 112b are located in the pincers of the pinch valves 1007e and 1007f, respectively, and the bubble sensors 314b and 314a 1001b and 1001c are formed when the portions 112a and 112d are in sufficient contact with each other so as to detect the presence of internal bubbles, respectively, and the hemoglobin detector is formed when the hemoglobin sensor 1003 is sufficiently in contact with the portion 112e and the pressure sensor 317 is formed when the portion 112f sufficiently contacts the pressure sensor unit 1011 so as to measure the pressure of the internal fluid. As shown in FIG. 6B, the valves 316 and 613 are formed when the portions 113f and 615 are located in the pincers of the pinch valves 1007h and 1007g, respectively.

  Operations of the central instrument section 810 and the cassette 820 shown in FIGS. 9 and 10 assembled in this way are as follows. The system is idle when the roller pump moves forward (impeller 1005a rotates counterclockwise as shown in FIG. 10) and pumps the infusate from container 15 through path 111 and path 112 to patient P. Or it can be considered as an injection mode. In this infusion mode, the pump 1005 administers the infusate to the patient at an appropriate infusion rate as described elsewhere herein.

  When it is time to perform a measurement, air is first pumped into the system and liquid is removed from a portion of paths 112, 113 in the manner described with reference to FIG. 7B. Here, the single air injector of FIG. 9 (extending from junction 829 to the opposite end 615 of path 813) functions in place of the manifold shown in FIGS. 7A-7J. Next, when inhaling the sample, the pump 1005 operates in the sample inhalation mode and operates in the opposite direction to deliver a sample of bodily fluid (eg, blood) from the patient to the path 112 via the junction 230. The sample is inhaled to the hemoglobin sensor 1003 and preferably aspirated until the output of the sensor 1003 reaches a predetermined plateau level indicating the presence of an undiluted blood sample in the path 112 near the sensor 1003.

  From this point on, the pumps 905, 1005, valves 1007e, 1007f, 1007g, 1007h, bubble sensors 1001b, 1001c, and / or hemoglobin sensor 1003 are arranged in a series of ways as described with reference to FIGS. 7D-7F. The bubble and sample-fluid columns can be operated to move to path 113. The pump 905 can be operated in place of the pump 328 by moving the piston controller 907 of the pump 905 in an appropriate direction (left or right direction shown in FIGS. 9 to 10) by the actuator 1009.

  As part of the bodily fluid sample and the desired bubble move into the path 113, the valve 1007h is closed and the sample aspirated first by operating the pump 1005 in the forward or infusion direction until the path 112 is again filled with infusate. Alternatively, the remainder of the body fluid in the pathway 112 can be returned to the patient.

  By appropriately operating the valves 1007a to 1007h and the pump 905 and / or the pump 1005, at least a part of the body fluid sample in the path 113 (10 to 100 microliters in volume, or 20, 30, 40 in various embodiments). , 50, or 60 microliters) moves through the sample preparation portion 332 (in the illustrated embodiment, a filter or membrane, or a centrifuge described in detail below). In this way, only one or more components of bodily fluid (eg, blood plasma only) enter the sample chamber or cell 903 through the sample preparation unit 332 or filter / membrane. Alternatively, in an alternative configuration that omits the sample preparation section 332, “all” liquid moves to the sample chamber 903 for analysis.

  Once the liquid component or all enters the sample chamber 903, the analysis is performed and glucose, lactic acid, carbon dioxide, blood urea nitrogen, hemoglobin, and / or other suitable analytes described elsewhere herein. One or more analyte levels or concentrations are measured. When the analyte detection system 1700 is of a spectroscopic type (for example, the system 1700 of FIG. 17 or FIGS. 44 to 46), a part or all of the liquid is subjected to spectroscopic analysis.

  After the analysis, the body fluid sample in the path 113 moves to the waste container 325. Preferably, the pump 905 is actuated by the actuator 1009 to push out the body fluid through the column of saline or infusion solution obtained from the path 909 and guide it to the waste container 325 through the sample chamber 903 and the sample preparation unit 332. Thus, the sample chamber 903 and the sample preparation unit 332 are filled with the reverse saline solution or infusion while the body fluid is guided to the waste container. After this wash, a second analysis can thus be performed on the saline or infusate that has flowed into the sample chamber 903 to read the “zero” or background value. At this time, there is no body fluid other than the waste treatment 325 in the liquid treatment network of FIG. 9, and other body fluid samples are ready to be drawn for analysis.

  In the liquid processing and analysis device 140 of some embodiments, a pincer set of pinch valves operates to switch the flow at the two branches of the path to one. FIGS. 13A and 13B are a front view and a cross-sectional view of the pinch valve 1300 of the first embodiment in the open state capable of guiding the flow to either of two branches or sections of the path. The pinch valve 1300 has two individually controllable pinch valves that operate on a “Y” shaped path 1310 to switch fluid flow between various sections. Specifically, the inner surface of the path 1310 intersects the first section 1311 having the flexible pinch area 1312, the second section 1313 having the flexible pinch area 1314, and the first section and the second section. A third section 1315 is connected at 1317. The first pinch valve pincer set 1320 is disposed about the pinch region 1312 and the second pinch valve pincer set 1330 is disposed about the pinch region 1314. A pincer set 1320, 1330 of each pinch valve is positioned perpendicular to the path 1310, opposite to each side of the respective pinch regions 1312, 1314, and the controller 210 controls the opening and closing individually, The fluid can be communicated or not communicated via the pinch region. Thus, for example, when the pincer set 1320 (or 1330) of the pinch valve is sufficiently closed, one part of the pinch region 1312 (or 1314) contacts the other part of the pinch region and the liquid passes through the pinch region. It will not flow through.

  An example of use of the pinch valve 1300 will be described. FIG. 13B shows a set of pincers 1320, 1330 for the first and second pinch valves in the open state. The pincer set 1320 of the pinch valve approaches FIG. 13C, and a part of the first section 1311 is closed with respect to the second and third sections 1313 and 1315. Since there is a distance between the pincer 1320 and the intersection point 1317, the space 1321 is present as an isolated “dead space” in the first section 1311. The dead space is preferably minimized so that different types of liquid can be switched between different sections of the pinch valve. In one embodiment, dead space is reduced by providing a pinch valve near the intersection of the sections. In other embodiments, dead space is reduced by providing various thicknesses for the walls of the path. Thus, for example, the surplus material between the pinch valve and the intersection will separate the valve more effectively by moving through the space 1321 portion.

  In one use case of the pinch valve 1300 in the collection system 300, the pincer sets 1320, 1330 are positioned to operate as valves 323, 236, respectively.

  14A and 14B show a pinch valve 1400 of the second embodiment. FIG. 14A is a front view of a pinch valve with one valve in the closed position, and FIG. 14B is a cross-sectional view thereof. The pinch valve 1400 differs from the pinch valve 1300 in that the pincer sets 1320 and 1330 of the pinch valve used with the path 1310 are replaced with pincers 1420 and 1430, respectively.

  An alternative embodiment pinch valve has two, three, four, or more pathways that connect at a common junction, and places the pincer in one or more pathways near the junction.

  11 and 12, a disposable part of the cassette 820 can be formed as a patient artery joint 1100 of one embodiment and a patient vein joint 1200 of one embodiment, or a disposable part of the cassette 820 can be attached. Fig. 5 illustrates a joint 230 of various embodiments. The joint portions 1100 and 1200 are substantially the same as those of the embodiment shown in FIGS. 1 to 10, but the differences will be described in detail below.

As shown in FIG. 11, the patient artery junction 1100 has a stopcock 1101, a first tube portion 1103 having a length X, a blood collection port 1105 for obtaining a blood sample for laboratory analysis, and a length Y. A second tube 1107 and a tube joint 1109 are included. Further, the patient arterial junction 1100 includes a pressure sensor unit 1102 that is substantially similar to the pressure sensor unit 1011 on the opposite side of the sampling element unit 220. The length X is preferably 6 inches (0.15 meters) to 50 inches (1.27 meters), or approximately 48 inches (1.2 meters) long. The length Y is preferably 1 inch (25 millimeters) to 20 inches (0.5 meters), or approximately 12 inches (0.3 meters) long. As shown in FIG. 12, the patient vein junction 1200 includes a clamp 1201, an injection port 1105, and a tube junction 1109.

Part IV-Sample analysis system

  In some embodiments, plasma is analyzed. In such an embodiment, it is necessary to separate the plasma from the whole blood obtained from the patient, and the work of separating the plasma from the whole blood can be performed, for example, at the patient junction 110 or when blood is drawn along the path 113. It may be done at any point in time until the time when blood is analyzed. In a system that performs measurement on whole blood, it is not always essential to separate blood at the time of measurement or before performing measurement.

For purposes of illustration, this section describes a separator and analyte detection system of some embodiments that may constitute the liquid processing system 10. The separator described herein may comprise a liquid component separator in certain embodiments. As used herein, “liquid component separator” has a broad meaning and is used in its ordinary sense and includes, but is not limited to, equipment that separates one or more liquid components to produce two or more different substances. . For example, a liquid component separator can separate a sample of whole blood into a plasma component and a non-plasma component, and / or a solid liquid mixture (eg, a liquid mixed with solids) into a solid component and a liquid component. Liquid component separators need not completely separate the different materials thus produced. Examples of liquid component separators include filters, membranes, centrifuges, electrolyzers, or combinations thereof. The liquid component separator is “active” in that it separates the liquid faster than by the action of gravity on the stationary “stand-by” liquid. Hereinafter, Part IV discloses a filter that can be used as a blood separator in the device of an embodiment disclosed herein. In Part IV B, an analyte detection system that can be used with the apparatus of an embodiment disclosed herein is disclosed below. Part IV C discloses sample elements that can be used with the apparatus of certain embodiments disclosed herein. Part IV discloses a centrifuge and sample chamber that can be used with the apparatus of certain embodiments disclosed herein.

Part IV A-Blood Filter

  Although not limiting the scope of the present invention, a blood filter 1500 will be described as a sample preparation unit 332 of one embodiment with reference to FIGS. 15 and 16. FIG. 15 is a side view of a filter according to an embodiment, and FIG. 16 is an exploded perspective view of the filter.

  As shown in FIG. 15, the filter of the present embodiment includes a housing 1501 having an inlet portion 1503, a first outlet portion 1505, and a second outlet portion 1507. The housing 1501 has a membrane 1509 that divides the internal space of the housing 1501 into a first space 1502 and a second space 1504 in which the inlet portion 1503 and the first outlet portion 1505 exist. FIG. 16 shows a first plate 1511 having an inlet portion 1503 and an outlet portion 1505, a first spacer 1513 having an opening portion that defines a first space 1502, and an opening portion that defines a second space 1504. The filter 1500 of one embodiment is shown including a second spacer 1515 having a second plate 1517 having an outlet 1507.

  Filter 1500 continuously filters plasma from whole blood. For this reason, for example, when whole blood flows into the inlet portion 1503 and a slight decompression is applied to the second space 1504 side of the membrane 1509, the membrane filters blood cells and allows plasma to pass through the first outlet portion 1507. Preferably, the blood flow crosses the surface of the membrane 1509 to prevent blood cells from clotting on the filter 1500. Therefore, the inlet portion 1503 and the first outlet portion 1505 in one embodiment may be configured to flow across the membrane 1509.

  In one embodiment, membrane 1509 is a thin, strong polymer thin film. For example, the thin film filter may be a 10 micron thick polyester film or polycarbonate film. Preferably, the membrane filter has a smooth glassy surface and the pores are uniform, precisely sized and well defined. The substances constituting the membrane are chemically inert and have low protein binding properties.

  One method for manufacturing the film 1509 is a track etching method. Preferably, the “raw film” is exposed to charged particles in the reactor, leaving a “track” on the membrane. The track may be etched into the film. This produces a uniform cylindrical hole with precise dimensions. For example, GE Osmonics, Inc. (4636 Somerton Rd. Trevose, PA 19053-6783) uses a similar process to produce a material that functions well as a thin film filter. The surface of the above-described thin film filter is a polycarbonate TE film manufactured by GE Osmonics.

  As an example of use of filter 1500, plasma may be extracted from 3 cc of blood using a polycarbonate track etch membrane (“PCTE”) as a thin film filter. The PCTE hole size is 2 μm and the effective area is 170 square millimeters. Preferably, the inner diameter of the tubing connected to the supply port, the discharge port and the plasma port is 1 millimeter. In the method of one embodiment performed in such a configuration, 100 μm of plasma can be first extracted from plasma. After washing the supply side of the cell with saline, a further 100 μm clear plasma can be extracted. The plasma extraction rate in the present methods and configurations may be about 15-25 μl / min.

  There are several advantages to extracting plasma using a continuous flow mechanism. In one preferred embodiment, the continuous flow mechanism can be reused with multiple samples, and the possibility that the remainder of the sample will contaminate the next sample is negligible. In one embodiment, occlusions rarely occur. Furthermore, in a preferred configuration, the internal capacity is small.

For more information on filters, filter usage, and related techniques, see US Patent Application No. 2005/0038357 published February 17, 2005 entitled “SAMPLE ELEMENT WITH BARRIER MATERIAL” and “SAMPLE ELEMENT WITH SEPARATOR”. In US patent application Ser. No. 11/122794 filed May 5, 2005. The entire contents of the above publications and patent applications are hereby incorporated by reference and made a part hereof.

Part IV B-Sample Detection System

  Although the sample detection system 334 of one embodiment does not limit the scope of the present invention, it will be described as an optical sample detection system 1700 in FIG. The analyte detection system 1700 measures the plasma spectrum. The plasma supplied to the specimen detection system 334 is processed by the sample preparation unit 332 including the filter 1500, but is not limited thereto.

  The analyte detection system 1700 includes an energy source 1720 disposed along the main axis X of the system 1700. In operation, the energy source 1720 generates an energy beam E that travels along the principal axis X from the energy source 1702. In one embodiment, energy source 1720 comprises an infrared source and the energy beam comprises an infrared energy beam.

  The energy beam E travels through the optical filter 1725 disposed on the main axis X and reaches the probe region 1710. The probe region 1710 is part of a device 322 that receives the material sample S on the path of the excited beam E. In one embodiment shown in FIG. 17, the probe region 1710 is adapted to receive a sample element or cuvette 1730 that supports or contains a material sample S. In one embodiment of the invention, the sample element 1730 is part of a path 113, such as a tube or optical cell. After passing through the sample element 1730 and the sample S, the energy beam E reaches the detector 1745.

  As used herein, “sample element” is broadly used in its ordinary sense and includes, but is not limited to, a sample chamber and a structure having at least one sample chamber wall, but more generally Includes any number of cuvettes, specimens, and other structures that hold, support, or contain a material sample and allow electromagnetic radiation to pass through the held, supported, or contained sample.

  In one embodiment of the present invention, the sample element 1730 forms a disposable part of the cassette 820, the remaining part of the system 1700 forms part of the instrument part 810, and the probe area 1710 is the probe area 1002. .

  Still referring to FIG. 17, detector 1745 generates an electrical signal in response to incident radiation and sends the signal to processor 210 for analysis. Based on the signal thus sent by the detector 1745, the processor can determine the concentration of the analyte of interest in the sample S and / or the sample S at one or more wavelengths or wavelength bands employed to analyze the sample. Absorption / transmission characteristics are calculated. The processor 210 executes data processing algorithms or program instructions resident in a memory 212 accessible by the processor 210 to calculate concentration, absorbance, permeability, and the like.

  In the embodiment shown in FIG. 17, the filter 1725 measures the wavelength or wavelength band of the energy beam E passing through the filter 1725 used for analyzing the sample S at the time of measurement using the apparatus 322 and / or the transition of time. A variable pass band filter may be provided so that it can be easily changed. (In various other embodiments, the entire filter 1725 may be omitted.) Examples of variable passband filters that can be used with the device 322 include, but are not limited to, filter wheels (details will be described later), For example, electronically tunable filters such as filters manufactured by Aegis Semiconductor (Woburn, Mass.), Custom filters using “Active Thin Films platform”, Scientific Solutions, Inc. Fabry-Perot interferometer manufactured by (North Chelmsford, MA), custom liquid crystal Fabry-Perot (LCFP) tunable filter, or HORIBA (Jobin Yvon, Inc. (Edison, NJ) H1034 type equipped with 7-10 μm grating) Tunable monochromator or custom design system.

In the detection system 1700 according to one embodiment, the filter 1725 measures the wavelength or wavelength band of the energy beam E passing through the filter 1725 used for analyzing the sample S at the time of measurement using the detection system 1700 and / or the time. A variable pass-band filter is provided so that it can be easily changed in the transition of. Since the energy beam E is filtered by the variable pass band filter, the absorption / transmission characteristics of the sample S can be discretely and continuously analyzed at a plurality of wavelengths or wavelength bands. For example, if the sample S is analyzed at N different wavelengths (wavelength 1 to wavelength N), first, the detector 1745 senses at the same time that the energy beam E is passed through the variable passband filter at wavelength 1. It is tuned to substantially block all or most of the energy beam E components of other possible wavelengths (2-N). Next, based on the beam E that has passed through the sample S and reached the detector 1745, the absorption / transmission characteristics of the sample S of wavelength 1 are measured. In addition, the variable passband filter is operated or tuned to pass the energy beam E at wavelength 2 and at the same time substantially block the components of the energy beam E at other wavelengths as described above. As with wavelength 1, analysis is also performed for wavelength 2. This step is repeated for all target wavelengths to analyze the sample S. The absorption / transmission data collected in this way is analyzed by the processor 210 to measure the target analyte concentration in the material sample S. The spectrum of the measured sample S is herein referred to as C _s (λi). This is a wavelength dependent spectrum, C _s is, for example, transmission, absorbance, optical density, or other measurement of the optical properties of sample S at or near wavelength λ, and the range of i is The number of measurements to be made. The measured value C _s (λi) is a linear array of measured values and may instead be represented as C _s .

  The spectral region of the system 1700 depends on the analytical technique, the analyte of interest and the mixture. For example, a spectral region available for measuring glucose in blood using absorption spectroscopy is mid-infrared (eg, about 4 microns to about 11 microns). In one embodiment of the detection system 1700, the energy source 1720 produces a beam E whose output ranges from about 4 microns to about 11 microns. Although water primarily contributes to the total absorption in this spectral region, the peaks and other distributions present in the blood spectrum from about 6.8 microns to about 10.5 microns are due to the absorption spectra of other blood components. The 4-11 micron region has a strong absorption peak structure between about 8.5 and 10 microns of glucose, while the other blood components have a low and flat absorption spectrum in this 8.5 to 10 micron range. Thus, it is known to be advantageous. The main exceptions are water and hemoglobin, which are interfering substances in this area.

  The details of the spectral quantities obtained by the detection system 1700 depend on the analytical technique, the analyte of interest and the mixture. For example, measurement of glucose in blood by mid-infrared absorption spectroscopy is performed with 11 to 25 filters in the spectral region. In one embodiment of the system 1700, the energy source 1720 generates a beam E with an output in the range of about 4 microns to about 11 microns, and the filters 1725 each pass only energy at a particular wavelength or wavelength band. A plurality of narrow-band filters in this range. Thus, for example, the filter 1725 of one embodiment has a nominal wavelength of approximately 3 μm, 4.06 μm, 4.6 μm, 4.9 μm, 5.25 μm, 6.12 μm, 6.47 μm, 7.98 μm, 8 A filter wheel having eleven filters, one of .35 μm, 9.65 μm and 12.2 μm.

  In one embodiment, the individual infrared filters that make up the filter wheel may be OCLI (JDS Uniphase, San Jose, Calif.) Or Spectrogon US, Inc. It is composed of a multi-cavity, narrow-band dielectric stack made of germanium or sapphire made by (Parsippany, NJ). Thus, each filter may have a nominal thickness of 1 millimeter and 10 square millimeters. The peak transmittance of the filter stack is typically 50% to 70% and the bandwidth is typically 150 nm to 350 nm with a center wavelength of 4 to 10 μm. Alternatively, the second light shielding infrared filter is provided in front of the individual filter. The temperature sensitivity is preferably 0.01% / ° C. so that almost constant measurement can be performed under various environmental conditions.

  The detection system 1700 of one embodiment first measures the electromagnetic radiation detected at each central wavelength or wavelength band by the detector 1745 with no sample element 1730 disposed on the main axis X to provide an analyte concentration reading. (Reading) is calculated (this is called “air” reading). Next, the system 1700 places a sample element 1730 carrying the material sample S on the principal axis X and measures the electromagnetic radiation detected by the detector 1745 at each central wavelength or wavelength band (this is a “wet” reading). Called value). Finally, the processor 210 calculates the concentration, absorbance and / or permeability for the sample S based on these readings.

In one embodiment, a path length correction spectrum is generated using a plurality of air readings and wet readings as follows. First, the measured value is normalized to obtain the transmittance of the sample at each wavelength. If S _i represents the signal of the detector 1745 at wavelength i and R _i represents the signal of the detector at wavelength i, then the transmittance T _{i at} wavelength i using the signal at each wavelength and the reference measurement is It can be calculated from the following formula. T _i = S _i (wet) / S _i (air). If necessary, the spectrum may be calculated as optical density OD _i , Log (T _i ). Next, the path length is determined by analyzing the transmission in the wavelength range of about 4.5 μm to about 5.5 μm. Specifically, water is the main blood absorption species in this wavelength region, the optical density is the product of the optical path length and the known water absorption coefficient (OD = Lσ, L is the optical path length, Since σ is an absorption coefficient), the optical path length L may be determined from the measured optical density OD using one of the standard curve fitting procedures. The path length may be used to determine the sample absorption coefficient at each wavelength. Alternatively, the optical path length may be used in calculations that convert the absorption coefficient into optical density.

  Blood samples can be prepared and analyzed in various configurations by system 1700. In one embodiment, the sample S may be obtained using a syringe or withdrawing blood from a syringe or part of a blood flow system and transporting this blood to the sample chamber 903. In other embodiments, sample S is withdrawn into a sample container, which is a sample chamber 903 for injection into system 1700.

  FIG. 44 is a diagram illustrating an analyte detection system 1700 according to another embodiment. Although it is almost the same as the embodiment shown in FIG. 17, the differences will be described in detail below. In the embodiment shown in FIG. 17 and the embodiment shown in FIG. 44, the same reference numerals are assigned to the same components.

  The specimen system 1700 shown in FIG. 44 includes a collimator 30 positioned between the light source 1720 and the filter 1725, and a beam condensing element 90 positioned between the filter and the sample element 1730. The filter 1725 includes a main filter 40 and a filter wheel assembly 4420 that can insert one of a plurality of optical filters into the energy beam E. The system 1700 further includes a sample detector 150 that is substantially similar to the sample detector 1725 except as described in detail below.

As shown in FIG. 44, the energy beam E from the light source 1720 passes through the collimator 30 and reaches the main light filter 40 located downstream of the wide end 36 of the collimator 30. The filter 1725 is aligned with the light source 1720 and the collimator 30 on the main axis X, and preferably only selected bands emitted from the light source 1720, for example, about 2.5 μm to 12.5 μm, as described below. It is comprised so that it may operate | move as a broadband filter which passes. In one embodiment, the energy source 1720 includes an infrared source and the energy beam E includes an infrared energy beam. One suitable energy source 1720 includes TOMA TECH ^™ IR-50 available from HawkEye Technologies, Milford, Connecticut.

  As shown in FIG. 44, the main filter 40 is attached to the mask 44 so that the portion of the energy beam E incident on the main filter 40 passes through the surface of the mask-main filter assembly. The main filter 40 is substantially centered on the main axis X and is orthogonal to the main axis X, and is preferably a circle having a diameter of about 8 mm (a plane orthogonal to the main axis X). Obviously, any other size or shape may be used. As already described, the main filter 40 preferably operates as a wideband filter. In the illustrated embodiment, the main filter 40 preferably passes only energy having a wavelength of about 4 μm to about 11 μm. However, other ranges of wavelengths can be selected. The main filter 40 has an advantage of reducing the filter load of the second optical filter 60 located downstream of the main filter 40 and improving the radiation prevention of electromagnetic waves having wavelengths other than the desired wavelength band. Furthermore, the main filter 40 functions to minimize the heating of the second filter due to the passage of the energy beam E. Even with such advantages, in an alternative embodiment of the system 1700 shown in FIG. 44, the main filter 40 and / or mask 44 may be omitted.

