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WO2015161219A1 - Plate-forme de microdialyse - Google Patents

Plate-forme de microdialyse Download PDF

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Publication number
WO2015161219A1
WO2015161219A1 PCT/US2015/026414 US2015026414W WO2015161219A1 WO 2015161219 A1 WO2015161219 A1 WO 2015161219A1 US 2015026414 W US2015026414 W US 2015026414W WO 2015161219 A1 WO2015161219 A1 WO 2015161219A1
Authority
WO
WIPO (PCT)
Prior art keywords
platform
microdialysis
reagent
dialysate
well plate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2015/026414
Other languages
English (en)
Inventor
Champak Das
Anu AGGARWAL
Brad LEDDEN
Guochun WANG
Sai Kumar
Qian Sun
Chien Nguyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SFC Fluidics Inc
Original Assignee
SFC Fluidics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SFC Fluidics Inc filed Critical SFC Fluidics Inc
Publication of WO2015161219A1 publication Critical patent/WO2015161219A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14525—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using microdialysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
    • A61B5/14557—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases specially adapted to extracorporeal circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means

Definitions

  • the field of the invention is microdialysis, and in particular to an automated microdialysis platform for near real-time analysis.
  • Microdialysis is a well-known technique of sampling biomolecules by means of an implantable probe consisting of a membrane and an appropriate perfusion mechanism. It is widely used in neuroscience research since its inception almost three decades ago. Microdialysis is an organ-specific technique, depending on its physiological location; its potential application has been demonstrated in the liver, skin, blood, stomach, ears, eye, and brain. This technique, notwithstanding its extensive use in research, has not realized successful transition to actual clinical use, mainly because of the logistical inconvenience and the questionable clinical value of the information obtained from a patient care perspective.
  • the current method of monitoring based on microdialysis does not involve an all-in-one system; rather, the dialysate samples are collected periodically, labeled and stored, and subsequently analyzed offline in batches using bulky instruments.
  • This protocol not only requires trained practitioners, but also is prone to errors in handling tiny amounts of dialysate. The significant delay in the reported data may render this data clinically irrelevant, inappropriate, or unusable.
  • current commercial instruments are limited to the analysis of small molecule metabolic biomarkers like lactate, glutamate, pyruvate, and glucose; these instruments do not detect large molecule biomarkers such as proteins.
  • Availability of a nurse-friendly, fully integrated system that automatically collects, analyzes, and reports the dynamic changes in concentrations of clinically relevant biomarkers in near real time could significantly ameliorate the limitations of microdialysis for patient care in clinical applications, such as Neurointensive Care Units (NICU).
  • NICU Neurointensive Care