  The main filter 40 preferably has its operating characteristics (center wavelength, passband width) even if part or all of the energy beam E deviates from normal incidence until the cone angle is about 12 degrees with respect to the main axis X. Is configured to be substantially maintained. In further embodiments, the cone angle may be from about 15 degrees to 35 degrees, alternatively from about 15 degrees to 20 degrees. The primary filter 40 “maintains” its operating characteristics means that the degree of variation that occurs when using the system 1700 is insufficient to affect the performance or operation of the detection system 1700, and the system user It is also possible to make it so that there is no significant concern.

  In the embodiment illustrated in FIG. 44, the filter wheel assembly 4420 includes an optical filter wheel 50 and a step motor 70 configured to connect to the filter wheel and generate a force to rotate the filter wheel 50. Yes. Further, the position sensor 80 is arranged over the circumference of the filter wheel 50 so as to detect the angular position of the filter wheel 50, generate one signal of the corresponding filter wheel, and indicate the position on the main axis X of the filter. It has become. Alternatively, the step motor 70 may track or count its rotation to detect the angular position of the filter wheel and send a corresponding position signal to the processor 210. Two suitable position sensors include EE-SPX302-W2A and EE-SPX402-W2A available from Omron Corporation, Kyoto, Japan.

  The second filter 60 is selectively placed on the main axis X and / or the energy beam E using the optical filter wheel 50 as a variable passband filter. Accordingly, the filter wheel 50 can selectively tune the wavelength of the energy beam E downstream of the filter wheel 50. These wavelengths vary according to the characteristics of the second filter 60 attached to the filter wheel 50. The filter wheel 50 arranges the second filters 60 “one by one” at the position of the energy beam E, and sequentially changes the wavelength or wavelength band used for analyzing the material sample S as described above. Instead of the filter wheel 50, a linear filter that is translated by a motor (not shown) may be used. The linear filter may be, for example, a linear array of independent filters, or a single filter having filter characteristics that vary in two dimensions.

  In an alternative configuration, the single main filter 40 shown in FIG. 44 may be replaced with an additional main filter attached to the filter wheel 50 upstream of each second filter 60, or may be interpolated. Alternatively, the main filter 40 may be configured as a main filter wheel (not shown) and another main filter may be placed on the main axis X during another operation of the detection system 1700, or as a tunable filter It may be configured.

  The filter wheel 50 of the embodiment shown in FIG. 45 includes a wheel body 52 and a plurality of second filters 60 arranged on the wheel body 52, and the centers of the filters are equally spaced from the rotation center RC of the wheel body. To be located. The filter wheel 50 rotates about an axis that is (i) parallel to the main axis X and (ii) an orthogonal distance approximately equal to the distance between the center of rotation RC and the center of the second filter 60. It is like that. With this configuration, when the wheel body 52 rotates, each filter sequentially passes through the main axis X and affects the energy beam E. However, only a predetermined filter group on the filter wheel 50 may be used in a predetermined measurement run according to the target specimen or a desired measurement speed. A home position notch 54 may be provided to indicate the home position of the filter wheel 50 to the position sensor.

  In one embodiment, the wheel body 52 may be formed of a molded plastic having a plurality of second filters 60, each of which is, for example, square, 10 mm × 10 mm or 5 mm × 5 mm, and 1 mm thick. In the wheel body of this embodiment, the filters 60 are arranged in the axial direction with respect to a circular opening having a diameter of 4 mm, and the center of the opening has a diameter of about 1.70 inches concentric with the wheel body 52. Define a circle. The wheel body 52 itself is circular with an outer diameter of 2.00 inches.

  Each of the second filters 60 preferably operates as a narrowband filter that passes only a selected energy wavelength or wavelength band (ie, a filtered energy beam (Ef)). As the filter wheel 50 rotates about its center of rotation RC, the second filters 60 are each positioned along the main axis X for a selected dwell time corresponding to each of the second filters 60 in turn.

  The predetermined “dwell time” of the second filter 60 corresponds to the following conditions: (i) a state where the filter is located along the main axis X and (ii) a voltage is applied to the light source 1720. , And the time interval between individual measurement runs performed by the system 1700. The dwell time for a given filter may be equal to or longer than the time the filter is positioned along the main axis X during an individual measurement run. In the analyte detection system 1700 of one embodiment, the dwell time corresponding to each of the second filters 60 is less than about 1 second. However, the second filter 60 may have other dwell times, and each filter 60 may have a different dwell time during a given measurement run.

  The energy beam (Ef) filtered from the second filter 60 has a surface 4400a that forms an angle θ with respect to the main axis X, and passes through the beam condensing element 90 including the beam splitter 4400 disposed along the main axis X. To do. The beam splitter 4400 preferably separates the filtered energy beam (Ef) into a sample beam (Es) and a reference beam (Er).

  As shown in FIG. 44, the sample beam (Es) further passes through a first lens 4410 arranged along the main axis X alongside the beam splitter 4400. The first lens 4410 is configured to collect the sample beam (Es) on the material sample S substantially along the axis X. Sample S is preferably placed inside sample element 1730 between first window 122 and second window 124 of sample element 1730. Further, the sample element 1730 is preferably detachably disposed in the holder 4430, and the holder 4430 has a first opening 132 and a second opening formed so as to correspond to the first window 122 and the second window 124, respectively. Two openings 134 are provided. Alternatively, the sample element 1730 and the sample S may be arranged along the main axis X without using the holder 4430.

  At least a part of the sample beam (Es) passes through the sample S and subsequently enters the second lens 4440 disposed along the main axis X. The second lens 4440 is configured to collect the sample beam (Es) on the sample detector 150 and increase the light beam density of the sample beam (Es) incident on the sample detector 150. The sample detector 150 is configured to generate a signal corresponding to the detected sample beam (Es) and send the signal thus generated to the processor 210. Details of this will be described later.

  The beam condensing element 90 further includes a third lens 160 and a reference detector 170. The reference beam (Er) from the beam splitter 4400 is guided by the beam condensing element 90 to the third lens 160 arranged along the slave axis Y substantially orthogonal to the main axis X. The third lens 160 is configured to collect the reference beam (Er) in the reference detector 170 and increase the luminous flux density of the reference beam (Er) incident on the reference detector 170. In one embodiment, the lenses 4410, 4440, 160 may be composed of a material that is highly transmissive to infrared radiation, such as germanium or silicon. Furthermore, any of the lenses 4410, 4440, and 160 may be configured as an optical system composed of a plurality of lenses according to desired optical performance. The reference detector 170 is further configured to generate a signal corresponding to the detected reference beam (Er) and send the signal thus generated to the processor 210. Details of this will be described later. As will be described below, the sample detector 150 and the reference detector 170 may have substantially the same configuration as the detector 1745 shown in FIG. Based on the signals received from the sample detector 150 and the reference detector 170, the processor 210 executes data processing algorithms or program instructions that reside in a memory 212 accessible to the processor 210 to provide concentration, absorption for the sample S. Calculate degrees, transparency, etc.

  In a further aspect of the detection system 1700 shown in FIG. 44, in the operation of the detection system 1700, particularly when the output intensity of the light source 1720 is sufficiently stable that it is not necessary to refer to the light source intensity, The beam condensing element 90 including the upper beam splitter 4400, the reference detector 170, and other structures may be omitted. For example, if sufficient signals are generated by detectors 170, 150, one or more of lenses 4410, 4440, 160 may be omitted. Further, in any embodiment of the analyte detection system 1700 described herein, a portion of or the entire processor 210 and / or memory 212 may be a standard personal computer (“PC”) connected to the detection system 1700. ) May be provided.

  FIG. 46 is a partial cross-sectional view of an analyte detection system 1700 according to another embodiment. Although it is substantially the same as that of embodiment shown in FIG.17, FIG.44, FIG.45, a difference is demonstrated in detail below. Components similar to those in the embodiment described in FIGS. 17, 44 and 45 are denoted by the same reference numerals.

  The energy source 1720 of the embodiment shown in FIG. 46 preferably includes a light emitting region 22 that is approximately centered on the main axis X. In one embodiment, the light emitting region 22 may be square. However, the light emitting region 22 may have other suitable shapes, for example, a rectangle, a circle, an ellipse, and the like. An example of a suitable light emitting region 22 is a square with a side of about 1.5 mm, but it will be appreciated that the light emitting region 22 may have other suitable shapes or dimensions.

  The energy source 1720 is preferably configured to selectively operate at a modulation frequency between about 1 Hz and 30 Hz and have a peak operating temperature between about 1070 degrees Kelvin to 1170 degrees Kelvin. Furthermore, the light source 1720 preferably operates at a modulation depth greater than about 80% at all modulation frequencies. Energy source 1720 is preferably greater than about 0.8 μm to about 20.0 μm in any of a number of spectral ranges, for example, in the infrared wavelength, in the mid-infrared wavelength, greater than about 0.8 μm. And / or emit electromagnetic radiation between about 5.25 μm and about 12.0 μm. However, in other embodiments, the detection system 1700 may be unmodulated and / or any wavelength from the visible spectrum to the microwave spectrum, eg, from about 0.4 μm to about An energy source 1720 that emits at any wavelength above 100 μm may be used. In still other embodiments, the energy source 1720 has a range of about 3.5 μm to about 14 μm, or about 0.8 μm to about 2.5 μm, or about 2.5 μm to 20 μm, or about 20 μm. Electromagnetic radiation can be emitted at a wavelength in the range of ˜100 μm, or in the range of about 6.85 μm to about 10.10 μm. In still other embodiments, the energy source 1720 can emit electromagnetic radiation in the radio frequency (RF) range or terahertz range. All of the operational characteristics detailed above are for illustrative purposes only, and the light source 1720 may have any operational characteristic suitable for use with the analyte detection system 1700.

  The power source (not shown) of the energy source 1720 is preferably configured to selectively operate with a duty cycle ranging from about 30% to about 70%. In addition, the power supply is preferably configured to selectively operate at a modulation frequency in the range of about 10 Hz, or about 1 Hz to about 30 Hz. The operation of the power supply can be in the form of a square wave, a sine wave, or other waveform defined by the user.

  As shown in FIG. 46, the collimator 30 includes a tube 30a having one or more highly-reflective inner surfaces 32. The inner surface extends downstream from the relatively narrow upstream end 34 toward the relatively wide downstream end 36 as it moves away from the energy source 1720. The narrower end 34 defines an upstream opening 34 a located close to the light emitting region 22. The upstream opening 34a propagates the radiation emitted from the light emitting region 22 to the downstream collimator. The wider end 36 defines a downstream opening 36a. As with the light emitting region 22, each of the highly reflective inner surface 32, the upstream opening 34 a and the downstream opening 36 a is preferably centered about the main axis X.

  As shown in FIG. 46, the highly reflective inner surface (including a plurality of cases) 3 of the collimator may have a substantially curved shape such as a parabola, hyperbola, ellipse, or sphere. One suitable collimator 30 is a compound parabolic concentrator (CPC). In one embodiment, the length of the collimator 30 can be up to about 20 mm. In other embodiments, the length of the collimator 30 can be up to about 30 mm. However, the collimator 30 may be of any length and the highly reflective inner surface (including multiple cases) 32 may be of any shape, as appropriate for use with the analyte detection system 1700.

  The highly reflective inner surface 32 of the collimator 30 allows the rays that make up the energy beam E to be emitted so that the energy beam E becomes progressively or substantially cylindrical and substantially parallel to the principal axis X. When E moves downstream, it travels straight (that is, propagates at an angle gradually parallel to the main axis X). Accordingly, the highly reflective inner surface 32 is highly reflective and has minimal absorptivity at wavelengths of interest such as infrared wavelengths.

  The tube 30a itself may be coated on the highly reflective inner surface 32 to be highly reflective at the wavelength of interest, or if it is otherwise treated, a rigid material such as aluminum or steel, or other You may manufacture with an appropriate material. For example, a polished gold film may be used. Preferably, the highly reflective inner surface 32 (including a plurality of cases) of the collimator 30 has a circular cross section when viewed so as to be orthogonal to the main axis X. However, in alternative embodiments, the cross-section may have other shapes, such as a square or other polygonal, parabolic or elliptical shape.

  As already described, the filter wheel 50 shown in FIG. 46 preferably has a plurality of second filters 60, each filter operating as a narrow band filter that passes only energy in a particular wavelength or wavelength band. In one configuration suitable for the detection of glucose in the sample S, the filter wheel 50 has 20 or 22 second filters 60, each of which is described below, ie 3 μm, 4.06 μm. , 4.6 μm, 4.9 μm, 5.25 μm, 6.12 μm, 6.47 μm, 7.98 μm, 8.35 μm, 9.65 μm, and 12.2 μm, a nominal wavelength approximately equal to one of the following: It is configured to allow the energy beam (Ef) filtered in (1) to pass through. (Furthermore, this set of wavelengths may be used with either the analyte detection system 1700 of the embodiment disclosed herein or the analyte detection system 1700 of the embodiment.) Each second filter The center wavelength of 60 is preferably ± about 2% of the desired nominal wavelength. Further, the second filter 60 is preferably configured to have a bandwidth of about 0.2 μm, or ± about 2% to 10% of the nominal wavelength.

  In other embodiments, the filter wheel 50 has twenty second filters, each of which is 4.275 μm, 4.5 μm, 4.7 μm, 5.0 μm, 5.3 μm, 6. 056 μm, 7.15 μm, 7.3 μm, 7.55 μm, 7.67 μm, 8.06 μm, 8.4 μm, 8.56 μm, 8.87 μm, 9.15 μm, 9.27 μm, 9.48 μm, 9.68 μm, A filtered energy beam (Ef) having a nominal center wavelength of 9.82 μm and 10.6 μm is configured to pass. (This set of wavelengths may be used with either the analyte detection system 1700 of the embodiment disclosed herein or the analyte detection system 1700 of the embodiment.) In yet other embodiments. The second filter 60 has the following specifications: center wavelength tolerance of ± 0.01 μm, power-half bandwidth tolerance of ± 0.01 μm (half-power bandwidth tolerance), 75% Peak transmission above, cut-on / cut-off slope below 2%, center wavelength temperature coefficient below 0.01% per degree Celsius (center-wavelength temperature coefficiency) out of band attenuation over OD5 of 3 μm to 12 μm, flatness of less than 1.0 wave at 0.6328 μm (flatness less than 1.0 wave at 0.6328 μm), Mil-F- The surface quality of EE according to 48616 (surface quality of EE per MIL-F-48616) and the total thickness of about 1 mm may be adapted to any one or a combination thereof.

In other further embodiments, the second filter described above may conform to any one or combination of the following half-power bandwidth (HPBW) specifications.

  In a further embodiment, the second filter may have a center wavelength tolerance of ± 0.5% and a power half bandwidth tolerance of ± 0.02 μm.

  The number of second filters used, the center wavelength, and other characteristics vary depending on whether glucose is detected, whether other analytes are detected, other analytes are detected in addition to glucose, etc. It is apparent that the system may be changed for each system 1700 according to the embodiment. For example, in other embodiments, the filter wheel 50 may have fewer than 50 second filters 60. In still other embodiments, the filter wheel 50 may have fewer than 20 second filters 60. In still other embodiments, the filter wheel 50 may have fewer than ten second filters 60.

  In one embodiment, each of the second filters 60 has a length of about 10 mm, a width of about 10 mm, and a thickness of about 1 mm on a plane orthogonal to the main axis X. However, the second filter 60 may have any other (eg, smaller) dimensions that are suitable for operation of the analyte detection system 1700. Furthermore, the second filter 60 preferably operates at a temperature in the range of about 5 ° C. to about 35 ° C. and is configured to have greater than about 75% transmission for the energy beam E of the wavelength that the filter passes. it can.

  In the embodiment shown in FIG. 46, the main filter 40 operates as a wideband filter, and the second filter 60 disposed on the filter wheel 50 operates as a narrowband filter. However, those skilled in the art will appreciate that other structures can be used to filter energy wavelengths in accordance with the disclosed embodiments. For example, the main filter 40 may be omitted and / or an electronically tunable filter or a Fabry-Perot interferometer (not shown) may be used in place of the filter wheel 50 and the second filter 60. Can do. Such a tunable filter or interferometer can be configured to analyze the material sample S through a set of wavelengths or wavelength bands of electromagnetic radiation that are continuously transmitted “one by one”.

  The reflector tube 98 is preferably arranged to receive the filtered energy beam (Ef) emerging from the second filter (s) 60. In order to prevent stray electromagnetic radiation, such as stray light, from entering the reflector tube 98 from outside the analyte detection system 1700, the reflector tube 98 is in contact with the second filter (s) 60. It is preferable to fix them. The inner surface of the reflecting tube 98 is highly reflective at the wavelength, and preferably has a cylindrical shape whose cross section is substantially circular and perpendicular to the major axis X and / or the minor axis Y. However, the inner surface of the reflecting tube 98 may have an appropriately shaped cross section such as an oval, square, or rectangle. Like the collimator 30, the reflector tube 98 is coated to be highly reflective at the wavelength of interest, or if it is otherwise treated, a rigid material such as aluminum or steel, or other suitable material. It may be made of any material. For example, a polished gold film may be used.

  In the embodiment shown in FIG. 46, the reflector tube 98 preferably includes a main cross section 98a and a secondary cross section 98b. As illustrated, the reflecting tube 98 is T-shaped, and the length of the main cross section 98a can be made longer than the length of the subsection 98b. In other embodiments, the main section 98a and the secondary section 98b can be the same length. The main cross section 98a extends along the main axis X between the first end 98c and the second end 98d. The secondary section 98b extends along the secondary axis Y between the main section 98a and the third end 98e.

  The main cross section 98a guides the filtered energy beam (Ef) from the first end 98c to the beam splitter 100 accommodated in the main cross section 98a at the intersection of the main axis X and the secondary axis Y. The main cross section 98a further guides the sample beam (Es) from the beam splitter 100 through the first lens 4410 to the second end 98d. The sample beam (Es) travels from the second end 98d through the sample element 1730, the holder 4430, and the second lens 4440 to the sample detector 150. Similarly, the longitudinal section 98b guides the reference beam (Er) from the beam splitter 4400 to the third end 98e through the beam condensing element 90 and the third lens 160. The reference beam (Er) travels from the third end 98e to the reference detector 170.

  The sample beam (Es) preferably has about 75% to about 85% of the energy of the filtered energy beam (Ef). More preferably, the sample beam (Es) has about 80% of the filtered energy beam (Ef). The reference beam (Er) preferably has about 10% to about 50% of the energy of the filtered energy beam (Ef). More preferably, the reference beam (Er) has about 20% of the energy of the filtered energy beam (Ef). Here, it is clear that the energy taken in by the sample beam and the reference beam may be any ratio with respect to the energy beam E.

  The reflecting tube 98 further accommodates the first lens 4410 and the third lens 160. As shown in FIG. 46, the reflecting tube 98 houses the first lens 4410 between the beam splitter 4400 and the second end 98d. The first lens 4410 is preferably arranged so that the surface 4612 of the lens 4410 is substantially perpendicular to the principal axis X. Similarly, the tube 98 houses a third lens 160 between the beam splitter 100 and a third end 98e. The third lens 160 is preferably arranged so that the surface 162 of the third lens 160 is substantially perpendicular to the minor axis Y. Each of the first lens 4410 and the third lens 160 includes a sample beam (Es) and a reference beam (Er) when the sample beam (Es) and the reference beam (Er) pass through the first lens 4410 and the third lens 160, respectively. The focal length is configured so that the reference beam (Er) can be substantially focused. In particular, the first lens 4410 focuses the sample beam (Es) and is configured so that almost all of the sample beam (Es) passes through the material sample S disposed in the sample element 1730. Is arranged against. Similarly, the third lens 160 is configured to focus the reference beam (Er) so that almost all of the reference beam (Er) is incident on the reference detector 170.

  The sample element 1730 is held in the holder 4430, and the holder 4430 is preferably disposed on a plane substantially perpendicular to the main axis X. The holder 4430 is configured to be slidable and movable between the mounting position and the measurement position in the specimen detection system 1700. In the measurement position, the holder 4430 is in contact with the stop end 136 and the sample element 1730 and the sample S contained therein are arranged on the main axis X.

  If the holder arranges the sample element 1730 and the sample S on the main axis X so as to be substantially orthogonal to the main axis X, and further allows the energy beam E to pass through the sample element 1730 and the sample, FIG. The details of the structure of the holder 4430 shown are not important. As in the embodiment described with reference to FIG. 44, the holder 4430 may be omitted, and only the sample element 1730 may be disposed at a position shown on the main axis X. However, the holder 4430 is useful when the sample element 1730 (which will be described in further detail below) is manufactured from a very brittle and unstable material such as barium fluoride, or very thin.

  As in the embodiment described with reference to FIG. 44, the sample detector 150 and the reference detector 170 shown in FIG. 46 generate a signal when radiation is incident, and send the generated signal to the processor 210. Based on these signals received from the sample detector 150 and the reference detector 170, the processor 210 executes data processing algorithms or program instructions resident in the memory 212 accessible by the processor 210 to provide a concentration for the sample S. Calculate absorbance, transmittance, and the like. In various aspects of the analyte detection system 1700 shown in FIG. 46, particularly when the output intensity of the light source 1720 is sufficiently stable that the operation of the detection system 1700 need not refer to the light source intensity. The beam splitter 4400 on Y, the reference detector 170 and other structures may be omitted.

  FIG. 47 shows a cross-sectional view of the sample detector 150 of one embodiment. The sample detector 150 is installed in a detector housing 152 having a receiving portion 152a and a cover portion 152b. However, any structure may be used as long as the sample detector 150 and the housing 152 are appropriate. The receiving part 152a preferably defines the opening 152c and the lens chamber 152d so as to be aligned with the main axis X when the housing 152 is installed in the specimen detection system 1700. The opening 152c is configured such that at least a part of the sample beam (Es) passing through the sample S and the sample element 1730 passes through the opening 152c and into the lens chamber 152d.

  The receiving part 152a accommodates the second lens 4440 in the vicinity of the opening 152c in the lens chamber 152d. The sample detector 150 is disposed downstream of the second lens 4440 in the lens chamber 152d so that the detection surface 154 of the detector 150 is substantially perpendicular to the main axis X. The second lens 4440 is arranged so that the surface 142 of the lens 4440 is substantially perpendicular to the main axis X. The second lens 4440 is preferably placed relative to the holder 4430 and the sample detector 150 to focus the sample beam (Es) on the detection surface 154 so that almost all of the sample beam (Es) is detected on the detection surface 154. And the beam density of the sample beam (Es) incident on the detection surface 154 is increased.

  Further, as shown in FIG. 47, the support member 156 preferably holds the sample detector 150 in a position within the receiving portion 152a. In the illustrated embodiment, the support member 156 is a spring 156 disposed between the sample detector 150 and the cover portion 152b. The spring 156 is configured to hold the detection surface 154 of the sample detector 150 so as to be substantially orthogonal to the main axis X. Preferably, the gasket 157 is disposed between the cover portion 152b and the receiving portion 152a so as to surround the support member 156.

  Further, the receiving portion 152a preferably accommodates a printed circuit board 158 disposed between the gasket 157 and the sample detector 150. The printed circuit board 158 is connected to the sample detector 150 through at least one connection member 150a. The sample detector 150 generates a detection signal corresponding to the sample beam (Es) incident on the detection surface 154. The sample detector 150 communicates with the printed circuit board 158 via the connection member 150 a to transmit a detection signal, and the printed circuit board 158 transmits this detection signal to the processor 180.

  In one embodiment, the sample detector 150 is a TO-39 “metal can” package (type TO) that defines a generally cylindrical housing 150a, eg, a generally circular housing opening 150b at its upstream end. -39 "metal can" package). In one embodiment, the housing 150a has a diameter of about 8.23 mm (0.323 inches) and a depth of about 6.29 mm (0.248 inches), and the opening 150b is about 5.00 mm (. (197 inches) in diameter.

  A detector window 150c is positioned adjacent to the opening 150b, and its upstream side preferably has about 0.078 inches (± 0.004 inches) from the detection surface 154. . (The sensing surface 154 is approximately 0.088 inches from the upstream edge of the housing 150a when the housing has a thickness of approximately 0.25 mm (approximately 0.010 inches) (± 0.10 mm (0 .004 inches)).) Detector window 150c preferably has infrared energy transparency in the passband of at least 3-12 μm. Thus, one suitable material for detector window 154c is germanium. The end point of the passband may be further “expanded” to be less than 2.5 μm and / or greater than 12.5 μm so that unnecessary light absorption does not occur within the wavelength of interest. Good. Preferably, the transmittance of detector window 150c does not vary by more than 2% in its passband. The thickness of the detector window 150c is preferably about 0.020 inches. The sample detector 150 preferably retains its operating characteristics in the temperature range of −20 ° C. to + 60 ° C.

  FIG. 48 is a cross-sectional view of the reference detector 170 according to one embodiment. The reference detector 170 is installed in a detector housing 172 having a receiving portion 172a and a cover portion 172b. However, any suitable structure may be used as the sample detector 150 and the housing 152. The receiving portion 172a preferably defines the opening 172c and the chamber 172d so as to be aligned substantially in line with the follower Y when the housing 172 is installed in the specimen detection system 1700. The opening 172c is configured such that the reference beam (Er) passes through the opening 172c and travels into the chamber 172d.

  The receiving portion 172a houses the reference detector 170 near the opening 172c in the chamber 172d. The reference detector 170 is disposed in the chamber 172d so that the detection surface 174 of the reference detector 170 is substantially perpendicular to the minor axis Y. The third lens 160 focuses the reference beam (Er), almost all of the reference beam (Er) is incident on the detection surface 174, and the light flux density of the reference beam (Er) incident on the detection surface 174 is reduced. Configure to increase.

  Further, as shown in FIG. 48, the support member 176 preferably holds the reference detector 170 in a position within the receiving portion 172a. In the illustrated embodiment, the support member 176 is a spring 176 disposed between the reference detector 170 and the cover portion 172b. The spring 176 is configured to hold the detection surface 174 of the reference detector 170 so as to be substantially orthogonal to the driven shaft Y. Preferably, the gasket 177 is disposed between the cover portion 172b and the receiving portion 172a so as to surround the support member 176.

  Further, the receiving portion 172a preferably houses a printed circuit board 178 disposed between the gasket 177 and the reference detector 170. The printed circuit board 178 is connected to the reference detector 170 through at least one connection member 170a. The reference detector 170 generates a detection signal corresponding to the reference beam (Er) incident on the detection surface 174. The reference detector 170 communicates with the printed circuit board 178 via the connection member 170 a to transmit a detection signal, and the printed circuit board 178 transmits this detection signal to the processor 210.

  In one embodiment, the structure of the reference detector 170 is substantially the same as the sample detector 150 described above.

  In one embodiment, both sample detector 150 and reference detector 170 are configured to detect electromagnetic radiation in the spectral wavelength range of about 0.8 μm to about 25 μm. However, any suitable subset from the set of wavelengths described above can be selected. In other embodiments, the sample detector and reference detector 170 are configured to detect electromagnetic radiation in a wavelength range between about 4 μm and about 12 μm. The detection surfaces 154, 174 of the sample detector and reference detector 170 may each have an active area of about 2 mm × 2 mm, or about 1 mm × 1 mm to about 5 mm × 5 mm, of course. However, any other dimensions and ratios may be applied as appropriate. Further, the sample detector and reference detector 170 may be configured to detect electromagnetic radiation directed at itself at a cone angle within about 45 degrees from the main axis X.

  In one embodiment, the sample detector 150 and reference detector 170 subsystems may further comprise a system (not shown) for adjusting the temperature of the detector. The temperature adjustment system may include a suitable electric heat source, thermistor, proportional integral derivative (PID) control, and the like. Using these components, the temperature of the sample detector 150 and the reference detector 170 may be adjusted to about 35 ° C. Sample detector 150 and reference detector 170 can optionally be operated at other desired temperatures. Further, the PID control may preferably have a control rate of about 60 Hz, and together with the electrical heat source and the thermistor, the temperature of the sample detector 150 and the reference detector 170 may be about 0% of the desired temperature. Maintain within 1 ° C.

  The sample detector 150 and the reference detector 170 can operate in either a voltage mode or a current mode, and the operation in either mode preferably uses a pre-amp module. Suitable voltage mode detectors for use with the analyte detection system 1700 disclosed herein include models LIE302 and LIE312 from InfraTech (Dresden, Germany), model L2002 from BAE Systems (Rockville, Maryland), and Dias ( Model LTS-1 manufactured by Dresden, Germany). Suitable current mode detectors include InfraTec 301, 315, 345, and 355, and 2 × 2 current mode detectors available from Dias.

In one embodiment, one or both of the sample detector 150 and the reference detector 170 have the following specifications: an incident radiation intensity of about 9.26 × 10 ⁻⁴ W / cm ² (rms), with 10 Hz modulation. When the cone angle is about 15 degrees or less, the area of the detection unit is 0.040 cm ² (2 mm × 2 mm square), the input of the detection unit is 10.70 × 10 ⁻⁵ W (rms) at 10 Hz, The sensitivity is 360 V / W at 10 Hz, the output of the detection unit is 1.333 × 10 ⁻² V (rms) at 10 Hz, the noise is 8.00 × 10 ⁻⁸ volts / sqrtHz at 10 Hz, and the signal-to-noise ratio is 1.67 × 10 ⁵ rms. / SqrtHz and 104.4 dB / sqrtHz, and the detection ability may satisfy 1.00 × 10 ⁹ cm sqrtHz / W.

  In alternative embodiments, the sample detector 150 and the reference detector 170 may comprise a microphone and / or other sensor suitable for the analyte detection system 1700 to operate in the photoacoustic mode.

  In any embodiment, in order to prevent the influence of stray electromagnetic radiation such as stray light from reaching the energy beam E, parts or components of the stray electromagnetic radiation analyte detection system 1700 are partially or entirely a casing or casing. You may store in (not shown). Any casing may be used if appropriate. Similarly, the components that make up detection system 1700 are mounted on a suitable frame or chassis (not shown) to maintain operational integrity, as shown in FIGS. 17, 44 and 46. May be. The frame and the chassis may be an integral part or member, or may be composed of a plurality of members.

  In one method of operation, the analyte detection system 1700 shown in FIG. 44 or FIG. 46 can measure the concentration of one or more analytes in the material sample S and, in part, the electromagnetic radiation detected by the sample detector 150 and the reference detector 170. Compare and measure. During the operation of the specimen detection system 1700, each of the second filters 60 is arranged on the main axis X in order for the dwell time corresponding to the second filter 60. (If an electronically tunable filter or Fabry-Perot interferometer is used instead of the filter wheel 50, each of the second filters can be electronically tunable instead of being placed on the main axis X in turn. The filter or Fabry-Perot interferometer is tuned in turn to each of the desired wavelength or set of wavelength bands.) The energy source 1720 operates at the above-described modulation frequency for a dwell time. The dwell time may be different for each of the second filters 60 (or for each wavelength or band that tunes the tunable filter or interferometer). In the analyte detection system 1700 of one embodiment, the dwell time of each second filter 60 is less than about 1 second. If the dwell time is unique to each of the second filters 60, there is an advantage that the operation time of the sample detection system 1700 can be increased at a wavelength that is easily affected by an error in the calculation of the sample concentration in the material sample S. Similarly, the operating time of the sample detection system 1700 can be shortened at wavelengths that are not easily affected by errors in the calculation of the sample concentration. Alternatively, the dwell time may be non-uniform for each filter / wavelength / band used by the detection system.

  For each of the second filters 60 that are selectively positioned on the main axis, the sample detector 150 transmits a sample beam (Es) that has passed through the material sample S at a wavelength or wavelength band corresponding to the corresponding second filter 60. Detect ingredients. The sample detector 150 generates a detection signal corresponding to the detected electromagnetic radiation and sends this signal to the processor 210. At the same time, the reference detector 170 detects the reference beam (Er) transmitted at the wavelength or wavelength band corresponding to the corresponding second filter 60. The reference detector 170 generates a detection signal corresponding to the detected electromagnetic radiation and sends this signal to the processor 210. Based on the signals sent by the sample detector 150 and the reference detector 170, the processor 210 may determine the concentration of the analyte of interest within the sample S and / or the absorption / absorption of the sample S at one or more wavelengths or wavelength bands. The permeability is calculated and the sample is analyzed. The processor 210 executes data processing algorithms or program instructions resident in a memory 212 accessible by the processor 210 to calculate concentration, absorbance, permeability, and the like.

  The signal generated by the reference detector 170 may be used to monitor the intensity variation of the energy beam emitted by the light source 1720. Intensity variations are often caused by drift effects, aging, wear or other malfunctions of the light source itself. By monitoring intensity variations, the processor 210 identifies intensity changes in the sample beam (Es) that occur independent of the components of the sample S due to changes in the radiation intensity of the light source 1720. This eliminates or minimizes the cause of errors that may occur when calculating density, absorption characteristics, and the like.

  In one embodiment, the detection system 1700 first detects electromagnetic radiation detected at each central wavelength or wavelength band by the sample detector 150 and the reference detector 170 without the sample element 1730 being placed on the main axis X. Measure and calculate the analyte concentration reading (this is called the “air” reading). Next, the detection system 1700 uses the sample detector 150 and the reference detector 170 to place the material sample S on the sample element 1730 and place the sample element 1730 and the sample S on the main axis X in the respective center wavelengths or wavelength bands. The analyte concentration reading is calculated by measuring the electromagnetic radiation detected in (referred to as “wet” reading). Finally, the processor 180 calculates the concentration, absorbance and / or permeability for the sample S based on the readings thus obtained.

In one embodiment, a path length correction spectrum is generated using air readings and wet readings as follows. First, the measured values are normalized to obtain the transmittance at each wavelength. Using reference measurements and the signal at each wavelength, the signal of the detector 150 at a wavelength i and S _i, when the signal of the detector 170 at a wavelength i and R _i, the transparency and tau _i, permeability tau _i Is calculated by the following equation. τ _i = S _i (wet) / R _i (wet) / S _i (air) / R _i (air). If necessary, the spectrum may be calculated with spectral intensity as OD _i , Log (T _i ).

  Next, the transmission in the wavelength range of about 4.5 to about 5.5 μm is analyzed to determine the path length. Specifically, water is the main blood absorbing species in this wavelength region, and the optical density is the product of the optical path length and the known water absorption coefficient (OD = Lσ, L is the optical path length, σ is the absorption Therefore, the optical path length L may be determined from the measured optical density OD using one of standard curve fitting procedures. The path length may be used to determine the sample absorption coefficient at each wavelength. Alternatively, the optical path length may be used for calculations that convert the absorption coefficient into optical density.

In addition to the analyte detection system, its method of use, and related techniques, the above-referenced US patent application published on Feb. 17, 2005, entitled “SAMPLE ELEMENT WITH BARRIER MATERIAL”. Reference may be made to 2005/0038357.

Part IV C-Sample elements

  18 is a top view of the sample element 1730, FIG. 19 is a side view of the sample element, and FIG. 20 is an exploded perspective view of the sample element. The sample element 1730 of one embodiment of the present invention includes a sample chamber 903 that communicates with the sample preparation unit 332 and receives the filtered blood from the sample preparation unit 332. Sample element 1730 includes a sample chamber 903 defined by a sample chamber wall 1802. The sample chamber 903 is configured to hold a material sample that is extracted from the patient and analyzed with the sample element 1730 by the detection system.

  In the embodiment shown in FIGS. 18 and 19, the sample chamber 903 is defined by a first side chamber wall 1802a, a second side chamber wall 1802b, an upper chamber wall 1802c, and a lower chamber wall 1802d. However, any number and any configuration of chamber walls may be used as appropriate. At least one of the upper chamber wall 1802c and the lower chamber wall 1802d is formed of a material that is sufficiently transparent to the electromagnetic radiation of the wavelength used by the sample analyzer 322 (or other system that uses the sample element). Such a permeable chamber wall is called a “window”. In one embodiment, the upper chamber wall 1802c and the lower chamber wall 1802d have a first window and a second window that allow electromagnetic radiation of the appropriate wavelength to pass through the sample chamber 903. In another embodiment, at least one of the upper chamber wall 1802c and the lower chamber wall 1802d has a window. In this embodiment, the other of the upper chamber wall 1802c and the lower chamber wall 1802d has a reflective surface that back reflects electromagnetic energy radiated to the sample chamber 903 by the analyte detection system using the sample element 1703. Therefore, the present embodiment is suitable for use with an analyte detection system in which an energy source and an electromagnetic energy detector are arranged on the same surface of a sample element.

  In various embodiments, the material comprising the detector window of sample element 1730 is fully transmissive, i.e. does not absorb any electromagnetic radiation incident from light source 1720 and filter 1725. In other embodiments, the detector window material has some absorption in the desired electromagnetic range, but the absorption is negligible. In yet another embodiment, the detector window material has a non-negligible absorption, but is stable over a relatively long period of time. In other embodiments, the absorbance of the detector window is stable for only a relatively short period of time, but the sample analyzer 322 may monitor the absorbency of the substance and measure changes in the substance's properties. Previously configured to remove it from the analyte measurement. In yet another embodiment, the absorption of the material (s) of the window (s) is not negligible, but it is stable for a relatively long time. In another embodiment, the absorption of the window (s) is stable only for a relatively short period of time, but the analyte detection system 10 may be used before the material properties can change measurable. Observe the absorption of the material and remove it from the analyte measurement. Suitable materials for forming the detector window (s) of sample element 1730 include, but are not limited to, calcium fluoride, barium fluoride, germanium, silicon, polypropylene, polyethylene, or others And polymers having suitable permeability (that is, permeability per unit thickness) at the corresponding wavelength. When the detector window is formed of a polymer, the polymer structure selected can be isotactic, atactic or syndiotactic to enhance sample flow between the detector windows. One type of polyethylene suitable for forming the sample element 1730 is KUBE Ltd. Extruded or blow molded type 220 available from (Staefa, Switzerland).

In one embodiment, the sample element 1730 is configured to be sufficiently transparent to electromagnetic energy having a wavelength between about 4 μm and about 10.5 μm through its detector window. However, the sample element 1730 can be configured to transmit any spectral range of wavelengths emitted by the energy source 1720. In other embodiments, the sample element 1730 is configured to receive optical power greater than about 1.0 MW / cm ² from a sample beam (Es) incident on it for electromagnetic radiation wavelengths transmitted through the filter 1725. Is done. Preferably, the sample chamber 903 of the sample element 1730 is configured to allow a sample beam (Es) traveling from the main axis X (see FIG. 17) to the material sample S within a 45 degree cone angle.

  In the embodiment shown in FIGS. 18 and 19, the sample element further includes a supply path 1804 extending from the sample chamber 903 to the supply opening 1806, and a vent path 1808 extending from the sample chamber 903 to the vent opening 1810. Have Although vent opening 1810 and supply opening 1806 are shown at one end of sample element 1730, in other embodiments, if vent opening 1810 and supply opening 1806 are in fluid communication, these openings may be Each may be formed on a separate side of the sample element.

  In operation, the supply opening 1806 of the sample element 1730 is in contact with a material sample such as a liquid flowing from the patient. This liquid is carried to the sample chamber 903 via the sample supply path 1804 by an external pump or capillary action.

  When the upper chamber wall 1802c and the lower chamber wall 1802d are provided with a window, the distance T between them (measured along an axis substantially perpendicular to the sample chamber 903 and / or the windows 1802a and 1802b, or is not limited thereto). The distance measured along the axis of an energy beam such as the energy beam E described above) includes their optical path length. Various embodiments have path lengths between about 1 μm and about 300 μm, between about 1 μm and about 100 μm, between about 25 μm and about 40 μm, between about 10 μm and about 40 μm, between about 25 μm and about 60 μm, Or between about 30 μm and about 50 μm. In still other embodiments, the optical path length is about 50 μm or about 25 μm. In some cases, it is desirable to maintain the path length T within about ± 1 μm of the path length specified by the analyte detection system using the sample element 1730. Similarly, depending on the analyte detection system using sample element 1730, walls 1802c, 1802d are oriented parallel to each other within ± 1 μm, and / or walls 1802c, 1802d are each on a (planar) plane within ± 1 μm. It is desirable to hold. In alternative embodiments, the walls 1802c, 1802d are flat, rough, angular, or a combination thereof.

  In one embodiment, the lateral dimension of sample chamber 903 (ie, the dimension defined by lateral chamber walls 1802a, 1802b) is approximately equal to the dimension of the working surface of sample detector 1745. Thus, in a further embodiment, the sample chamber 903 is circular with a diameter of about 4 mm to about 12 mm, more preferably about 6 mm to about 8 mm.

  The sample element 1730 shown in FIGS. 18 and 19 has the following dimensions and diameters in one embodiment. The supply path 1804 preferably has a length of about 15 mm, a width of about 1.0 mm, and a height equal to the path length T. Further, the supply opening 1806 preferably has a width of about 1.5 mm and smoothly transitions to the width of the sample supply path 1804. The sample element 1730 is about 12 mm (about 0.5 inches) wide and about 25 mm (about 1 inch) long and has an overall thickness between about 1.0 mm and about 4.0 mm. The vent path 1808 preferably has a length of about 1.0 mm to 5.0 mm and a width of about 1.0 mm, and has a thickness approximately equal to the path length between the walls 1802c, 1802d. The vent opening 1810 is approximately the same height and width as the vent path 1808. Of course, other dimensions may be used in other embodiments as long as the benefits of the sample element 1730 are realized.

  Sample element 1730 is preferably sized to receive a material sample S having a volume of about 15 μl or less (or about 10 μl or less, or about 5 μl or less), more preferably a material sample S having a volume of about 2 μl or less. Have. Of course, the volume of the sample element 1730, the volume of the sample chamber 903, etc., depends on the size and sensitivity of the sample detector 1745, the radiant intensity from the energy source 1720, the expected flow characteristics of the sample, and the sample element 1730 is a flow enhancer. It is obvious that the change can be made according to various factors such as whether or not (flow enhancer) is incorporated. The liquid may be carried to the sample chamber 903, preferably by capillary action, but may be carried by wicking action or vacuum action, or a combination of wicking action, capillary action, peristalsis, pump and / or vacuum action. .

  FIG. 20 shows one method for constructing the sample element 1730. In this method, the sample element 1730 includes a first layer 1820, a second layer 1830, and a third layer 1840. The second layer 1830 is preferably located between the first layer 1820 and the third layer 1840. The first layer 1820 forms the upper chamber wall 1802c, and the third layer 1840 forms the lower chamber wall 1802d. If the upper chamber wall 1802c and the lower chamber wall 1802d have windows, the target detector window / wall 1802c / 1802d uses a different material to form the rest of the layer 1820/1840 on which the wall is placed. May be manufactured. Alternatively, the entire layer 1820/1840 may be made of a material selected to form the detector windows / walls 1802c, 1802d. In this case, the detector windows / walls 1802c, 1802d are integrally formed with the layers 1820, 1840 and have regions of the respective layers 1820, 1840 on the sample chamber 903.

  As shown in FIG. 20, the entire second layer 1830 may be composed of an adhesive that joins the first layer 1820 and the third layer 1840. In other embodiments, the second layer 1830 may be composed of the same material as the first layer 1820 and the third layer 1840, or other suitable material. The second layer 1830 may further be formed as a carrier with adhesive on both sides. The second layer 1830 includes voids that at least partially form the sample chamber 903, the sample supply path 1804, the supply opening 1806, the vent path 1808, and the vent opening 1810. The thickness of the second layer 1830 may be the same as any of the path lengths described above as suitable for the sample element 1730. The first and third layers can be formed of any of the materials described above as preferred for forming the detector window of the sample element 1730. In one embodiment, the first layer 1820 and the third layer 1840 are formed from a material that has sufficient structural integrity to maintain its shape when the sample S is filled. The first layer 1820 and the third layer 1840 may be, for example, calcium fluoride having a thickness of 0.5 mm. In another embodiment, the second layer 1830 is manufactured by Adhesive Transfer Tape no. 9471LE adhesive may be included. In other embodiments, the second layer 1830 can be formed by applying pressure and heat to the layers, such as, for example, available from TechFilm (31 Dunham Road, Billerica, MA 01821). Epoxy that bonds layer 1840 may be included.

  Sample chamber 903 preferably includes a no-reactant chamber. In other words, the interior space of the sample chamber 903 and / or the walls 1803 defining the sample chamber 903 are preferably inert to the sample introduced into the chamber for analysis. Here, “inert” has a broad meaning and is used in its ordinary sense, and is not limited to this. However, a sufficient time is required to measure the analyte concentration after the sample is introduced into the sample chamber 903. It means a state in which no reaction occurs with the sample that greatly affects the measurement of the analyte concentration in the sample performed using the sample analyzer 322 or other suitable system for a while (for example, 1 to 30 minutes). Alternatively, the sample chamber 903 may contain one or more reagents to facilitate use of the sample elements in a sample analysis technique that includes reacting a sample with a reagent.

  In one embodiment of the invention, the sample element 1730 is used for a limited number of measurements and is disposable. Thus, as shown in FIGS. 8-10, the sample element 1730 forms a disposable part of the cassette 820 in which the sample chamber 903 can be placed within the probe region 1002.

Sample elements, their method of use and related techniques are further described in US patent application 2005/0038357, published February 17, 2005, entitled “SAMPLE ELEMENT WITH BARRIER MATERIAL”, which forms part of the above-mentioned specification. And US patent application Ser. No. 11 / 122,794, filed May 5, 2005, entitled “SAMPLE ELEMENT WITH SEPARATOR”.

Part IV D-Centrifuge

  FIG. 21 is a schematic diagram of a sample preparation unit 2100 according to an embodiment using a centrifuge. Although it is substantially the same as the sample preparation part 332, a difference is demonstrated in detail below. In general, the sample preparation unit 332 includes a centrifuge instead of the filter such as the filter 1500 or in addition to the filter. The sample preparation unit 2100 includes a centrifuge 2110 including a sample element 2112 and a liquid processing element in front of the liquid boundary 2120. As shown in FIG. 21, the sample element 2112 has a substantially cylindrical configuration. This embodiment is exemplary, and the sample element may be cylindrical, flat, or configured to have a function of holding material (preferably liquid) in the centrifuge 2110. Any shape is possible. The centrifuge 2110 can be used to rotate the sample element 2112 to separate the material held in the sample element 2112.

  In some embodiments, the liquid boundary 2120 selectively controls transport of the sample from the path 113 to the sample element 2112 when performing sample centrifugation. In other embodiments, the liquid boundary 2120 can also prepare the sample element for cleaning liquid through the sample element 2112 or for performing analyte measurements. In this way, the liquid boundary 2120 can be used to flush or fill the sample element 2112.

  As shown in FIG. 21, the centrifuge 2110 includes a sample element 2112 and a rotor 2111 controlled by the control unit 210 having a shaft 2113 equipped with a motor (not shown).

  Furthermore, as shown in FIG. 21, the liquid boundary 2120 includes a liquid injection probe 2121 having a first needle 2122 and a liquid removal probe 2123. The liquid removal probe 2123 has a second needle 2124. When sample element 2112 is positioned in the proper orientation relative to liquid boundary 2120, sample fluid or other liquid is injected into sample element 2112 and flows through. Specifically, the liquid injection probe 2121 has a path for receiving a sample such as a body fluid from the patient joint 110. Body fluid can travel through the liquid injection probe 2121 and the first needle 2122 to the sample element 2112. To remove material from the sample element 2112, the sample element 2112 can be aligned with the second cider 2124 as shown. The substance can travel through the second needle 2124 to the liquid removal probe 2123. The material can then be discharged from the sample element 2112 through the path of the removal probe 2123.

  One possible position when the sample element 2112 rotates is a sample measurement position 2140. The sample measurement position 2140 may coincide with an area of an analysis system such as an optical analyte detection system. The sample measurement position 2140 may coincide with the measurement position of the probe region 1002 or other device, for example.

  The rotor 2111 is driven in the direction indicated by the arrow R so that a centrifugal force is generated in the sample in the sample element 2112. When the sample rotates at a distance from the center of rotation, centrifugal force is generated. In some embodiments, the sample element 2112 holds whole blood. This centrifugal force causes the high concentration portion of the whole blood sample cylindrical container to be more distant from the center of rotation than the light portion of the blood sample. In this way, one or more components of whole blood can be separated from each other. Other liquids or samples can also be removed by centrifugal force. In one embodiment, the sample element 2112 is a disposable container attached to a disposable rotor 2111. Preferably, the container is plastic and is reusable and washable. In other embodiments, the sample element 2112 is a non-disposable container that is permanently attached to the rotor 2111.

  The illustrated rotor 2111 is a substantially circular plate fixed to the shaft 2113. Alternatively, the rotor 2111 may have other shapes. The rotor 2111 is preferably made of a low density material with strength and stability sufficient to keep the rotational inertia low and maintain its shape during operating loads, so that the optical arrangement can be kept close (close optical alignment). I have to. For example, the rotor 2111 may be made of GE brand ULTEM (registered trademark) polyetherimide. This material is stable but is available in plate form that can be easily machined. Furthermore, other substances can be used as long as they have similar characteristics.

  The size of the rotor 2111 can be selected so as to obtain a desired centrifugal force. In some embodiments, the rotor 2111 has a diameter of about 75 mm to about 125 mm, alternatively about 100 mm to about 125 mm. The thickness of the rotor 2111 may preferably be just enough to support centrifugal force, for example from about 1.0 to about 2.0 mm.

  In an alternative embodiment, the liquid boundary 2120 selectively draws plasma from the sample element 2112 after centrifugation. This plasma is sent to an analyte detection system for analysis. In one embodiment, the liquid thus separated is withdrawn from the sample element 2112 via the bottom joint. Preferably, the position and orientation of the bottom joint and the container are such that red blood cells can be extracted first. In one embodiment, it may be configured with a red blood cell detector. The red blood cell detector may detect when most red blood cells have exited the container by measuring the level of hemostasis. The plasma remaining in the container may then be diverted to the analysis chamber. After draining the liquid from the container, the top junction may inject liquid (eg, saline) into the container to re-wash the system and prepare for the next sample.

  FIGS. 22A-23C show another embodiment of a liquid processing and analysis device 140 using a removable, disposable liquid processing cassette 820. Cassette 820 includes a centrifuge rotor assembly 2016 to facilitate sample preparation and analysis. 22A to 22C is substantially the same as the apparatus 140 of the other embodiment already described, and the cassette 820 of the present embodiment is the cassette of the other embodiment already described. Although it is substantially the same as 820, the differences will be described in detail below.

  The removable liquid processing cassette 820 can be detachably engaged with the main analytical instrument section 810. When the liquid processing cassette 820 is coupled to the central instrument section 810, the drive system 2030 of the central instrument section 810 couples with the rotor assembly 2016 of the cassette 820 (FIG. 22B). When the cassette 820 is connected to the central instrument section 810, the drive system 2030 engages with the rotor assembly 2016 to rotate the rotor assembly 2016 and applies a centrifugal force to the body fluid sample carried by the rotor assembly 2016.

  In some embodiments, the rotor assembly 2016 includes a rotor 2020 and a sample element 2448 (FIG. 22C) that holds a sample to be centrifuged. As the rotor 2020 rotates, centrifugal force is applied to the sample in the sample element 2448. Centrifugal force separates one or more components of a sample (eg, separates plasma from whole blood). The components thus separated are analyzed by the device 140. This point will be described in detail below.

  The central instrument unit 810 includes a centrifuge drive system 2030 and a specimen detection system 1700, part of which protrudes from the housing 2049 of the central instrument unit 810. The drive system 2030 is configured to be releasably coupled to the rotor assembly 2016 so as to transmit rotational motion to the rotor assembly 2016 so that the rotor 2020 can be rotated at a desired speed. After the centrifugation step, the analyte detection system 1700 can analyze one or more components separated from the sample carried by the rotor 2020. The protrusion of the illustrated analyte detection system 1700 has a groove 2074 that receives a portion of the rotor 2020 carrying the sample element 2448 so that the analyte detection system 1700 can analyze the sample or component carried on the sample element 2448. Is formed.

  When assembling the liquid processing and analyzing apparatus 140 shown in FIG. 22C, the cassette 820 is arranged in the central instrument section 810 in the direction indicated by the arrow 20007 shown in FIGS. 22A and 22B. When the cassette 820 is properly attached to the central instrument section 810, the rotor assembly 2016 can reach the drive system 2030 such that the drive system 2030 is operatively engaged with the rotor assembly 2016. When drive system 2030 is energized, rotor 2020 rotates at a desired speed. The rotating rotor 2020 can repeatedly pass through the groove 2074 of the detection system 1700.

  After the centrifugation step, the rotor 2020 rotates and is located at an analysis position (see FIGS. 22B and 22C) where the sample element 2448 is disposed in the groove 2074. When the rotor 2020 and the sample element 2448 are in the analysis position, the analyte detection system 1700 can analyze one or more components of the sample carried on the sample element 2448. For example, the detection system 1700 can analyze at least one of the components separated during the centrifugation process. After using the cassette 820, the cassette 820 can be removed from the central instrument section 810 and discarded. Thereafter, another cassette 820 can be attached to the central instrument section 810.

  As shown in FIG. 23A, the illustrated cassette 820 includes a housing 2400 that surrounds the rotor assembly 2016, and the rotor 2020 is rotatably connected to the housing 2400 by the rotor assembly 2016. The rotor 2020 includes a rotor connecting portion 2051 that engages and drives the drive system 2030 when the cassette 820 is attached to the central instrument portion 810.

  In some embodiments, the cassette 820 is a disposable liquid processing cassette. A reusable central instrument section 810 can be used for as many cassettes 820 as desired. Additionally or alternatively, the cassette 820 may be a portable, hand-held cassette for convenient transportation. In these embodiments, the cassette 820 can be manually attached to and detached from the central instrument section 810. In some embodiments, the cassette 820 may be a non-disposable cassette that is permanently attached to the central instrument section 810.

  25A and 25B show a centrifuge rotor 2020 that can carry a sample such as a body fluid. The illustrated centrifuge rotor 2020 can be thought of as a liquid processing element that holds a sample during spectroscopic analysis and can prepare the sample for analysis. The rotor 2020 preferably includes an elongated body 2446, at least one sample element 2448, and at least one bypass element 2452. Sample element 2448 and bypass element 2452 can each be disposed at opposite ends of rotor 2020. The bypass element 2452 provides a fluid bypass path that can clean or flush the fluid path of the liquid processing and analysis device 140 without allowing the sample element 2448 to flow liquid.

  The illustrated rotor body 2446 may be a substantially planar member that defines a mounting opening 2447 that connects to the drive system 2030. The illustrated rotor 2020 has a somewhat rectangular shape. In alternate embodiments, the rotor 2020 may have a generally circular, polygonal, elliptical, or any other desired shape. The shape shown in the figure is easy to correspond to the specimen detection system 1700 when arranged horizontally.

  As shown in FIG. 25B, a pair of the first liquid joint 2027 and the second liquid joint 2029 facing each other extends outward from the front surface of the rotor 2020, and the sample element 2448 and the bypass are passed through the rotor body 2446. It facilitates the flow of liquid toward element 2452 respectively. First liquid junction 2027 defines an exhaust port 2472 and an injection port 2474 that are in fluid communication with sample element 2448. In the illustrated embodiment, the liquid channels 2510, 2512 extend from the discharge port 2472 and the injection port 2474 to the sample element 2448, respectively (see FIGS. 25E and 25F). The discharge port 2472, the injection port 2474, and the liquid flow paths 2510 and 2512 define a flow path that flows into and returns from the sample element 2448 via the rotor 2020.

  As shown in FIG. 25B, the rotor 2020 further includes a bypass element 2452 that allows the flow of liquid from the discharge port 272 to the injection port 2574. A flow path 2570 extends between the discharge port 2572 and the injection port 2574 to facilitate this liquid flow. The flow path 2570 extending in this way defines a closed flow path from the port 2572 through the rotor 2020 to one discharge port 2572 to the other injection port 2574. In the illustrated embodiment, the exhaust port 2572 and the injection port 2574 of the bypass element 2452 are spaced approximately the same as between the exhaust port 2572 and the injection port 2574 on the rotor 2020.

  One or more windows 2460a, 2460b may be provided for optical access through the rotor 2020. The window 2460a adjacent to the bypass element 2452 may be a through hole (FIG. 25E) through which electromagnetic radiation can pass through the rotor 2020. Furthermore, a similar through hole through which electromagnetic radiation can pass may be provided in the window 2460b adjacent to the sample element 2448. Alternatively, one or both of the detector windows 2460a, 2460b may be made of calcium fluoride, barium fluoride, germanium, silicon, polypropylene, polyethylene, or combinations thereof, or appropriate transmission (ie units) at the appropriate wavelength. It may be a sheet formed of a material having permeability per thickness). The detector windows 2460a and 2460b are arranged such that one of the detector windows 2460a and 2460b is positioned in the groove 2074 when the rotor 2020 faces in the vertical direction.

  The rotor 2020 can be manufactured using various manufacturing techniques. In some embodiments, the rotor 2020 can be manufactured by a manufacturing process such as molding (eg, compression molding or injection molding), machining, or a combination of these manufacturing processes, and in some embodiments, the rotor 2020 is made of plastic. The compliance of the plastic material can be selected such that the ends of the pins 2542, 2544 of the liquid interface 2028 can be sealed (this is described in detail below). Non-limiting exemplary plastics that form ports (eg, ports 2572, 2574, 2472, 2474) are chemically relatively inert and can be injection molded or machined. These plastics include, but are not limited to, PEEK or polyphenylene sulfide (PPS). Both of these plastics have high resilience, but the fluid seal can be created by smoothing the sealing surface and reducing the area of the sealing area so that the area under high contact pressure is very small. This seals the material used to form the rotor 2020 and pins 2542, 2544 to achieve the desired interaction between the rotor 2020 and pins 2542, 2544, described in detail below.

  The rotor assembly 2016 shown in FIG. 23A is rotatable to the cassette housing 2400 via a rotor shaft 2430 and a rotor shaft boss 2426 that rotatably holds the rotor 2020 with respect to the cassette housing 2400. Connect to. The rotor shaft 2430 extends outward from the rotor shaft boss 2426 and is preferably fixed to a rotor bracket 2436 that is connected and fixed to the rear surface of the rotor 2020. Thus, the rotor assembly 2016 and the drive system 2030 cooperate to ensure that the rotor 2020 rotates about the axis 2024 even at high speeds. The illustrated cassette 820 has a single rotor assembly 2016. In other embodiments, the cassette 820 can have more than one rotor assembly 2016. Multiple samples may be prepared and tested (preferably simultaneously) using multiple rotor assemblies 2016.

  Again, as shown in FIGS. 25A, 25B, 25E, and 25F, the sample element 2448 is coupled to the rotor 2020 to hold a sample of bodily fluid for processing with a centrifuge. The sample element 2448 is, in certain embodiments, substantially similar to other sample elements or cuvettes disclosed herein (eg, sample elements 1730, 2112), but the differences are described in detail below.

  The sample element 2448 includes a sample chamber 2464 that holds a sample for centrifugation, and liquid channels 2466 and 2468 that are in fluid communication with the channels 2412 and 2510 of the chamber 2464 and the rotor 2020, respectively. Therefore, the liquid flow paths 2512 and 2466 define a first flow path between the port 2474 and the chamber 2464, and the liquid flow paths 2510 and 2468 are a second flow path between the port 2472 and the chamber 2464. Is defined. Depending on the direction of the liquid flowing to the sample element 2448, one of the first flow path and the second flow path becomes a flow path, and the other becomes a return flow path.

  A portion of the sample chamber 2464 is considered an interrogation region 2091 that is the portion of the sample chamber through which electromagnetic radiation passes when the liquid contained in the chamber 2464 is analyzed by the detection system 1700. Accordingly, this interrogation area 2091 is aligned with the detector window 2460b when the sample element 2448 is coupled to the rotor 2020. The interrogation area 2091 shown has a radially inner portion of the chamber 2464 (ie, relatively close to the rotational axis 2024 of the rotor 2020) and, after centrifugation, a low body fluid sample (eg, plasma of a whole blood sample). This makes it easy to perform spectroscopic analysis of the concentration part. This will be described in detail below. When a high-concentration portion of the body fluid sample is the target of spectroscopic analysis, the interrogation region 2091 can be located in a portion radially outside the chamber 2464 (that is, relatively far from the rotation axis 2024 of the rotor 2020).

  The rotor 2020 can hold the sample element 2448 temporarily or permanently. As shown in FIG. 24F, the rotor 2020 has a recess 2502 that receives the sample element 2448. The sample element 2448 can be held in the recess by mutual frictional action, adhesive, or other suitable coupling means. The illustrated sample element 2448 is embedded in the rotor 2020. However, the sample element 2448 may be disposed on the rotor 2020 or may protrude from the rotor 2020.

  The sample element 2448 can be used for a predetermined period of time, such as preparing a predetermined amount of sample fluid or performing multiple analyzes. If necessary, the sample element 2448 can be removed from the rotor 2020 and discarded. Thereafter, another sample element 2448 can be placed in the recess 2502. Thus, even when the cassette 820 is disposable, multiple disposable sample elements 2448 can be used with a single cassette 820. Thus, a single cassette 820 can be used with a desired number of sample elements. Alternatively, the cassette 820 may have a sample element 2448 permanently connected to the rotor 2020. In some embodiments, at least a portion of the sample element 2448 is integral or identical with the rotor body 2446. Additionally or alternatively, the rotor 2020 may have multiple sample elements (eg, with a record sample element instead of the bypass element 2452). In this embodiment, the sample preparation time can be shortened by preparing a plurality of samples (for example, body fluids) simultaneously.

  FIG. 25A and FIG. 25B illustrate a layered construction technique that can be used to form a sample element 2448 of a particular embodiment. The illustrated layered sample element 2448 includes a first layer 2473, a second layer 2475, and a third layer 2478. The second layer 2475 is preferably located between the first layer 2473 and the third layer 2478. The first layer 2473 forms the upper chamber wall 2482 and the third layer 2478 forms the lower chamber wall 2484. The lateral walls of the second layer 2475 define the sides of the chamber 2464 and the fluid flow paths 2466, 2468.

  The second layer 2475 can be formed by stamping a substantially uniform thickness of sheet material into the shape of the lateral wall of FIG. 26A. The second layer 2475 is formed of a layer of a lightweight and flexible substance such as a polymer material. As shown in FIG. 26B, the second layer 2475 is bonded to the opposing side of the first layer 2473 and the third layer 2478 and the adhesive. The structure is sandwiched between them. Alternatively, the second layer 2475 may comprise an “adhesive only” layer formed by stamping a layer of adhesive having a substantially uniform thickness into the illustrated lateral wall shape.

  However, the second layer 2475 thus configured preferably defines a sample chamber 2464 and / or interrogation region 2091 with a uniform thickness and a substantially uniform thickness or path length. The path length (and hence the thickness of the second layer 2475) is preferably between 10 microns and 100 microns, or in various embodiments 20, 40, 50, 60, 80 microns.

  Upper chamber wall 2482, lower chamber wall 2484, and lateral wall 2490 cooperate to form chamber 2464. Upper chamber wall 2482 and / or lower chamber wall 2484 can pass electromagnetic energy. Thereby, the first layer 2473 and the third layer 2478 are relatively transparent to electromagnetic radiation (preferably infrared radiation or mid-infrared radiation) such as calcium fluoride, silicon, polyethylene, polypropylene, or the like. It consists of a sheet or layer of material that is relatively permeable to electromagnetic radiation. If one layer of the first layer 2473 and the third layer 2478 is transmissive, the other layer preferably causes the incident beam of radiation to be identical to the sample element 2448 when the radiation is emitted. It has reflectivity to reflect back so that detection can be performed on the side of the lens. Upper chamber wall 2482 and / or lower chamber wall 2484 can be considered an optical window. These windows are located on one or both sides of the interrogation area 2091 of the sample element 2448.

  In one embodiment, the sample element 2448 is described, for example, in U.S. Patent Application No. 2005/0036146, published February 17, 2005, entitled “SAMPLE ELEMENT QUALIFICATION”. As such, it is transparent to infrared radiation and has opposite sides that are suitable for performing optical measurements. The present invention is, in some embodiments, US patent application 2003/0090649, published May 15, 2003, entitled “REAGENT-LESS WHOLE-BLOOD GLUCOSE METER”, or “DEVICE AND METHOD FOR FOR US patent application 2003/0086075 published on May 8, 2003 entitled "IN VITRO DETERMINATION OF ANALYTE CONCENTRATIONS WITHIN BODY FLUIDS", or "METHOD OF TERMINING ANONA TRAIN TE NON ATR Released on January 29, 2004 One or more implementations described in US Patent Application No. 2004/0019431, or US Patent No. 6,652,136 issued to Marziali on November 25, 2003 entitled "METHOD OF SIMULTANEOUS MIXING OF SAMPLES". However, the differences will be described in detail below. Further, the embodiments, features, systems, devices, materials, methods, and techniques described herein are, in certain embodiments, described in the above-mentioned U.S. patent applications, 2003/0090649, 2003/0086075, It can be applied to or used in combination with one or more of the embodiments, features, systems, devices, materials, methods and techniques disclosed in US 2004/0019431 or US Pat. No. 6,652,136. All of the aforementioned patent publications and patents are hereby incorporated by reference and made a part hereof.

  As shown in FIGS. 23B and 23C, the cassette 820 further includes a movable liquid boundary 2028 for filling the sample element 2448 with sample liquid and / or for removing sample liquid from the sample element 2448. In the illustrated embodiment, the liquid boundary 2028 is rotatably mounted on the housing 2400 of the cassette 820. The liquid boundary 2028 is operable between a low position (FIG. 22C) and a raised or filled position (FIG. 27C). When the liquid boundary 2028 is in the low position, the rotor 2020 can rotate freely. When moving the sample fluid to the sample element 2448, the rotor 2020 is stationary at the sample element mounting position (see FIG. 22C) and the liquid boundary 2028 can be actuated to the upper filling position as shown by arrow 2590. Yes. When the liquid boundary 2028 is in the fill position, the liquid boundary 2028 can send sample fluid to the sample element 2448 and / or drain the sample fluid from the sample element 2448.

  Further, as shown in FIGS. 27A and 27B, the liquid boundary portion 2028 has a main body portion 2580 that is rotatably attached to the housing 2400 of the cassette 820. Using the opposing brackets 2581 and 2584, the main body 2580 is rotatably mounted on the housing 2400 of the cassette 820, and the main body 2580 and the pins 2542 and 2544 are rotated between the low position and the filling position around the rotation shaft 2590. Can be moved. Central instrument portion 810 may include an actuator (not shown) such as a solenoid or pneumatic actuator that is horizontally movable and deployable from an opening 2404 (see FIG. 23B) of cassette housing 2400. During deployment, the actuator hits the main body 2580 of the liquid boundary 2028 and rotates the main body 2580 to the filling position shown in FIG. 27C. The body 2580 is preferably biased by a spring in the direction of the retracted position (see FIG. 23A) so that when the actuator is retracted, the body is returned to the retracted position. This allows the liquid interface 2028 to operate such that periodically the fluid path of the pins 2542, 2544 is in fluid communication with the sample element 2448 located in the rotor 2020.

  The liquid interface 2028 shown in FIGS. 27A and 23B includes liquid junctions 2530 and 2532 that can fluidly communicate the liquid interface 2028 and one or more of the apparatus 140 and / or collection system 100/800. This point will be described in more detail below. The illustrated joining portions 2530 and 2532 are positioned so as to extend upward from the opposing end portions of the main body portion 2580, respectively. The liquid junctions 2530 and 2532 can be disposed in other directions and / or positions along the main body 2580. The main body 2580 has a first internal path (not shown) that communicates between the joint 2530 and the pin 2542, and a second internal path (not shown) that communicates between the joint 2532 and the pin 2544. Not).

  The liquid pins 2542, 2544 can extend outward from the body 2580 and engage the rotor to deliver sample fluid to and / or out of the rotor 2020. The liquid pins 2542 and 2544 have pin bodies 2561 and 2563 and pin end portions 2571 and 2573, respectively. Pin ends 2571, 2573 have dimensions that fit within corresponding ports 2472, 2474 of liquid joint 2027 and / or ports 2572, 2574 of liquid joint 2029 of rotor 2020. The pin ends 2571, 2573 can be slightly chamfered at their respective tips to enhance the seal between the pin ends 2571, 2573 and the rotor port. In some embodiments, the outer diameter of the pin ends 2573, 2571 is slightly larger than the inner diameter of the rotor 2020 port to ensure sealing, and the inner diameter of the pins 2542, 2544 is preferably In other embodiments, the outer diameters of the pin ends 2571 and 2573 are set to be equal to or smaller than the inner diameter of the port of the rotor 2020.

  The connection between the pins 2542, 2544 and corresponding portions of the rotor 2020, such as the discharge port 2472 or injection port 2474 leading to the sample element 2448, or the ports 2572, 2574 following the bypass element 2452 is relatively simple, Can be cheap. At least a portion of the rotor 2020 may be configured to assist in ensuring that the pins 2542, 2544 are sealed. Alternatively or additionally, a seal member (eg, gasket, O-ring, etc.) may be used to prevent leakage between the pin ends 2571, 2573 and the corresponding ports 2472, 2474, 2574.

  23A and 23B show a cassette housing 2400 that surrounds the rotor assembly 2016 and the liquid boundary 2028. The housing 2400 is modular and defines an opening or opening 2404 that receives the drive system housing 2050 when the cassette 820 is operably coupled to the central instrument portion 810. The housing 2400 protects the rotor 2020 from external forces and can limit contamination due to sample flowing into the sample elements in the rotor 2020 when the cassette 820 is attached to the central instrument section 810.

  The illustrated cassette 820 includes notches 2408 that are compatible with opposing sets of side walls 2041, 2043, an upper portion 2053, and a detection system 1700. A front wall 2045 and a rear wall 2047 extend between the side walls 2041 and 2043. The rotor assembly 2016 is attached to the inner surface of the rear wall 2047. The front wall 2045 is coupled to the central instrument section 810 and further allows the drive system 2030 to be attached to the rotor assembly 2016.

  The illustrated front wall 2045 has an opening 2404 for mounting the rotor assembly 2016. The drive system 2030 can penetrate through the opening 2404 into the interior of the cassette 820 until it is operatively engaged with the rotor assembly 2016. The opening 2404 in FIG. 23B is configured to couple and securely surround the drive system 2030. The illustrated opening 2404 is substantially circular and has an upper notch 2405 that allows the liquid boundary actuator of the central instrument portion 810 to operate on the liquid boundary 2028 as described above. The opening 2404 may have other configurations that are suitable for introducing the drive system 2030 and the actuator into the cassette 820.

  The notch 2408 of the housing 2400 can at least partially surround the protrusion of the analyte detection system 1700 when the cassette 820 is loaded into the central instrument portion 810. The notch 2408 shown defines a cassette groove 2410 (FIG. 23A) that is loaded with the cassette 820 and is aligned with the elongated groove 2074 shown in FIG. 22C. For this reason, the rotating rotor 2020 can pass through the grooves 2410 and 2074 arranged in a straight line. In some embodiments, the notch 2408 is substantially U-shaped in axial cross section, as shown. More generally, the configuration of the notch 2408 can be selected depending on the design of the protrusion of the detection system 1700.

  Although not shown, fasteners, clips, mechanical clamps, stops, or other coupling means can be used to ensure that the cassette 820 remains connected to the central instrument 810 during operation. Alternatively, the cassette 820 can be secured to the central instrument portion 810 by interaction between the housing 2400 and the components of the central instrument portion 810.

  FIG. 28 is a cross-sectional view of the central instrument section 810. The illustrated centrifuge drive system 2030 extends outwardly from the front surface 2046 of the central instrument section 810 so that it can be easily coupled to the rotor assembly 2016 of the cassette 820. When the centrifuge drive system 2030 is activated, the drive system 2030 can rotate the rotor 2020 at a desired rotational speed.

  The centrifuge drive system 2030 shown in FIG. 23E and FIG. 28 includes a centrifuge drive motor 2038 and a drive spindle 2034 that is connected so as to be drivable by the drive motor 2038. The drive spindle 2034 extends outward from the drive motor 2038 and forms a centrifuge boundary 2042. The centrifuge boundary 2042 extends outwardly from the drive system housing 2050 that houses the drive motor 2038. To provide rotational motion to the rotor 2020, the centrifuge boundary 2042 engages the key member, protrusion, notch, detent, recess, pin, or rotor 2020 to connect the drive spindle 2034 and the rotor 2020. Other structures can be included.

  The centrifuge drive motor 2038 of FIG. 28 may be any motor that is suitable for imparting rotational motion to the rotor 2020. When the drive motor 2038 is activated, the drive motor 2038 can rotate the drive spindle 2034 at a constant or variable speed. Although not limited thereto, various types of motors such as a centrifuge motor, a step motor, a spindle motor, an electric motor, and other motors that output torque can be used. The centrifuge drive motor 2038 preferably drives the drive system housing 2050 of the central instrument section 810.

  The drive motor 2038 may be a motor of the type normally used in personal computer hard drives capable of rotating at about 7,200 rpm with a precision bearing, such as the motor of Seagate Model ST38OO11A hard drive (Seagate Technology, Scotts Valley, Calif.). In one embodiment, the drive spindle 2034 may rotate at 6,000 rpm, yielding about 2,000 G for a 2.5 inch (64 mm) radius rotor. In other embodiments, the drive spindle 2034 may rotate at a speed of about 7,200 rpm. The rotational speed of the drive spindle 2034 can be selected to achieve the desired centrifugal force applied to the sample carried by the rotor 2020.

  Central instrument section 810 includes a main housing 2049 sized to house a filter wheel assembly 2300 including a filter drive motor 2320 and a filter wheel 2310 of analyte detection system 1700. The main housing 2049 defines a detection system opening 3001 that is configured to receive the analyte detection system housing 2070. The illustrated specimen detection system housing 2070 extends or projects outward from the housing 2049.

  The central instrument unit 810 of FIGS. 23C and 23E includes a bubble sensor unit 321, a pump 2619 constituted by a peristaltic pump roller 2620a, a roller support unit 2620b, and valves 323a and 323b. The illustrated valves 323a and 323b are a pair of pincers, but other types of valves can be used. When the cassette 820 is installed, these parts can engage the parts of the liquid processing network 2600 of the cassette 820. This will be described in detail below.

  As shown in FIG. 28, the specimen detection system housing 2070 surrounds and houses some of the internal components of the specimen detection system 1700. The elongated groove 2074 extends downward from the upper surface 2072 of the housing 2070. The elongated groove 2074 is sized and dimensioned to receive a portion of the rotor 2020. As the rotor 2020 rotates, the rotor 2020 periodically passes through the elongated groove 2074. When the sample element of the rotor 2020 is in the detection region 2080 defined by the groove 2074, the analyte detection system 1700 can analyze the substance in the sample element.

  The analyte detection system 1700 may preferably be a spectroscopic fluid analyzer with an energy source 1720. The energy source 1720 can generate an energy beam that is directed along the main optical axis X toward the sample detector 1745 via the groove 2074. Thus, the groove 2074 can position at least a portion of the rotor (eg, the interrogation region 2091 of the sample element 2448 or the sample chamber 2464) on the optical axis X. When analyzing a sample carried by the sample element 2448, the sample element and the sample are detected on the optical axis X so that light emitted from the light source 1720 passes through the groove 2074 and the sample disposed in the sample element 2448. 2080.

  The liquid detection system 1700 can include one or more lenses positioned to transmit energy emitted from the energy source 1720. An analyte detection system 1700 shown in FIG. 28 includes a first lens 2084 and a second lens 2086. The first lens 2084 is configured to match the energy from the light source 1720 to approximately the sample element and material sample. The second lens 2086 is located between the sample element and the sample detector 1745. The energy from the energy source 1720 can pass through the second lens 2086 after passing through the sample element. The third lens 2090 is preferably disposed between the beam splitter 2093 and the reference detector 2094. Reference detector 2094 is arranged to receive energy from beam splitter 2093.

  Using the sample detection system 1700, the sample concentration of the sample carried by the rotor 2020 can be measured. Other types of detection or analysis systems can be used with the illustrated centrifuge device or sample preparation section. Although the liquid processing and analyzing apparatus 140 is used together with the sample detection system 1700 as an example, the sample preparation unit and the sample detection system are not limited to the illustrated configuration, or are not limited to those used together.

  When assembling the liquid processing and analysis device 140, the cassette 820 can be moved and attached in the direction of the central instrument portion 810, as shown by the arrow 2007 in FIG. 22A. When the cassette 820 is installed, the drive system 2030 passes through the opening 2040 and the spindle 2034 is coupled to the rotor 2020. At the same time, the notch 2408 of the cassette 820 receives the protrusion of the detection system 1700. When the cassette 820 is attached to the central instrument 810, the groove 2410 of the notch 2048 and the groove 2074 of the detection system 1700 are aligned in a straight line as shown in FIG. 22C. When the cassette 820 and the central instrument 810 are assembled in this manner, the rotor 2020 can rotate about the shaft 2024 and pass through the grooves 2410 and 2074.

  After the cassette 820 is assembled to the central instrument section 810, the sample can be added to the sample element 2448. The cassette 820 can be connected to the infusate source and the patient and in fluid communication with the bodily fluid to analyze the system. When cassette 820 is connected to the patient, bodily fluids can be withdrawn from the patient into cassette 820. The rotor 2020 rotates, resulting in a vertical mounting position in which the sample element 2448 is located near the liquid boundary 2028 and the bypass element 2452 is located in the groove 2074 of the detection system 1700. When the rotor 2020 is in the vertical mounting position, the pins 2542 and 2544 of the liquid boundary portion 2028 are positioned so as to be connected to the discharge port 2472 and the injection port 2474 of the rotor 2020. Next, the liquid boundary 2028 rotates upward until the ends 2571, 2573 of the pins 2542, 2544 are inserted into the discharge port 2472 and the injection port 2474.

  Thus, when the liquid boundary 2028 and the sample element 2448 are engaged, the sample fluid (eg, whole blood) is pumped to the sample element 2448. The sample flows via pins 2544 to the rotor channel 2512 and the sample element channel 2466 and to the sample chamber 2464. As shown in FIG. 25C, the sample chamber 2464 can be partially or fully filled with the sample fluid. In some embodiments, the sample fills at least the sample chamber 2464 and the interrogation area 2091 of the sample element 2448. The sample may also fill a portion of the sample element channels 2466, 2468, if desired. The illustrated sample chamber 2464 is filled with whole blood, but the sample chamber 2464 may be filled with other materials. When the sample element 2448 is filled with the desired amount of liquid, the liquid boundary 2028 moves to a low position, allowing the rotor 2020 to rotate.

  The centrifuge drive system 2030 rotates the sample element 2448 associated with the rotor 2020 as necessary to separate one or more components of the sample. The separated sample components may be collected or separated into a portion of the sample element for analysis. In the illustrated embodiment, the sample element 2448 of FIG. 25C is filled with whole blood prior to centrifugation. Centrifugal force can be applied to whole blood until plasma 2594 is separated from blood cells 2592. After centrifugation, plasma 2594 is preferably located in the radially inner portion of sample element 2448, including interrogation region 2091. Blood cells 2592 collect radially outside the plasma 2594 and interrogation region 2091 that are part of the sample chamber 2464.

  Next, the rotor 2020 can move to a vertical analysis position where the sample element 2448 is positioned in the groove 2074 and aligned with the light source 1720 and the sample detector 1745 on the main optical axis X. When the rotor 2020 is located at the analysis position, the interrogation area 2091 is preferably aligned on the main optical axis X of the detection system 1700. The analyte detection system 1700 can analyze the sample in the sample element 2448 using spectroscopic techniques as previously described.

  After analysis of the sample, the sample can be removed from the sample element 2448. The sample may be carried to a waste container and the sample element 2448 can be reused for subsequent sample extraction and analysis. The rotor 2020 rotates and returns from the analysis position to the vertical mounting position. When the sample element 2448 is emptied, the liquid boundary 2028 is again engaged with the sample element 2448 and a new liquid (a new bodily fluid sample or infusate) flows through the sample element 2448. The liquid boundary 2028 rotates and the pins 2542 and 2544 are connected to the discharge port 2472 and the injection port 2474 of the rotor 2020. Liquid interface 2028 pumps liquid from one of pins 2542, 2544 until the sample flows out of sample element 2448. Various types of fluids such as infusate, air, water, etc. can be used to flush the sample element 2448. After flowing fluid through the sample element 2448, the sample element 2448 can again be filled with another sample.

  In an alternative embodiment, the sample element 2448 may be removed from the rotor 2020 and replaced after every analysis or after a predetermined number of analyses. When the patient's treatment is complete, the fluid pathway or conduit may be removed from the patient and the sample cassette 820 in fluid contact with the patient's body fluid may be discarded or sterilized for reuse. However, the central instrument section 810 is not in contact with the patient's bodily fluid at any time during the analysis, so it can easily be connected to a new liquid treatment cassette 820 and used for the next patient analysis.

  The rotor 2020 may be used to generate a liquid flow bypass. To facilitate bypass flow, the rotor 2020 is first rotated to a vertical analysis / bypass position where the bypass element 2452 is located near the liquid boundary 2028 and the sample element 2448 is located in the groove 2074 of the analyte detection system 1700. To do. When the rotor 2020 is in the vertical analysis / bypass position, the pins 2542, 2544 can be coupled to the ports 2572, 2574 of the rotor 2020. In the illustrated embodiment, the liquid boundary 2028 rotates upward until the ends 2571, 2573 of the pins 2542, 2544 are inserted into the ports 2572, 2574. Bypass element 2452 can be a closed fluid circuit that allows liquid to flow through one of pins 2542, 2544 to bypass element 2452, through bypass element 2452, and then to pins 2542, 2544. In this way, the bypass element 2452 can be utilized to facilitate cleaning or disinfection of the liquid system connected to the cassette 820.

  As shown in FIG. 23B, cassette 820 preferably includes a liquid processing network 2600 that can be used to deliver liquid to sample element 2448 of rotor 2020 for analysis. The central instrument portion 810 extends through an opening in the front surface 2045 of the cassette 820 and is engageable with parts of the liquid network 2600 when the cassette 820 is attached to the central instrument portion 810, as described below. A plurality of parts are provided.

  The liquid processing network 2600 of the liquid processing and analysis device 140 includes a path 111 that extends from the junction 120 in the direction of the cassette 820. Path 111 becomes path 112 that extends to patient junction 110 via cassette 820. A portion 111 a of the path 111 extends through the opening 2613 of the front surface 2045 of the cassette 820. When the cassette 820 is attached to the central instrument section 810, the roller pump 2619 engages with the portion 111a and is positioned between the impeller 2620a and the impeller support section 2620b (see FIG. 23C).

  The liquid treatment network 2600 further includes a path 113 that extends from the patient junction 110 into the cassette 820. After cassette 820 is attached to central instrument section 810 and cassette 820 is inserted, path 113 extends through opening 2615 in front surface 2045 and path 113 engages bubble sensor 321 in central instrument section 810. become able to. The path 113 goes to the junction 2532 of the liquid boundary 2028 where the path 113 extends to the pin 2544. The liquid withdrawn from the patient flows through the liquid boundary 2028 via the path 113 and reaches the pin 2544. The withdrawn bodily fluid can further flow from the pin 2544 to the sample element 2448 as described in detail below.

  Pathway 2609 extends from junction 2530 at liquid boundary 2028 and is in fluid communication with pin 2542. The path 2609 branches into a waste pipe 324 and a pump pipe 327. Waste tube 324 extends to waste container 325 through opening 2617 in front surface 2045. Pump tube 327 extends to pump 328 through opening 2619 in front surface 2045. When the cassette 820 is attached to the central instrument section 810, the pinch valves 323a, 323b engage the paths 324, 327 through the openings 2617, 2619, respectively.

  A waste container 325 is attached to the front face 2045. Waste liquid passing from the liquid boundary 2028 can flow into the waste container 325 via paths 2609 and 324. When the waste container 325 is full, the cassette 820 can be removed from the central instrument section 810 and discarded. Alternatively, the filled waste container 325 may be replaced with an empty waste container 325.

  The pump 328 may be a variable pump (for example, a syringe pump). When the cassette 820 is attached to the central instrument unit 810, the piston control unit 2645 extends from at least a part of the opening 2621 of the cassette surface 2045 and can be engaged with the actuator 2652. When the cassette 820 is attached, the actuator 2652 (FIG. 23E) of the central instrument unit 810 engages with the piston control unit 2645 of the pump 328, and the piston control unit 2645 can be displaced by a desired flow rate.

  Note that when the cassette 820 of FIG. 23A is attached to the central instrument portion 810 of FIG. 23E, a fluid circuit similar to that shown in the collection portion 200 (FIG. 23E) of FIG. 3 is formed. This fluid circuit can operate in a manner similar to that described using the apparatus of FIG. 3 (eg, the methods shown in FIGS. 7A-7J and Table 1).

  FIG. 24A is a diagram illustrating another embodiment of a liquid processing network 2700 that can utilize a cassette 820. The liquid processing network 2700 may have substantially the same configuration and function as the network 2600 of FIG. 23B, but the differences will be described in detail below. The network 2700 includes a path 111 that extends from the junction 120 to the cassette 820, and the path 111 becomes a path 112 that extends from the cassette 820 to the patient junction 110. A portion 111 a of the path 111 extends through an opening 2713 in the front surface 2745 of the cassette 820. When cassette 820 is attached to central instrument section 810, roller pump 2619 of central instrument section 810 of FIG. 24B engages portion 111a in a manner similar to that described with reference to FIGS. 23B-23C. Path 113 extends from patient junction 110 into cassette 820. After the cassette 820 is inserted, the path 113 extends through the opening 2773 in the front surface 2745 and can engage the valve 2733 in the central instrument section 810. The waste pipe 2704 extends from the path 113 to the waste container 325 and passes through the opening 2641 of the front surface 2045. The path 113 goes to the junction 2532 of the liquid boundary 2028 where the path 113 extends to the pin 2544. The path 113 extends beyond the opening 2743 of the front surface 2045 so that the path 113 can engage the bubble sensor 2741 of the central instrument section 810 of FIG. 24B. When the cassette 820 is attached to the central instrument section 810, the pinch valves 2732 and 2733 engage the paths 113 and 2704 through the openings 2731 and 2743, respectively.

  The illustrated liquid treatment network 2700 also includes a path 2723 that extends between path 111 and path 2727. Path 2727 extends between path 2723 and liquid boundary 2028. Path 2727 extends through opening 2733 in front surface 2745. Pump tube 2139 extends from pump 328 to paths 2723 and 2727. When cassette 820 is attached to central instrument portion 810, pinch valves 2716, 2718 extend through openings 2725, 2733 in front surface 2745 and engage pathways 2723, 2727, respectively.

  Note that when cassette 820 is attached to central instrument section 810 (as shown in FIG. 24A), a fluid circuit is formed that is operable in a manner similar to that described with reference to the apparatus of FIGS. I want to be.

As is clear from the above description, the liquid processing and analysis device 140 of various embodiments shown in FIGS. 22A to 28 (having the central instrument unit 810 and the cassette 820) is the sampling system shown in FIGS. Obviously, any 100/300/500 liquid processing and analysis device 140 or liquid processing system 10 can function. Further, the liquid processing and analysis device 140 shown in FIGS. 22A-28 may be similar to the liquid processing and analysis device 140 shown in FIG. 1, FIG. 2, or FIG. 8-10 in certain embodiments. The difference will be described in detail below.

Part V—Method of measuring analyte concentration from sample spectrum.

  In this chapter, it is used to calculate the concentration of the target sample (including a plurality of cases) in the sample S and / or to calculate other measurement values that can be used to assist the calculation of the sample concentration. A calculation method or algorithm that can be used will be described. Any one or a combination of the algorithms disclosed in this section is stored as program instructions in the executable memory 212 and accessed by the liquid processing and analysis device 140 or the processor 210 of the analyte detection system 334 and stored in the sample S. The concentration of the target specimen (including a plurality of cases) can be calculated, or other measurement values can be calculated.

  Embodiments disclosed herein are apparatus and methods for analyzing measured values of a material sample and quantifying one or more analytes in the presence of an interfering substance. If the presence of the interfering substance affects the quantification of the analyte, the interfering substance may include a component of the material sample that is the subject for the analyte analysis. For this reason, for example, in the spectroscopic analysis of a sample whose analyte concentration is to be measured, the interfering substance may be a compound having a spectral characteristic that overlaps with the spectral characteristic of the specimen. The presence of such interfering substances can cause errors in the quantification of the specimen. Specifically, the presence of interfering substances is particularly sensitive when the system is calibrated in the absence of interfering substances or when the amount of interfering substances is unknown. Can be affected.

  As described above, independent of or in combination with the contribution of the interfering substance, the interfering substance can be endogenous (ie, originating from within the body) and extrinsic (derived from outside the body or made outside the body). Can be classified. As an example of these types of interfering substances, consider the analysis of a blood sample (or blood component sample or plasma sample) for analyte glucose. Endogenous interfering substances are blood components from the body that affect the quantification of glucose and may include water, hemoglobin, blood cells, and other components that occur naturally in the blood. An exogenous interfering substance is a blood component derived from outside the body that affects the quantification of glucose, and is administered to the human body by oral administration, intravenous administration, local administration, etc., such as pharmaceuticals, drugs, foods, and herbs. Can be included.

  As described above, independent of or in combination with the contribution of the interfering substance, the interfering substance may contain components that may be present in the sample type to be analyzed but are not required for the analysis. As an example when analyzing a blood or plasma sample drawn from a patient undergoing drug treatment, a drug such as acetaminophen may be present, but this sample type is not essential. In contrast, water is essential for samples such as blood or plasma.

  In order to facilitate understanding of the present invention, an embodiment is described here in which one or more analyte concentrations are obtained by spectroscopic measurement of a sample at a wavelength that includes one or more wavelengths that identify the analyte. Although the embodiments disclosed herein generally describe spectroscopic measurements, they are not intended to limit the scope of the invention except in the claims.

  As an example, a case will be described in which the concentration of a specific compound (analyte) in a mixture containing a compound (interfering substance) that affects the measurement is quantitatively determined from the measured value using the specific method disclosed herein. . In certain embodiments, each analyte and interfering substance component has important properties in the measurement, and the measured value is affine (ie, includes linear components and offsets) for each analyte and interfering substance concentration. It is particularly effective in some cases. In one embodiment, the method includes a calibration step that includes an algorithm that determines a set of coefficients and an offset value that allow quantification of the analyte. In another embodiment, there is a method to modify the HLA (mixed linear algorithm) to accommodate a group of random interferents while maintaining high sensitivity to the desired component. The data used to deal with a group of random interfering substances includes: (a) a signature for each family member of components that may be added, and if present, (b) for each additional component The usual quantitative level of

  The particular method disclosed herein relates to determining analyte concentration in a material sample where an interfering substance may be present. Certain embodiments may be performed by processor 210 of system 334 using any one or a combination of methods disclosed herein. The processor 210 can be connected to a computer network to send data obtained from the system 334 via the network to one or more individual computers that implement the method. The methods disclosed herein can also include manipulation of data relating to sample measurements and other information provided to the method, including but not limited to interferant spectra, sample population models, and thresholds. Some or all of this information and individual algorithms may be updated or changed to improve the method, or other information such as additional analytes or interfering substances may be added.

  The disclosed method generates a “calibration constant”. The calibration constant is multiplied by the measured value to obtain the measured value of the analyte concentration. The calibration constant and the measured value can each include a number sequence. The calibration constants are calculated to minimize or eliminate the effect on calibration on the presence of interfering substances that may be present and identified in the sample. The particular method described here 1) identifies the presence of potential interfering substances, and 2) uses information about the identified interfering substances to generate calibration constants. These particular methods do not require that the information about the interfering substance include an estimate of the concentration of the interfering substance, but merely identify the interfering substance as likely present. In one embodiment, the method uses a set of training spectra, each corresponding to a known analyte concentration, to obtain a calibration factor that minimizes variations in analyte concentration measurements that contain interfering substance concentrations. The calibration constant thus obtained is proportional to the analyte concentration and, on average, does not react to the concentration of interfering substances.

  In one embodiment, the training spectrum need not include (but is not forbidden) a separate spectrum that measures analyte concentration. That is, “training”, when used in connection with the method disclosed herein, does not require training using individual measurements to estimate analyte concentration (eg, analysis of body fluid samples drawn from individual patients). .

  Here, the estimation process will be described using some terms. A “sample population” is broad, but not limited to, a large number of samples having measurements used to calculate a calibration value, in other words, training a method for generating a calibration value. In embodiments relating to spectroscopic measurement of glucose concentration, the sample population measurements may include a spectrum (spectroscopic measurement) and a glucose concentration (analyte measurement), respectively. In one embodiment, sample population measurements are stored in a database called a “population database”.

  The sample population may or may not be derived from measurements of material samples that contain interfering substances with respect to measurements of the analyte of interest (including multiple cases). The various interfering substances can be separated based on whether the interfering substances are present in both the sample population and the sample to be measured or only in the sample. Here, the “type A interfering substance” means an interfering substance present in both the sample population and the material sample for measuring the analyte concentration. In certain methods, the type A interferent is endogenous because the sample population contains only endogenous interferents and no exogenous interferents. The number of type A interfering substances varies depending on the measurement and the target analyte, and may generally be from zero to a very large number. The material sample to be measured, for example sample S, may contain interfering substances that are not present in the sample population. Here, “type B interfering substances” are 1) not found in the sample population, but found in the material sample to be measured (eg, exogenous interfering substances), or 2) found naturally in the sample population. However, it refers to any interfering substance that is found in material samples at very high concentrations (eg, endogenous interfering substances). An example of a type B exogenous interfering substance is a drug, and an example of a type A endogenous interfering substance is urea of a patient suffering from renal failure. In an example in which glucose in blood is subjected to mid-infrared spectrophotometry, water is present in all blood samples, and thus is a type A interference substance. In a sample population consisting of individual humans who are not receiving intravenous medication and a material sample taken from a hospital patient who is selectively receiving intravenous medication, the selectively administered drug is the type B interferant.

  In one embodiment, the list of one or more possible Type B interferers is referred to as an “interferer library” and each interferer in the library is referred to as a “library interferer”. The library interfering substance includes, for example, an exogenous interfering substance and an endogenous interfering substance that may be present in the material sample because the concentration of the endogenous interfering substance increases as the condition becomes abnormal depending on the medical condition.

  In addition to the components naturally present in the blood, the concentration of exogenous interfering substances can rapidly change and become very high due to ingestion or injection of drugs or illegal drugs. This is a problem when measuring specimens in the blood of patients in hospitals or emergency rooms. An example in which the blood component and the spectrum of the drug are superimposed is shown in FIG. FIG. 29 shows pure glucose and four spectral interferences, specifically mannitol (chemical formula: hexane-1,2,3,4,5,6-hexaol), N-acetyl L-cysteine, dextran, and procainamide. It shows the relationship between the absorption coefficient and the optical path length when the concentration of (chemical formula: 4-amino-N- (2-diethylaminoethyl) benzamide) is the same. FIG. 30 shows the change in the absorption spectrum of the blood component of the sample population in logarithm as a function of the wavelength of blood, where blood is the component, glucose is specifically twice the glucose concentration of the sample population, mannitol. , N acetyl L cysteine, dextran and procainamide are believed to contain various amounts. It can be seen that these components affect the absorbance over a wide range of wavelengths. When measuring the concentration of one species, it can be understood that there is a problem in the measured value unless the concentration of another species is known in advance or measured separately.

  One method for estimating the analyte concentration in the presence of an interfering substance will be described with reference to the flowchart 3100 of FIG. In the first step (block 3110), a measurement of the sample is obtained. In a second step (block 3120), the obtained measurement data is analyzed to identify possible interfering substances for the specimen. In a third step (block 3130), a model is generated that predicts the analyte concentration in the presence of the identified possible interferent. In the fourth step (block 3140), the analyte concentration in the sample is estimated from the measured value using this model. Preferably, the step of block 3130 should minimize the error of the presence of interfering substances when there are no identified interfering substances in the general population to which the sample belongs.

  The method blocks 3110, 3120, 3130, 3140 may be repeated for each analyte for which concentration is to be determined. If one measurement is sensitive to one or more analytes, blocks 3120, 3130, 3140 may be repeated for each analyte. If each specimen has a separate measurement, blocks 3110, 3120, 3130, 3140 may be repeated for each specimen.

A flowchart 3100 of a method of an embodiment for determining the concentration of an analyte from a spectroscopic measurement value will be described below. Furthermore, although this Embodiment estimates the quantity of the glucose concentration in the blood sample S, it does not limit the scope of the present invention disclosed here. In one embodiment, the measured value of block 3100 is the absorption spectrum, C _s (λ _i ) of the measurement sample S, and typically includes one analyte of interest, glucose, and one or more interfering substances. In one embodiment, the method includes generating a calibration constant κ (λ _i ) that, when multiplied by the absorption spectrum C _s (λ _i ), results in an estimate g _est of the glucose concentration g _s .

  As described below, block 3120 of one embodiment includes statistically comparing the absorption spectrum of sample S with the combination of the spectrum of the sample population and the spectrum of the individual library interfering substances. After the analysis of block 3120, depending on the analysis result of block 3120, the library interfering substance is not present in the list of library interfering substances identified as possibly contained in the sample S, or Include the presence of one or more library interferents. At block 3130, multiple spectra are generated using the multiple spectra of the sample population, each known analyte concentration, and the known spectra of the identified library interferents. At block 3130, the spectrum thus generated is used to generate a calibration constant matrix to convert the measured spectrum to an analyte concentration that is at least responsive to the presence of the identified library interferent. At block 3140, the generated calibration constant is applied to predict the glucose concentration in sample S.

At block 3110, a sample measurement is obtained. For illustration, the measured value C _s (λ _i ) is a plurality of measured values obtained by measuring the sample S at various wavelengths, or a measured value obtained by analyzing the measured values. It shall indicate strength. Obviously, the spectroscopic measurements and calculations may be performed in one or more domains including, but not limited to, transmission, absorption, and / or optical density domains. The measured value C _s (λ _i ) is the absorbance, transmittance, optical density, or other spectroscopic measurement value of the sample at the selected wavelength or wavelength band. Such a measurement value may be acquired using the specimen detection system 334, for example. In general, sample S contains a Type A interfering substance, preferably at a concentration within the range present in the sample population.

  In one embodiment, the absorbance measurement is converted to a path length normalized measurement. For example, the absorbance is converted to an optical density by dividing the absorbance by the optical path length L at which the measurement is made. In one embodiment, the path length L is measured from one or more absorbance measurements for a known compound. In one embodiment, the sample S in water or a salt solution of known concentration is permeated to determine one or more absorbance measurements, and the path length L is calculated from the absorbance measurements thus obtained. In another embodiment, an absorbance measurement is obtained even for a portion of the spectrum that is less affected by the analyte and the interfering substance, and the analyte measurement is interpolated with the absorbance measurements at these wavelengths.

  Some methods are “insensitive to path length” and can be used without knowing the exact path length in advance. The sample can be placed in a sample chamber 903 or 2464, a sample element 1730 or 2448, a cuvette, or other sample container. Electromagnetic radiation emitted from the radiation source (eg, mid-infrared range) can travel through the sample chamber. The detector can be placed where the radiation passes or, for example, on the opposite side of the radiation source to the sample chamber. The distance that the radiation passes through the sample can be referred to as the “path length”. In some embodiments, the radiation detector can be placed on the same side of the sample chamber as the radiation source, such that the radiation reflects off one or more inner walls of the sample chamber and reaches the detector.

  As already explained, the sample chamber can be filled with various substances. In addition to a sample (including a plurality of cases) containing a specimen (including a plurality of cases), a reference liquid such as water or a saline solution can be filled, for example. In some embodiments, a saline reference liquid is filled into the sample chamber and radiation is injected into the reference liquid. The detector measures the amount and / or nature of radiation that has passed through the sample chamber and the reference liquid without being absorbed or reflected. By measuring with a reference liquid, information about the path length along which the radiation travels is obtained. For example, there may be data obtained from measurements previously made in similar environments. That is, radiation can be transmitted through sample chambers having various known path lengths to establish reference data that can be created, for example, in a “look-up table”. By filling the sample chamber with a reference liquid, a one-to-one relationship between various detector readings and various path lengths can be clarified experimentally. This relationship can be recorded in a lookup table and stored, for example, in a computer database or electronic memory.

One method of measuring the radiation path length can be performed using a thin empty sample chamber. In particular, this method can measure the thickness of a narrow sample chamber or cell with two reflecting walls. (Because the chamber is filled with the sample, this thickness is the “path length” for the radiation to travel through the sample.) A range of wavelengths of radiation can be continuously transmitted through the cell or sample chamber. As radiation enters the cell, it reflects off the inner walls of the cell and can be reflected one to several times between these walls before exiting the cell and entering the radiation detector. This creates intermittent interference fringes, or “fringes”, that are repeatedly formed at the maximum and minimum. This intermittent pattern can be graphed with the horizontal axis representing the wavelength range and the vertical axis representing, for example, the percentage range of the measured transmission relative to the total transmission. The maximum occurs when the distance traveled by the radiation reflected by the two internal surfaces of the cell is an integer multiple N of the wavelength of the radiation transmitted without reflection. Whenever the wavelength is 2b / N, constructive interference occurs. Here, “b” is the cell thickness (ie, path length). For this reason, if ΔN is the maximum number of the stripe patterns in the predetermined wavelength range λ ₁ -λ ₂ , the cell thickness b is obtained from the following equation.
b = ΔN / 2 (λ ₁ −λ ₂ )
This method can be useful to increase reflectivity, especially if the refractive index of the material in the sample chamber or liquid cell is not equal to the refractive index of the cell walls.

  Once the path length is determined, it can be used to calculate or determine a reference value or reference spectrum for interfering substances (such as protein or water) that may be present in the sample. For example, both an analyte such as glucose and an interfering substance such as water may absorb radiation of a predetermined wavelength. When the radiation source emits radiation of that wavelength and this radiation passes through the sample containing the analyte and the interfering substance, both the analyte and the interfering substance absorb this radiation. For this reason, the reading of the absorbance of the detector as a whole does not originate entirely from either the specimen or the interfering substance, but originates from a combination of both. However, if there is data on how much radiation is absorbed by a given interfering substance when it passes through a sample with a given path length, the contribution of the interfering substance from the entire detector reading By subtracting the minutes, the remaining value can be obtained as information on the analyte concentration in the sample. Similar methods can be performed for full spectrum wavelengths. By subtracting the absorption spectrum of the interfering material from the total absorption spectrum, if there is data on how much the radiation is absorbed by the interfering material over a range of wavelengths as it passes through a sample with a given path length, The rest can be obtained as the absorption spectrum of the analyte in that wavelength range. Obtaining interfering substance absorbance data for a possible range of path lengths allows you to obtain accurate data for the samples measured in that sample chamber by first measuring the path lengths of the individual sample chambers. .

  The same process can be repeated for a plurality of interfering substances and / or a plurality of specimens, or can be performed simultaneously. For example, reducing both the water absorption spectrum and the protein absorption spectrum leaves the glucose absorption spectrum.

  The path length can also be calculated using the isosbestic wavelength. The isosbestic wavelength is a wavelength at which all components of the sample have the same absorbance. If the components (and absorption coefficients) of a specific sample are known, one or more isosbestic wavelengths are known for those specific components. The path length can be calculated using the absorbance data collected by the radiation detector at these isosbestic wavelengths. This is advantageous in that the required information can be obtained from multiple readings of the absorbance detector almost simultaneously using the same sample placed in the sample chamber. The path length is determined using the reading of the isosbestic wavelength and the interfering substance and / or analyte concentration is measured using the reading of the other selected wavelength. Thus, this method is efficient and does not require the reference liquid to be inserted into the sample chamber.

  In some embodiments, in a method for measuring an analyte concentration in a sample, a liquid sample is inserted into a sample container, and radiation from a radiation source is irradiated to the container and the liquid sample to transmit the absorption data of all samples. Obtainable. The amount of radiation that reaches the detector can be measured, and the accurate interference value or spectrum of the interfering substance can be subtracted from the absorption data of the entire sample, and the remaining absorption value or spectrum can be used to determine the analyte concentration in the liquid sample. An accurate interference substance absorption value can be specified using the calculated path length.

The analyte concentration in the sample can be calculated as follows using Beer-Lambert's law (or Beer's law). If the transmittance is T, the absorbance is A, P ₀ is the initial power of radiation toward the sample, and P is the power when it leaves the sample and reaches the detector,
T = P / Po, A = −log T = log (P ₀ / P). The absorbance is directly proportional to the concentration (c) of the light-absorbing species in the sample, also called the analyte or interfering substance. Therefore, when e is the molar extinction coefficient (1 / M I / cm), b is the path length (cm), and c is the concentration (M), Beer's law is expressed as follows. A = ebc Therefore, c = A / (eb).

Referring again to flowchart 3100, the next step is to determine which library interfering substances are present in the sample. In particular, block 3120 analyzes the measurements to identify possible interferents. In the spectroscopic measurement, it is preferable to make a determination by comparing the obtained measurement value with the spectrum of the interference substance and the optical density domain. The result of this step provides a list of interfering substances that may be present in the sample. In one embodiment, the glucose concentration g _est is estimated from the spectrum C _s measured using a plurality of input parameters. Input parameters include spectral measurements of samples such as previously collected measurement samples, including combinations of analytes and possible interfering substances from the interfering substance library, and spectra and concentration ranges for each possible interfering substance. Specifically, the input parameters are as follows.

Interfering substance library data : The interfering substance library data includes the absorption spectrum for each interfering substance, IF = {IF ₁ , IF ₂ ,..., IF _M }, for each interfering substance. Maximum density Tmax = {Tmax ₁ , Tmax ₂ ,..., Tmax _M }. Here, m = 1, 2,..., M.

Sample population data : The sample population data includes individual spectra of a statistically large population obtained over the same wavelength range as the sample spectrum _Csi and the analyte concentration corresponding to each spectrum. For example, when the sample population spectrum is N, the spectrum can be represented by C = {C ₁ , C ₂ ,..., C _N }. Here, n = 1, 2,..., N, and the analyte concentration corresponding to each spectrum can be expressed as g = {g ₁ , g ₂ ,..., G _N }.

  Preferably, the sample population does not contain any of the M interfering substances, and the material sample contains the interfering substances contained in the sample population and, optionally, one or more library interfering substances. For the type A and type B interfering substances already described, the sample population includes type A interfering substances. The material sample contains type A interfering substances, but may also contain type B interfering substances. Sample population data is used to statistically quantify the expected range of spectra and analyte concentrations. Thus, for example, in the system 10 or 334 used to measure glucose in human blood having unknown spectral characteristics, the spectral measurements are preferably obtained from a statistical sample of the population.

Hereinafter, the illustrated embodiment in which a plurality of specimens are measured using a spectroscopic technique will be described, but the scope of the present invention is not intended to be limited. When two or more specimens have spectral characteristics that do not overlap, a spectrum corresponding to each specimen is acquired in the first embodiment. Next, the measurement value is analyzed for each specimen according to the method of the flowchart 3100. In an alternative embodiment for a plurality of specimens having characteristics that do not overlap each other, or an embodiment for a plurality of specimens that have characteristics that overlap each other, a measurement value having spectral characteristics of two or more specimens is obtained. This measured value may be analyzed for each sample according to the method of the flowchart 3100. In other words, the analysis is performed with respect to the measured value for each sample, and the other samples are regarded as interfering substances for the sample to be analyzed.

Interfering substance measurement

  With reference to the flowchart of FIG. 32, the block 3120 of the method of one embodiment will be described in more detail. The method generates a statistical sample population model (block 3210), assembles the interferent library data (block 3220), and combines the acquired measurements with the statistical sample population model from the interferent library. Comparisons using substance-specific data (block 3230), and statistical tests for the presence of each interferent in the interferent library (block 3240) It is identified as a possible library interferent (block 3250). The steps of block 3220 may be performed once and updated as needed. The steps of blocks 3230, 3240, 3250 can be performed sequentially for all interfering substances in the library as previously described, or can be performed continuously and repeatedly for each interfering substance.

For each method of blocks 3210, 3220, 3230, 3240, and 3250 of one embodiment, an example of identifying a library interference substance in a sample from a spectroscopic measurement value using the sample group data and the interference substance library data described above is given. I will explain. Each sample population spectrum includes measurements (eg, optical density) performed on the sample in the absence of library interfering substances and has an associated known analyte concentration. All sample population spectra are combined to form a statistical population model (block 3120) over a range of analyte concentrations to obtain an average matrix and a covariance matrix for the sample population. Thus, for example, if each spectrum of n different wavelengths is represented by an nx1 matrix C, the average spectrum μ becomes an nx1 matrix having values (for example, optical density) averaged over the spectral range, and covariance The matrix V is an expected value of the deviation between C and μ, and V = E ((C−μ) (C−μ) ^T ). Matrix μ and matrix V are one model representing the statistical distribution of the sample population spectrum.

  In another step, library interferent information is assembled (block 3220). Identify multiple possible interfering substances as, for example, a list of drugs or foods measured by the system 10 or 334 or possibly taken by the intended patient population and their spectra (absorption, optical density) Or transmission domain). In addition, an expected concentration range of interfering substances in the blood or an expected sample substance is estimated. Thus, the spectrum IF and the maximum concentration Tmax are obtained for each of the M interference substances. Preferably, this information is assembled once and then accessed as needed.

  Next, the acquired measurement data and the statistical sample population model are compared with the data for each interfering substance in the interfering substance library (block 3230), and a statistical test is performed (block 3240) in the mixture. The interfering substance is identified (block 3250). This interfering substance test is first shown in detailed mathematical formulas and then described with reference to FIGS. 33A and 33B illustrating the method.

The test for the presence of interfering substances is performed mathematically as follows. For each interferent library against the measured optical density spectrum G _s, if present in the spectrum where the interference substance was determined by subtracting the effects analytically corrects. Specifically, the measured optical density spectrum G _s is corrected by subtracting the optical density spectrum of the interference substance for each wavelength. If there interferents M is, that to have an absorption spectrum IF _M by the interference substance density units, spectrum after modification,
C ′ _S (T) = C _S −IF _M T Here, T is the concentration of the interference substance in the range from the minimum value T _min to the maximum value T _max . The value of T _min is zero, or such as a fraction of the _{T max,} a value of from zero to _{T max.}

Next, the Mahalanobis distance (MD) between the corrected spectrum C ′ _S (T) and the statistical model (μ, V) of the sample population spectrum is calculated based on the following equation.

MD ² (C _s − (Tt), μ; ρ _S )
_{= (C S - (TIF m} ) -μ) T V -1 (C 8 - (TIF m) -μ) Equation (1)

The test for the presence of the interfering substance IF is performed by changing T from T _min to T _max (ie, estimating C _s (T) over a range of values of T), with the smallest MD at a given range over this interval It is determined whether or not it exists. For example, it may be determined whether the minimum MD in this interval is sufficiently small relative to the quantile obtained by dividing the random variable χ ² by the degree of freedom L (L is the number of wavelengths).

FIG. 33A shows a graph 3300 illustrating the steps of block 3230 and block 3240. Using the axes OD _i and OD _j of the graph 3300, the optical density at two wavelengths among the many wavelengths from which the measured values are obtained is graphed. A point 3301 is a measured value of the sample population distribution. It can be seen that the points 3301 form a group in an ellipse drawn so as to surround the majority of the points. A point 3301 within the ellipse 3302 represents a measured value when the library interfering substance is not present. A point 3303 is a sample measurement value. Point 3303 is considered outside the expansion of point 3301 due to the presence of one or more library interferents. Line 3304, line 3307, and line 3309 each show a correction of the measured value at point 3303 as the concentration T of three different library interferents increases over the range T _min to T _max . In this example, the three interfering substances are referred to as interfering substances # 1, # 2, and # 3. Specifically, lines 3304, 3307, and 3309 are obtained by subtracting the amount T of the library interference substance (interference substance # 1, interference substance # 2, interference substance # 3) from the sample measurement value, and obtaining the corrected sample measurement value. It is a graph as T increases.

FIG. 33B shows a graph that further describes the method of FIG. In FIG. 33B, the square MD ^{2 of the} Mahalanobis distance is calculated and graphed as a function of lines 3304, 3307, and 3309. As shown in FIG. 33A, line 3304 reflects a decrease in the concentration of interferent # 1 and is only slightly closer to the group of points 3301. As shown in FIG. 33B, the value of MD ² of line 3304 decreases slightly, and increased again when the concentration of interferent # 1 is reduced.

As shown in FIG. 33A, line 3307 reflects the decrease in the concentration of interfering substance # 2, and is close to or penetrating the group of points 3301. As shown in FIG. 33B, the value of MD ² of line 3307, greatly reduced when taking a certain value the concentration of the interferent # 2, and increased thereafter. As shown in FIG. 33A, line 3309 reflects a decrease in the concentration of interfering substance # 3 and is close to point 3303 or even penetrates a group of points 3303. As shown in FIG. 33B, the value of MD ² of line 3309, and further significantly reduced when taking a certain concentration of interferent # 3 value.

In one embodiment, the MD ² threshold level is set to indicate the presence of an individual interfering substance. For this reason, for example, FIG. 33B shows a line labeled “original spectrum” indicating MD ² that does not reduce the amount of interfering substances from the spectrum, and a degree of freedom L (here, L is the number of wavelengths represented in the spectrum). A line labeled “95% threshold” indicating the 95% quantile divided by the chi ² distribution is shown. This level is a value exceeding 95% of the weight value of MD ^2. In other words, the value of this level is unusual and, as mentioned above, is considered extremely rare. Only interferent # 3 of the three interfering substances shown in FIGS. 33A and 33B has a value of MD ² below the threshold. For this reason, in this sample analysis, interference substance # 3 shows the interference substance with the highest possibility of existing in a sample. Interfering substance # 1 is very unlikely to be present because its minimum value never exceeds the threshold level. Interfering substance # 2 slightly exceeds the threshold level, so its presence is higher than interfering substance # 1, but still much lower than interfering substance # 3.

A method for generating calibration constants that are relatively insensitive to the concentration of identified interfering substances in a possible range using information about the identified interfering substances is described below. Besides using the individual methods described below, the identification of interfering substances is interesting and there can be various useful methods. For example, a glucose monitor used in a hospital displays the identified interfering substance on the display unit 141 or transmits it to a hospital computer via a communication link 216.

Embodiment for generating calibration constants

  Once the library interfering substances that may be present in the sample at the time of analysis are identified, a calibration constant is generated to estimate the analyte concentration in the presence of the identified interfering substances (block 3130). Specifically, after block 3120, a list of library interferents that may be present is created. In the step of block 3120 of one embodiment, as shown in the flowchart of FIG. 34, block 3410 generates measurements of the synthesized sample population, and block 3420 converts the measurements of the synthesized sample population for calibration. In block 3430, a calibration constant is generated using the calibration group, and in block 3440, the analyte concentration of the test group is estimated using the calibration group, block 3450. Then, an error in the analyte concentration estimated based on the test group is calculated, and in block 3460, an average calibration constant is calculated.

  Each method of blocks 3410, 3420, 3430, 3440, 3450, 3460 of one embodiment will be described with an example of identifying interfering substances in a sample and generating an average calibration constant. In the step shown in block 3410, a random concentration of library interferents that may be present is added for each spectrum of the sample population to generate a composite sample population spectrum. The spectrum generated by the method of block 3410 is referred to as an interferent weighted spectrum database or IESD (Interferent-Enhanced Spectral Database). The IESD is generated by the steps shown in FIGS. FIG. 35 is a schematic diagram 3500 showing a process of generating a randomly scaled single interferer spectrum (RSIS), or RSIS. FIG. 36 is a graph 3600 illustrating scale change of an interfering substance. FIG. 37 is a schematic diagram of a process of combining RSIS with a mixed interference substance spectrum, that is, CIS (Combination Interferent Spectra). FIG. 38 is a schematic diagram of the process of combining CIS and sample population spectrum with IESD.

The first step of block 3410 is shown in FIGS. As outlined in the flowchart 3500 of FIG. 35 and the graph 3600 of FIG. 36, the previously identified library interferent (block 3510) having the spectrum IF _m is represented by a random number between zero and one, indicated by a random number distribution in the graph 3600. Multiply by the scaled maximum density (Tmax _m ) (block 3520) using a random coefficient (block 3530) to generate a plurality of RSIS (block 3540). In one embodiment, the scaling step generates a wide range of concentrations having this distribution, with the maximum concentration being the 95th percentile of a lognormal distribution with the standard deviation being half its mean. The random number distribution of the graph 3600 is a lognormal distribution with μ = 100 and σ = 50.

  When RSIS is generated by multiplying individual library interference substance spectra by random concentrations, RSIS is combined to generate CIS, which is a large group of interference-only spectra, as shown in FIG. Individual RSISs are independently combined to form a random mixture to produce a large family of CISs. Each spectrum in the CIS consisting of a mixture of random RSISs is selected from the entire group of identified library interferents. The method shown in FIG. 37 provides sufficient variation for each interfering substance regardless of the individual interfering substances.

  The next step is to combine the CIS and a copy of the sample population spectrum to generate an IESD, as shown in FIG. Since interferant data and sample population spectra may have been acquired with different path lengths, CIS first scales (ie, multiplies) to the same path length. Take M copies from the sample population database. Here, M is determined according to the size of the database and the number of interfering substances to be processed. The IESD contains M copies, each with a sample population spectrum. One copy is the original sample population data, and the remaining (M−1) copies each contain one of the randomly added CIS spectra. Each IESD spectrum includes an associated analyte concentration from the sample population spectrum used to form a separate IESD spectrum.

  In one embodiment, a 10-fold copy of the sample population database is used for 130 sample population spectra obtained from 18 library interferents and 58 different individual spectra. In order to increase the spectral variation between the library interfering substance spectra, it is necessary to reduce the copy ratio. However, in order to increase the amount of the library interfering substance, it is necessary to increase the copy ratio.

  The steps of blocks 3420, 3430, 3440, 3450 are performed to iteratively combine the different spectra of IESD and statistically average the effects of the identified library interferents. First, at block 3420, the IESD is divided into two groups: a calibration group and a test group. As will be described in detail later, the statistical importance of the calibration constant is improved by repeatedly dividing the IESD into a calibration group and a test group. In one embodiment, the calibration group is a portion of a randomly selected IESD spectrum and the test group is an unselected IESD spectrum. In the preferred embodiment, the calibration group includes approximately two-thirds of the IESD spectrum.

  In an alternative embodiment, instead of performing the steps of blocks 3420, 3430, 3440, 3450, one step of performing an average calibration constant using all available data is performed.

Next, at block 3430, a calibration constant is generated to predict the analyte concentration from the sample measurement using the calibration group. First, an analyte spectrum is obtained. In the embodiment for measuring glucose from absorption measurements, showing the glucose absorption spectrum at a _G. Next, a calibration constant is generated by the following procedure. Calibration spectra torr _{C = {C 1, C 2} , ···, C n} and the corresponding glucose concentration value _{G = {g 1, g 2} , ···, g n} using a group of calibration with , C ′ = {C ′ ₁ , C ′ ₂ ,..., C ′ _n } without glucose can be calculated as C ′ _j = C _j −a _G g ₁ . Next, a calibration constant K is calculated from C ′ and a _G according to the following five steps.
1) Decompose C ′ into C ′ = A _{C ′} ΔC _′ B _{C ′} . That is, singular value decomposition is performed using the A factor as the C orthogonal span or the orthonormal basis of the column space.
2) Based on the size of the diagonal element of C (singular value of C), a part of AC _′ is rounded down so as not to overfit the class r of the individual columns. The choice of r is a trade-off between accuracy and stability in calibration. As r increases, accuracy increases but solution stability decreases. In one embodiment, each spectrum C includes 25 wavelengths each, and r ranges from 15 to 19.
3) _'the first r columns of, Span (C' A C and orthonormal basis of).
4) Obtain the projection from the background as the product P _{C ′} = A _{C ′} A _{C ′} ^T , which is the diameter projection for the span of C ′, to form the projection onto the complementary subspace C ′ ^{補 完} Complementary) or zeroing projection (calculating the ^{_{nulling projection) P C '⊥ =}} 1-P C'.
5) A calibration vector K is obtained by performing a zeroed projection on the absorption spectrum of the target analyte as follows, and K _raw = ^PC _′ ^⊥ a _G , and is normalized as follows. K = K _raw / <K _raw , a _G >. Here, square brackets <> represent an inner product of standard vectors. The normalized calibration constants are unit responsive to a _G unit spectral inputs in groups for individual configurations.

The calibration constant is then used to estimate the analyte concentration in the test group (block 3440). Specifically, the calibration vector K obtained in block 3430 is assigned to each spectrum of the test group (each spectrum includes the associated glucose concentration from the sample population spectrum used to generate the test group). Multiply to calculate an estimate of glucose concentration. An error between the calculated glucose concentration and the known glucose concentration is calculated (block 3450). Specifically, the measurement value of the error may include a weight value averaged over the entire group of test by 1 / rms ^2.

Blocks 3420, 3430, 3440, 3450 are repeated for many different random combinations of calibration groups. Preferably, blocks 3420, 3430, 3440, 3450 are repeated hundreds to thousands of times. Finally, an average calibration constant is calculated from calibration constants and errors obtained from a number of calibration groups and test groups (block 3460). Specifically, the average calibration constant is calculated as a weighted average of calibration vectors. In one embodiment, all tests are weighted according to a normalized root mean square, such as K _ave = K * rms ² / Σ (rms ² ).

The end of block 3130 is performed according to the flowchart of FIG. 34, and the average calibration constant K _ave is applied to the acquired spectrum (block 3140).

Accordingly, the method of one embodiment for calculating the calibration constant based on the identified interfering substance can be summarized as follows.
1. The RSIS is added to the raw (interfering substance free) sample population spectrum to generate a synthetic sample population spectrum and form an interference material weighted spectral database (IESD). Here, each spectrum of IESD is synthesized from one of the spectra of the sample population, and each spectrum of IESD includes at least one associated known analyte concentration.
2. The spectrum of IESD is separated into a calibration spectrum group and a test spectrum group.
3. Generate calibration constants for the calibration spectrum groups based on the calibration spectrum groups and their known accurate analyte concentrations (eg, using matrix processing outlined in the five steps above).
4). Using the calibration constant generated in step 3, the error of the corresponding test group is calculated as follows (repeated for each spectrum of the test group).
a. Multiply (the spectrum selected from the test group) by (the average calibration constant generated in step 3) to obtain an estimate of the glucose concentration.
b. The difference between the estimated glucose concentration and the known and accurate glucose concentration associated with the selected test spectrum is compared to obtain an error for the selected test spectrum.
5. The errors calculated in step 4 are averaged to obtain a weighted or average error for the current set of calibration and test groups.
6). Steps 2 to 5 are repeated n times to obtain n calibration constants and n average errors.
7). Calculate the “large average” error from the n average errors, calculate the average calibration constant from the n calibration constants (preferably the weighted average excluding the maximum average error and the calibration constant), and the effect of the identified interfering substance Obtain a calibration constant that is least sensitive to.
Example 1

実施例２ As an example of the specific method disclosed herein, a case where glucose in blood is detected using mid-infrared absorption spectroscopy will be described. Table 2 lists 10 library interference substances (each having an absorbance characteristic superimposed on glucose) and the maximum concentration of each corresponding library interference substance. Table 2 further describes the case where the glucose sensitivity to the interfering substance is trained and the case where it is not trained. The glucose sensitivity to the interfering substance is calculated as a change in the estimated glucose concentration value with respect to the change per unit of the interfering substance concentration. In the technique of selectively detecting glucose from a specimen with high accuracy, this value is zero. The glucose sensitivity with respect to the interfering substance when training is not performed refers to the glucose sensitivity with respect to the interfering substance when the calibration value is determined by the above-described method without using the identified interfering substance. The glucose sensitivity with respect to the interfering substance in the case of training refers to the glucose sensitivity with respect to the interfering substance when the calibration value is determined by the above-described method using the identified appropriate interfering substance. In this case, urea was the least improved (in the sense of reduced sensitivity to interfering substances), only a 6.5-fold reduction in sensitivity, and the other improvement ratio was 60 to 80 times. Three interfering substances follow. In the remaining six interfering substances, the sensitivity is reduced from 100 times to 1600 times. The decrease in glucose sensitivity to interfering substances due to training indicates that the method is effectively generating a calibration constant that is selective for glucose in the presence of interfering substances.

Example 2

実施例３ Another embodiment illustrating the effect of the method on 18 interfering substances will be described. Table 3 lists the 18 interfering substances and their respective maximum concentrations and the glucose sensitivity for the interfering substances with and without training. The table summarizes the results of 1000 simulations of calibration and testing performed simultaneously in the absence of interfering substances and in the presence of all interfering substances. FIG. 39 shows the RMS error distribution of the glucose concentration estimate for 1000 trials. Table 3 shows that the sensitivity of many substances (sodium bicarbonate, magnesium sulfate, tolbutamide) is greatly reduced, while that of other substances (ethanol, acetoacetate) is increased. Yes. The curves in FIG. 39 show the calibration and test groups both in the absence of interfering substances and in the presence of 18 interfering substances. As can be seen by comparing the calibration and test curves of FIG. For example, the peak is shifted by about 2 mg / dL, and the width of the distribution is slightly increased. The height of the peak is also reduced due to the spread of the distribution, and as a result, the reduction in performance is mitigated.

Example 3

  In this example, mid-infrared absorption spectroscopy is performed in the presence of four interfering substances (type B interfering substances) that are not normally present in blood, which are often performed on patients in an intensive care unit (ICU) of a hospital. Was used to measure glucose in the blood by the specific method disclosed herein. The four type B interferents are mannitol, dextran, n-acetyl L cysteine, and procainamide.

  Of the four type B interferents, mannitol and dextran are both similar in spectrum to glucose (see FIGS. 40A and 40B), and the dose in ICU is very high compared to normal glucose levels. Have the potential to have a substantial impact on the assessment of glucose. Mannitol may be present, for example, in blood at a concentration of 2500 mg / dL and dextran may be present at a concentration greater than 5000 mg / dL. For comparison purposes, normal plasma glucose levels are on the order of 100-200 mg / dL. For other type B interferents, n-acetyl L cysteine and procainamide, the spectrum is significantly different from that of glucose.

40A, 40B, 40C, and 40D are respectively two different techniques, a Fourier Transform Infrared (FTIR) spectrometer (shown as a triangle and a solid line) with an interpolation resolution of 1 cm ⁻¹ , and 140 nm to 10 μm at 7.08 μm. Glucose obtained using a 25 cm ^-1 full wave width (FWHM) bandwidth corresponding to a bandwidth varying up to 279 nm and 25 finite bandwidth IR filters with Gaussian distribution (shown as circles and chain lines) and It is a graph which shows the comparison of the absorption spectrum of other interference substances. Specifically, these figures show glucose and respective interfering substances at a concentration level of 1 mg / dL and a path length of 1 μm, namely mannitol (FIG. 40A), dextran (FIG. 40B), n-acetyl L Comparison with cysteine (FIG. 40C), procainamide (FIG. 40D) is shown. 40A to 40D, the horizontal axis represents a wavelength in units of microns (μm) in the range of 7 μm to 10 μm, and the vertical axis is an arbitrary unit.

  The center wavelength of the data obtained using the filter is indicated by a circle along the chain line curve in FIGS. 40A, 40B, 40C, and 40D, and each of the following wavelengths in units of microns: 7.082, 7.158, 7.241, 7.331, 7.424, 7.513, 7.605, 7.704, 7.800, 7.905, 8.019, 8.150, 8.271, 8.. 598, 8.718, 8.834, 8.969, 9.099, 9.217, 9.346, 9.461, 9.579, 9.718, 9.862, 9.990 . The effect of the filter bandwidth on the spectral characteristics is evident from the fact that the sharpness of the spectral characteristics shown by the solid curve is reduced and the sharpness is lost in the dashed curve, as seen in FIGS. 40A-40D. .

  FIG. 41 is a graph of plasma spectrum in which six blood samples collected from three blood donors are represented in arbitrary units with a wavelength range of 7 μm to 10 μm, and the symbols on the curve are 25 filters, respectively. The center wavelength of is shown. The six blood samples are a sample population that does not contain any of the mannitol, dextran, n-acetyl L cysteine, or procainamide, which are type B interferents in this example. Three blood donors (indicated by donors A, B, and C) are providing blood at different times, so a YSI biochemistry analyzer (YSI Biochemistry Analyzer (YSI), shown in mg / dL on the graph). Blood glucose levels measured by Incorporated, Yellow Springs, OH)) are different. By analyzing the spectra scanned with saline in the same cell immediately before each sample spectrum was measured, the path length of these samples was estimated to be 36.3 μm, which was used to normalize these measurements. The composition vector was calculated in consideration of this quantity. When the vector thus obtained is applied to a spectrum obtained from another device, a path length is similarly estimated and normalized in order to obtain an effective result.

表４ 実施例３の干渉物質加重スペクトルデータベース Next, a random amount may be added to the spectrum for each type B interference substance of this example to form a mixture, for example, an interference substance weighted spectrum. As shown in Table 4, a random amount of one interfering substance is added and combined for one sample population spectrum, and the number indicated by N for each of the 54 spectra, donor, glucose concentration (GLU) Interfering substance concentration (conc (IF)) and interfering substances are summarized in a table. Using the conditions in Table 4, mixed spectra were formed, each consisting of two levels of one of the four interfering substances in one of the six plasma spectra.

Table 4 Interference substance weighted spectrum database of Example 3

  42A, 42B, 42C, and 42D include spectra formed by the conditions of Table 4. Specifically, these figures show random amounts of mannitol (FIG. 42A), dextran (FIG. 42B), n-acetyl L cysteine (FIG. 42C) when the concentration level is 1 mg / dL and the path length is 1 μm. FIG. 4 shows the spectrum of a sample population of 6 samples containing procainamide (FIG. 42D).

  Next, the spectra of FIGS. 42A-42D were used to generate a calibration vector that was valid for reproducing the steps of block 3120. The next step in this example subtracts the spectrum of water present in the sample to produce a spectrum in the absence of water. As already described, the individual method disclosed here estimates the analyte concentration in the presence of an interfering substance (type A interfering substance) present in both the sample population and the measurement sample. It is not necessary to remove the spectrum of interfering substances present in the population and the sample to be measured.

  The calibration vector as a spectrum in the absence of water is shown in FIGS. 43A to 43D for mannitol (FIG. 43A), dextran (FIG. 43B), n-acetyl Lcysteine (FIG. 43C), and procainamide (FIG. 43D). Show about. Specifically, each of FIGS. 43A-43D compares a calibration vector obtained by training in the presence of interfering substances with a calibration spectrum obtained by training only a clean plasma spectrum. The calibration spectrum is used by calculating the inner product with a vector representing the spectral absorbance value (normalized path length) of the filter used in the processing of the reference spectrum. A large value (whether positive or negative) usually represents the wavelength at which the corresponding spectrum is sensitive to the presence of glucose, and a small value is usually insensitive to the presence of the corresponding spectral absorption in the presence of glucose. It represents a certain wavelength. The presence of interfering substances makes this correspondence somewhat opaque, and the nature of the interfering substance masks the presence of glucose.

  The calibration vectors obtained to minimize the effects of the two interfering substances, n-acetyl L cysteine and procainamide, are similar to those obtained for pure plasma. Reflecting that the spectra of the two are completely different, the large difference between the calibration vector that minimizes the effects of dextran mannitol and that obtained for pure plasma is This indicates that the spectrum of glucose and the spectrum of glucose are very similar. If the interfering spectrum is similar to that of glucose (ie mannitol and dextran), the calibration vector will change significantly. If the interfering spectrum is different from that of glucose (ie, n-acetyl L cysteine and procainamide), the difference between the calibration vector obtained with and without the interfering substance added. Is difficult to detect.

  The method steps described herein, in one embodiment, are performed by a suitable processor (s) of a processing system (ie, a computer system) that executes instructions (or code segments) stored in a suitable storage device. Obviously it will be done. The methods and apparatus disclosed herein are not limited to individual implementations or programming techniques, and the methods and apparatus may be used with any technique that is appropriate for performing the functions described herein. Obviously, it may be realized. The method and apparatus are not limited to individual programming languages or operating systems. In addition, the various components that calibrate the device may be housed in a single housing or in multiple housings that can communicate via wired or wireless communication.

  Further, the interfering substance, specimen, or population data used in the method may be updated, changed, added, removed, or modified as necessary. Thus, for example, the spectral information and / or concentration of interfering substances associated with the method may be updated or changed by updating or changing a database of programs that implement the method. The update may be performed by providing a new computer readable medium or via a computer network. Other changes to the method or apparatus may be made by, but not limited to, adding new specimens or changing population spectral information.

  One embodiment of each of the methods disclosed herein may include a computer program accessible by and / or executable by a processing system, eg, one or more processors and memory that form part of an embedded system. Good. Therefore, for those skilled in the art, the embodiments of the present invention disclosed herein are realized by a device such as a dedicated device, a device such as a data processing system, or a carrier medium such as a computer program product or method. Obviously it is possible. The carrier medium has one or more computer readable code segments for controlling the processing system performing the method. Accordingly, the various aspects of the invention disclosed herein may be implemented in a method, an entirely hardware embodiment, an entirely software embodiment, or an embodiment combining software and hardware aspects. Further, one or more methods disclosed herein (including but not limited to measurement analysis, measurement of interfering substances, and / or generation of constitutive constants) may include one or more computer readable code segments or transports. It can be saved as a collection of data on the medium. A computer-readable carrier medium may be a magnetic storage device such as a diskette or a hard disk, a memory cartridge, a module, a card or a chip (including a single device or a device mounted in a large device), a CD, or An optical storage device such as a DVD may be used.

  In this specification, “one embodiment” or “an embodiment” means that at least one embodiment includes individual features, structures, or properties related to the embodiment. Thus, the phrases “in one embodiment” or “in an embodiment” described in various places in this specification are not necessarily referring to the same embodiment. Furthermore, it will be apparent to those skilled in the art from the present disclosure that individual features, structures, or properties may be appropriately combined in one or more embodiments.

  Similarly, in the above-described embodiments, in order to efficiently describe the present disclosure and to add an understanding of one or more of the various aspects of the present invention, in a single embodiment, drawing, or description thereof. Often, various features of the present invention are described together. Such disclosed methods, however, are not to be construed as requiring the following claims to be pointed out beyond the features explicitly recited in the claims. Rather, the claims set forth below reflect that the aspects of the invention may be met by combining fewer than all of the features of any one of the embodiments disclosed above. Yes. Thus, the claims following the detailed description of the invention are expressly incorporated into the detailed description of the invention, with each claim standing on its own as a separate embodiment.

  US patent published on May 15, 2003 entitled “REAGENT-LESS WHOLE-BLOOD GLUCOSE METER” for an analyte detection system, sample elements, analyte concentration calculation algorithm and method, and other related apparatus and methods U.S. Patent Application No. 2003/0178569 published on September 25, 2003 entitled "METHOD OF TERMINAL PRODUCTION TRIMENTIN TRAIN TRAIN TRAIN TRA DIN TRAIN TRAIN T AN ABSORPTION SPECTR US Patent Application No. 2004/0019431 published January 29, 2004 entitled "M", "METHOD OF DETERMINING AN ANALYTE CONCENTRATION IN A SAMPLE USING INFRARED TRANSMISSIO DATA" published February 17, 2005. Reference may also be made to US Application No. 2005/0036147 and US Patent Application No. 2005/0038357, published February 17, 2005, entitled “SAMPLE ELEMENT WITH BARRIER MATERIAL”. The entire contents of the above publications are hereby incorporated by reference and made a part hereof.

  A number of applications, publications and external documents are incorporated herein by reference. If there is a discrepancy between the description of the main body of this specification and the description of the incorporated document, the description of the main body of this specification should be interpreted with priority.

  Analysis of bodily fluid (eg, blood) from a patient is usually performed by drawing from the patient or obtaining a bodily fluid sample from the patient and delivering the bodily fluid sample to the sample analyzer 330. However, in order to properly measure and analyze the sample, it is necessary to pass the fresh undiluted sample through the sample analyzer 330 and clean the inside of the liquid processing system 10 in advance. For example, prior to the step of drawing blood or returning it to the liquid processing system 10, the catheter 11 that supplies blood to the sample analyzer 300 is filled with saline. This saline ensures that there is a fresh and undiluted blood sample at the junction of the patient junction path 112 and the collection path 113 before sending a small amount of sample to the sample analyzer 330 via the collection path 113. As such, it is advantageous to wash it off from the system 10. In order to fill the catheter used for blood supply before drawing or returning blood with saline, the saline can be diluted or mixed with the blood sample if not removed or “washed”. Blood samples that are carried along the fluid path to the spectrometer can be significantly diluted (eg, 1% or more). It is also advantageous to have an undiluted sample for analysis.

  A typical hospital liquid measurement and analysis device draws more than 3 ml of blood to clean the device, and the device discards this amount of blood before analyzing the sample. However, the liquid processing system 10 has the function of greatly reducing the amount of blood drawn for system cleaning. Since the colorimetric sensor 311 is used for detection when there is no longer dilution of the blood, the liquid processing system 10 can efficiently reduce the amount to be extracted. In contrast, manual instruments typically used in hospitals need to draw a large amount of blood to ensure that the instrument is properly cleaned and the sample is not diluted.

  Liquid treatment system 10, collection system 100/300/500/800, liquid treatment and analysis device 140, module or cassette 820, and other devices disclosed herein, process and collect body fluids of a patient, And / or facilitate the apparatus and method of various embodiments to analyze. For example, the liquid processing system 10, the collection system 100/300/500/800, the liquid processing and analysis device 140, the cassette 820, and the liquid processing and analysis device 140, in some embodiments, are 3 ml in a normal measurement cycle. A low volume system or device that, in various embodiments, draws and / or contains 2 ml or less, 1 ml or less, 400 μl or less, 300 μl or less, 200 μl or less, 100 μl or less, or 50 μl or less) from patient P including.

  As described above, in a low volume system of certain embodiments, a total of 3 ml or less is extracted or obtained from the patient. However, certain embodiments are designed to analyze a smaller amount of body fluid from even such a large sample. A small amount of sample is about a dozen microliters in volume and may range from about 10 to about 100 microliters. For example, in one embodiment where the body fluid is blood, the collection unit 200 provides a small amount of blood from the collection element unit 220 in the range of about 10 to about 100 μl, or more preferably about 40 μl of blood. Extract. In other embodiments, pump 328 draws sample S in an amount of 30-50 μl.

  However, even if the amount extracted by the low-capacity apparatus of various embodiments is small, it is sufficient for performing the measurement of the specimen. Thus, this amount is sufficient to, for example, deliver a portion of the extracted liquid to the sample detection system 334 and facilitate measurement of the sample concentration.

  After withdrawing the sample, the liquid processing system performs analysis on a further portion of the sample that is already small. Bubbles are injected into the extracted sample through valves 613a, 613b, and 613c shown in FIG. 7E. The bubble divides the sample withdrawn into a plurality of small portions each having a volume of about 10 μl. For example, a first group of small portions (eg, three small portions) is used to clean the liquid processing network. That is, these three small parts are washed with a saline solution through the liquid processing network and the sample preparation unit 332. Only subsequent small portions are analyzed by the analyte detection system 334. In one embodiment, the analysis portion (ie, the fourth sub-portion) is delivered by the sample preparation unit 332, the plasma component is separated from the analysis portion, and then only the plasma component is analyzed by the analyte detection system 334.

  In certain embodiments, a small volume sample is spectroscopically analyzed. Here, the sample detection system may include the sample detection system 334/1700 according to any of the embodiments disclosed herein, or may include any spectroscopic analyzer as appropriate. In other particular embodiments, a small volume sample is optically analyzed, where the analyte detection system may comprise any suitable optical system. In yet another specific embodiment, a small volume sample is analyzed electrochemically. Here, the analyte detection system may include any electrochemical system as appropriate.

  The liquid processing system 10, collection system 100/300/500/800, cassette 820, and liquid processing and analysis device 140 can include a liquid processing network or a liquid delivery network disclosed herein. The liquid treatment network or liquid delivery network comprises one or more pathways 20 through which blood (or other bodily fluid), infusate, and / or air pass during operation of the subject device. The pathway 20 forms a conduit that interconnects the container 15, the collection system 100/300/500/800 and the catheter 11.

  The collection system 100 and the path 20 of the cassette 820 include a liquid source path 111 from the junction 120 to the liquid treatment and analysis device 140, a patient junction path 112 from the liquid treatment and analysis device 140 to the patient junction 110, and a patient junction. A sampling path 113 from the section 110 to the liquid processing and analysis apparatus 140 is included.

  Further, the liquid processing and analysis device 140 may include, but is not limited to, a controller, a liquid sensor, a fluid regulator, and a wireless, wired or fiber optic communicator. The wireless, wired, or optical fiber communication device performs information transmission within the collection system 100 or information communication between the collection system 100 and a wireless, wired, or optical fiber network. The control unit may include, but is not limited to, a valve, a pump, and the liquid sensor includes, but is not limited to, a pressure sensor, a temperature sensor, a hematocrit sensor, a hemoglobin sensor, a colorimetric sensor, and a gas (or “bubble” )) May include a sensor, and the fluid regulator may include, but is not limited to, a gas injector, a gas filter, a liquid (eg, plasma) separator.

  During operation of system 10/100/300/500/800, cassette 820, or apparatus 140, path 20 and liquid processing network of liquid processing system 10 can reach a maximum extraction state. The maximum extraction state refers to a state in which the volume or amount of bodily fluid that has been extracted or acquired from the patient and present in the liquid processing network in the normal operating cycle of the system or device 10 is present. The maximum volume or volume of bodily fluid that corresponds to the maximum extraction state is the waste fluid that may be present in the liquid processing system 10 (eg, in one or more waste tubes and / or waste containers). All body fluids are removed.

  The maximum extraction area refers to the portion of the liquid processing network occupied by body fluids when the system 10/100/300/500/800, cassette 820, or device 140 is in the maximum extraction state. The maximum extraction area is defined by the patient end of the liquid treatment network. The patient end is the end of the liquid treatment network closest to the patient P, such as the patient junction 110/1100/1200, or a suitable junction of the liquid pathway or liquid network interposed between the liquid treatment network and the patient P. Part or region. Alternatively, the patient-side end may be the junction 230, or the end of the junction 110 opposite the device 140, or the sampling element 220 adjacent to the junction 1100/1200 when referring to FIG. An end can be included.

  In one embodiment, the maximum extraction state is reached in multiple operating states during operation of the collection system 100 or cassette 820. The plurality of operation states each indicate an operation state in which a sample can be distributed to different regions of the liquid processing network of the liquid processing system 10. Each of these different regions shall define a maximum extraction region of the liquid treatment network, and each of these regions has a maximum volume approximately equal to the maximum volume corresponding to the maximum extraction state.

  The first operating state leading to the maximum extraction state is a state in which body fluid is first withdrawn from the patient P and enters the patient junction path 112, as shown in FIG. 7C. As already explained, this step is preferably continued until the body fluid sample S has just passed through the junction of the paths 112, 113. In one embodiment, in order to ensure the presence of a sufficient amount of sample S, when drawing blood into the patient junction path 112, after a change in the output of the colorimetric sensor 311 indicates the presence of blood, The liquid extraction process is continued until a predetermined time has elapsed. In other specific embodiments, other types of sensors (eg, hemoglobin sensors or hematocrit sensors) are used. The sensor advantageously provides a signal indicating the presence of bodily fluid at the sensor location. In the state shown in FIG. 7C, the maximum extraction region is a portion of the path 112 occupied by the extracted body fluid from the patient side end to the head of the body fluid column. In one embodiment where a portion of the withdrawn bodily fluid is diluted with another liquid, the diluted liquid is removed from the volume that defines the maximum extraction state or maximum extraction area.

  The second operation state that reaches the maximum extraction state is a state in which bodily fluid enters the collection path 113 from the patient junction path 112, as shown in FIG. 7D. The maximum extraction region in this state is occupied by the extracted body fluid from the patient side end to the tip of the body fluid column in the path 112 and from the junction point of the paths 112 and 113 to the tip of the body fluid column in the path 113. It includes portions of paths 112 and 113. In certain embodiments where the state shown in FIG. 7D has the same volume or volume of body fluid as the state shown in FIG. 7C, both the state of FIG. 7C and the state of FIG. 7D each define a different maximum extraction region. can do. Here, when the body fluid is sent into the path 113 shown in FIG. 7D, when a new body fluid is extracted from the patient to the path 112, the state shown in FIG. 7C is the volume or amount of the body fluid extracted from the state shown in FIG. 7D. Note that the state shown in FIG. 7C is no longer the maximum extraction state and no longer the maximum extraction region, as it will be less.

  If the volume of body fluid in the system is equal to that shown in FIG. 7D, a further maximum extraction state is reached and a further maximum extraction region is defined in the state shown in FIGS. 7E, 7F. Here, the maximum extraction area is divided into a plurality of small areas by bubbles 702, 703, and 704.

  The maximum extraction area (and the maximum volume of bodily fluid drawn into the system during a normal measurement cycle) is preferably 400 μl or less in volume. In a further embodiment, the maximum extraction area or the maximum body fluid extracted is 300, 200, 100, 50 μl in volume.

  Particular embodiments include the liquid processing system 10, the collection system 100/300/500/800, the cassette 820, or the device 140 (or any suitable system or device having a fluid path in fluid communication with the desired body fluid of the patient P). A method of collecting and / or analyzing the body fluid of the patient P in a small volume using a system such as The method includes injecting an infusate into a patient via a fluid path 20 (eg, path 112), and occasionally a sample of bodily fluid from the patient via the liquid path 20 (or other path extending to the patient). A step of removing the. The step of withdrawing the sample can include the step of withdrawing the sample beyond the patient end of the pathway, as described in detail above.

  The sample removed is preferably 3 ml or less in volume, and in other embodiments, 2 ml or less, 1 ml or less, 400 μl or less, 300 μl or less, 200 μl or less, 100 μl or less, 50 μl or less. The method further includes analyzing at least a portion of the extracted sample and measuring the concentration or level of at least one analyte such as glucose, lactic acid, carbon dioxide, or hemoglobin based on the analysis. The analysis is accessible via path 20 (or system 10/100/300/500/800, cassette 820, or operably linked to path 20), analyte detection system 334/1700, or other suitable It can be performed by an analyte detection system such as a spectroscopic or non-spectral system.

  In the case where the extracted body fluid contains whole blood, the method can further include the steps of separating plasma from the blood and analyzing the separated plasma. The method can further include returning a portion of the sample of withdrawn bodily fluid to the patient, for example as described with reference to FIGS. 7F and 7G.

  While the invention has been disclosed using specific preferred embodiments and examples, those skilled in the art will recognize that the invention extends to other alternative embodiments beyond those specifically disclosed herein, and It is understood that the use of the present invention, obvious modifications of the present invention, and equivalents are also included. Accordingly, the scope of the invention is not limited to the individual embodiments disclosed herein, but is determined only by a fair reading of the claims set forth below.

It is the schematic of the liquid processing system of one embodiment. It is the schematic of a liquid processing system, Comprising: It is sectional drawing of the liquid processing and analyzer of a liquid processing system. 1B is a cross-sectional view of the tube bundle of the liquid treatment system of FIG. 1A taken along lines 1B-1B. It is the schematic of the collection device of one embodiment. It is the schematic which shows the detail of the collection device of one Embodiment. It is the schematic of the collection part of one Embodiment. It is the schematic of the collection device of one embodiment. 1 is a schematic view of an embodiment of a gas injection manifold. FIG. 1 is a schematic view of an embodiment of a gas injection manifold. FIG. 7A to 7J are schematic diagrams of a method using the infusion and blood analysis system, and FIG. 7A is a diagram illustrating an infusion method for a patient according to an embodiment. 7B to 7J are diagrams illustrating steps of a method of collecting from a patient, and FIG. 7B is a diagram illustrating a process of removing liquid from a part of the first path and the second path. It is a figure which shows the process of pumping a sample into the 1st path | route. It is a figure which shows the process of drawing in a sample to a 2nd path | route. It is a figure which shows the process of inject | pouring air into a sample. It is a figure which shows the process of removing a bubble from a 2nd path | route. It is a figure which shows the process of returning the blood of a 2nd path | route to a patient. It is a figure which shows the process of extruding a sample partially to a 2nd path | route, and then extruding a liquid and a bubble further. It is a figure which shows the process of extruding a sample partially to a 2nd path | route, and then extruding a liquid and a bubble further. It is a figure which shows the process of extruding a sample to an analyzer. It is a front perspective view of the collection device of one embodiment. It is a schematic front view of the cassette which comprises the collection device of one embodiment. It is a schematic front view of the instrument part which comprises the collection device of one embodiment. It is a figure which shows the patient artery junction part of one Embodiment. It is a figure which shows the patient vein junction part of one Embodiment. 13A, 13B, and 13C are various views of the pinch valve of one embodiment, and FIG. 13A is a front view of the pinch valve. It is sectional drawing of a pinch valve. It is sectional drawing of a pinch valve in the state where one valve is a closed position. 14A and 14B are various views of the pinch valve according to the embodiment, and FIG. 14A is a front view of the pinch valve. It is sectional drawing of a pinch valve in the state where one valve is a closed position. It is a side view of the separator of one embodiment. It is a disassembled perspective view of the separator shown in FIG. It is a figure which shows the liquid analyzer of one Embodiment. It is a top view of the cuvette used with the apparatus shown in FIG. It is a side view of the cuvette shown in FIG. It is a disassembled perspective view of the cuvette shown in FIG. It is the schematic of the sample preparation part of one Embodiment. It is a perspective view of the liquid processing and analyzer of other embodiment provided with the central instrument part and the cassette which can be attached or detached. FIG. 4 is a partially cut away side view of a liquid processing and analysis apparatus with the cassette removed from the central instrument section. FIG. 22B is a cross-sectional view of the liquid processing and analysis apparatus shown in FIG. 22A with the cassette attached to the central instrument section. FIG. 22B is a cross-sectional view of the cassette of the liquid processing and analysis apparatus shown in FIG. 22A along line 23A-23A. FIG. 23B is a cross-sectional view of the cassette shown in FIG. 23A along line 23B-23B. FIG. 3 is a cross-sectional view of a liquid processing and analysis apparatus having a network for liquid processing, and shows a state in which the rotor of the cassette is oriented substantially in the vertical direction. FIG. 3 is a cross-sectional view of a liquid processing and analysis apparatus having a network for liquid processing, and shows a state in which the rotor of the cassette is directed substantially in the horizontal direction. It is a front view of the central instrument part of the liquid processing and analyzer shown in FIG. 23C. It is sectional drawing of the liquid processing and analyzer which has the network for liquid processing of other embodiment. It is a front view of the central instrument part of the liquid processing and analyzer shown to FIG. 24A. It is a front view of a rotor having a sample element holding a sample fluid. FIG. 25B is a rear view of the rotor of FIG. 25A. FIG. 25B is a front view of the rotor of FIG. 25A, showing the sample element filled with the sample fluid. FIG. 25C is a front view of the rotor of FIG. 25C, showing a state after the sample fluid is separated. FIG. 25B is a cross-sectional view along line 25E-25E of the rotor of FIG. 25A. It is an expanded sectional view of the rotor of FIG. 25E. It is an exploded perspective view of the sample element used with a liquid processing and analysis device. It is a perspective view of the sample element of the assembled state. It is a front view of the liquid boundary part used with a cassette. It is a top view of the liquid boundary part of FIG. 27A. It is an enlarged side view of the liquid boundary part engaged with the rotor. FIG. 22B is a cross-sectional view along line 28-28 of the central instrument portion of the liquid processing and analysis apparatus of FIG. 22A. A graph showing the absorption spectra of various components that may be present in a blood sample. The figure which shows the change of the absorption spectrum of the blood which added the component shown in FIG. 29 with respect to the blood and glucose concentration of a sample group which subtracted the contribution by water from a spectrum. The figure explaining the analysis method of one embodiment which measures the density | concentration of a test substance in the state which can think of presence of an interfering substance. The figure explaining the method of one Embodiment which identifies the interference substance of a sample used with embodiment shown in FIG. The graph for demonstrating the method of one Embodiment shown in FIG. The graph for further explaining the method shown in FIG. FIG. 32 illustrates an embodiment method for generating a model for identifying possible interfering substances in a sample for use with the embodiment shown in FIG. It is the schematic explaining the production | generation method of one Embodiment of the interference substance spectrum rescaled at random. It is a graph which shows the density | concentration distribution of the interference substance of one Embodiment used with embodiment shown in FIG. It is the schematic explaining the production | generation method of one Embodiment of a mixed interference substance spectrum. It is the schematic explaining the production | generation method of one Embodiment of an interference substance weighted spectrum database. The graph which shows the influence which an interfering substance has on the error of a glucose estimated value. 40A, 40B, 40C, and 40D, respectively, are two different techniques: a Fourier transform infrared (FTIR) spectrometer (shown as a triangle and a solid line) with an interpolation resolution of 1 cm ⁻¹ , and 140 nm at 7.08 μm. Using 25 finite bandwidth IR filters (indicated by circles and chain lines) with a half wave height full width value (FWHM) bandwidth of 28 cm ⁻¹ corresponding to a bandwidth varying from 10 μm to 279 nm and a Gaussian distribution Is a graph comparing the absorption spectrum of glucose and various interfering substances with a path length of 1 μm, and FIG. 40A is a graph comparing glucose and mannitol. It is the graph which compared glucose and dextran. It is the graph which compared glucose and n-acetyl L cysteine. It is the graph which compared glucose and procainamide. 6 is a plasma spectrum graph showing six blood samples collected from three blood donors in arbitrary units with a wavelength range of 7 μm to 10 μm, and the symbols on the curves represent the central wavelengths of 25 filters, respectively. Show. It is a figure which shows the spectrum of the sample population of six samples containing a random quantity of mannitol when a density | concentration level is 1 mg / dL and a path | route length is 1 micrometer. It is a figure which shows the spectrum of the sample population of six samples containing a random amount of dextran when a density | concentration level is 1 mg / dL and a path | route length is 1 micrometer. It is a figure which shows the spectrum of the sample population of six samples containing a random amount of n-acetyl L cysteine when the concentration level is 1 mg / dL and the path length is 1 μm. It is a figure which shows the spectrum of the sample population of six samples containing a random amount of procainamide when a concentration level is 1 mg / dL and a path length is 1 μm. A graph comparing the calibration vector obtained by training in the presence of mannitol with the calibration spectrum obtained by training only a clean plasma spectrum. Graph comparing the calibration vector obtained by training in the presence of dextran with the calibration spectrum obtained by training only the clean plasma spectrum. A graph comparing the calibration vector obtained by training in the presence of n-acetyl Lcysteine with the calibration spectrum obtained by training only a clean plasma spectrum. A graph comparing the calibration vector obtained by training in the presence of procainamide with the calibration spectrum obtained by training only the clean plasma spectrum. Schematic of the specimen detection system of other embodiments. The top view of the filter wheel of embodiment suitable for the specimen detection system shown in FIG. The fragmentary sectional view of the sample detection system of other embodiments. 46 is a detailed sectional view of the sample detector of the specimen detection system shown in FIG. 46. FIG. FIG. 47 is a detailed sectional view of a reference detector of the specimen detection system shown in FIG. 46.

Claims (72)

Providing a liquid treatment system having one or more liquid paths;
Injecting an infusate into an extracorporeal fluid line via the one or more liquid pathways using the liquid processing system;
Using the liquid processing system to obtain a sample of 400 μl or less of bodily fluid from the fluid tube via the one or more liquid paths;
Using a sample detection system operatively associated with the liquid processing system to analyze at least an analysis portion of the acquired sample and measuring a concentration of at least one sample to collect a body fluid Method. Further separating the acquired sample into a first part and a second part;
Returning the second portion to the fluid line without analysis.   The method of claim 2, wherein the first portion is 60 μl or less in volume.   The method of claim 2, wherein the first portion is 40 μl or less in volume.   The method of claim 2, further comprising the step of separating the first portion into a plurality of portions, one of the plurality of portions including the analysis portion.   The method of claim 5, wherein the analysis portion is 10 μl or less in volume.   The method of claim 1, wherein the analyte is glucose.   The method of claim 1, wherein the specimen is lactic acid.   The method of claim 1, wherein the analyte is carbon dioxide.   The method of claim 1, wherein the specimen is blood. Further comprising separating plasma from said blood,
The method of claim 10, wherein analyzing at least a portion of the acquired sample comprises analyzing the plasma.   The method according to claim 1, wherein the obtained sample has a volume of 300 μl or less.   The method according to claim 1, wherein the obtained sample has a volume of 200 μl or less.   The method according to claim 1, wherein the obtained sample is 100 μl or less in volume.   The method of claim 1, wherein the acquired sample is 50 μl or less in volume.   The method of claim 1, further comprising returning a portion of the acquired sample to the fluid line.   The acquired sample is of sufficient volume to facilitate delivering at least a portion of the acquired sample to the analyte detection system and measuring the concentration of the analyte. The method described.   The method of claim 1, wherein obtaining the sample comprises withdrawing the sample beyond a patient end of the one or more fluid pathways.   The method of claim 1, wherein analyzing at least a portion of the acquired sample comprises optically analyzing at least a portion of the acquired sample.   20. The method of claim 19, wherein optically analyzing at least a portion of the acquired sample includes spectroscopic analysis of at least a portion of the acquired sample. A liquid treatment network configured to access a patient's bodily fluid and having a patient end;
A pump system coupled to the liquid treatment network, wherein the pump system operates to infuse an infusate through the liquid treatment network toward the patient; and from the patient to the bodily fluid A pump system having a second mode that operates to withdraw a sample of liquid into the liquid treatment network;
A body fluid treatment system comprising: an analyte detection system that is accessible to the liquid treatment network and configured to measure at least a portion of the specimen of the extracted body fluid sample;
The liquid treatment network has a maximum extraction region having a volume of 400 μl or less corresponding to the maximum extraction state of the body fluid treatment system.   The body fluid treatment system according to claim 21, further comprising a sample preparation unit that separates the extracted sample into a first part and a second part that is returned to the patient without analysis.   The body fluid treatment system according to claim 22, wherein the first part has a volume of 60 μl or less.   23. The body fluid treatment system according to claim 22, wherein the first portion has a volume of 40 μl or less.   23. The body fluid processing system according to claim 22, wherein the sample preparation unit is further configured to separate the first part into a plurality of parts, and one of the plurality of parts includes an analysis part.   26. The body fluid treatment system according to claim 25, wherein the analysis part has a volume of 10 μl or less.   The body fluid treatment system according to claim 21, wherein the specimen is glucose.   The body fluid treatment system according to claim 21, wherein the specimen is blood.   30. The bodily fluid treatment system according to claim 28, further comprising a separation portion that is in communication with the liquid treatment network and configured to separate at least one component from the sample of bodily fluid extracted.   30. The bodily fluid processing system according to claim 29, wherein the bodily fluid is blood, the at least one component is plasma, and the sample detection system is configured to measure the sample contained in the plasma.   The body fluid treatment system according to claim 21, wherein the maximum extraction region is 300 μl or less in volume.   The body fluid treatment system according to claim 21, wherein the maximum extraction region has a volume of 200 µl or less.   The bodily fluid treatment system according to claim 21, wherein the maximum extraction region is 100 μl or less in volume.   The body fluid treatment system according to claim 21, wherein the maximum extraction region has a volume of 50 µl or less.   The maximum extraction state is such that, during a normal operation cycle of the bodily fluid treatment system, the amount of the bodily fluid present in the liquid treatment network is maximized, excluding waste bodily fluid contained in the liquid treatment network. The bodily fluid treatment system according to claim 21, which is in a state of the bodily fluid treatment system.   The body fluid treatment system of claim 21, wherein the maximum extraction region is a portion of the liquid treatment network that is occupied by the body fluid in the maximum extraction state.   The body fluid treatment system of claim 21, wherein the maximum extraction region is defined by the patient-side end of the liquid treatment network.   The bodily fluid treatment system according to claim 21, wherein the specimen detection system includes an optical detection system.   39. A body fluid treatment system according to claim 38, wherein the optical detection system comprises a spectroscopic detection system.   The body fluid treatment system according to claim 21, wherein the pump system includes a first single mode pump operating in the first mode and a second single mode pump operating in the second mode. A liquid pathway;
An analyzer that is accessible to the liquid path and configured to deliver information about analyte measurement of the sample;
A processor in conjunction with the analyzer;
A body fluid analysis system comprising stored program instructions,
The stored program instructions are stored in the body fluid analysis system.
(A) injecting an infusate toward the patient side end of the liquid path;
(B) extracting the sample in a volume of 400 μl or less from the patient side end through the liquid path toward the analyzer;
(C) analyzing the at least a portion of the extracted sample to measure the concentration of at least one specimen, the body fluid analysis system executable by the processor to operate.   42. The body fluid analysis system according to claim 41, further comprising a sample preparation unit that separates the extracted sample into a first part and a second part that is returned to the patient without analysis.   43. The body fluid analysis system according to claim 42, wherein the first portion has a volume of 60 μl or less.   43. The body fluid analysis system according to claim 42, wherein the first portion has a volume of 40 μl or less.   43. The body fluid analysis system according to claim 42, further comprising a sample preparation unit configured to separate the first part into a plurality of parts, wherein one of the plurality of parts includes an analysis part.   46. The body fluid analysis system according to claim 45, wherein the analysis portion has a volume of 10 μl or less.   42. A body fluid analysis system according to claim 41, wherein the analyzer comprises a spectroscopic analyzer.   42. The body fluid analysis system according to claim 41, wherein at least one specimen of the extracted sample is selected from the group consisting of glucose, carbon dioxide, lactic acid, and hemoglobin.   42. The body fluid analysis system according to claim 41, wherein the extracted sample has a volume of 300 μl or less.   42. The body fluid analysis system according to claim 41, wherein the extracted sample has a volume of 200 μl or less.   42. The body fluid analysis system according to claim 41, wherein the extracted sample has a volume of 100 μl or less.   42. The body fluid analysis system according to claim 41, wherein the extracted sample has a volume of 50 μl or less.   42. The body fluid analysis system according to claim 41, further comprising a sample preparation unit capable of communicating with the liquid path.   54. The body fluid analysis system according to claim 53, wherein the sample preparation unit is configured to separate at least one component from the extracted sample.   55. The body fluid analysis system according to claim 54, wherein the sample preparation unit includes a centrifuge.   55. The body fluid analysis system according to claim 54, wherein the sample preparation unit includes a filter. A liquid processing module usable with a body fluid analyzer having a pump system and an analyte detection system,
The liquid treatment module is
A liquid delivery network having a patient end and a boundary portion spaced from the patient end, engaged with the pump system, and configured to obtain body fluid from the patient;
A sample analysis cell that is accessible to the liquid delivery network and configured to interface with the analyte detection system;
The liquid delivery module, wherein the liquid delivery network has a maximum extraction area of 400 μl or less in volume corresponding to the maximum extraction state of the liquid delivery network.   58. The liquid processing module according to claim 57, further comprising a sample preparation unit that separates the body fluid obtained from the patient into a first part and a second part that is returned to the patient without analysis.   59. The liquid processing module according to claim 58, wherein the first portion has a volume of 60 [mu] l or less.   59. The liquid processing module according to claim 58, wherein the first portion has a volume of 40 [mu] l or less.   59. The liquid processing module of claim 58, further comprising the sample preparation portion configured to separate the first portion into a plurality of portions, wherein one of the plurality of portions includes an analysis portion.   62. The liquid processing module according to claim 61, wherein the analysis portion has a volume of 10 [mu] l or less.   58. The liquid processing module according to claim 57, wherein the maximum extraction region is 300 μl or less in volume.   58. The liquid processing module according to claim 57, wherein the maximum extraction region has a volume of 200 μl or less.   58. The liquid processing module according to claim 57, wherein the maximum extraction region has a volume of 100 μl or less.   58. The liquid processing module of claim 57, wherein the maximum extraction region is 50 [mu] l or less in volume.   The liquid processing module in which the amount of the body fluid existing inside the liquid delivery network is maximized when the maximum extraction state excludes body fluid for waste inside the liquid delivery network during a normal operation cycle of the liquid processing module. 58. The liquid processing module according to claim 57, wherein:   58. The liquid processing module of claim 57, wherein the maximum extraction region is a portion of the liquid delivery network that is occupied by the body fluid when in the maximum extraction state.   58. The liquid processing module according to claim 57, further comprising a sample preparation unit capable of communicating with the liquid delivery network.   70. The liquid processing module of claim 69, wherein the sample preparation unit is configured to separate at least one component from the bodily fluid obtained from the patient.   The liquid processing module according to claim 70, wherein the sample preparation unit includes a centrifuge. The liquid processing module according to claim 70, wherein the sample preparation unit includes a filter.

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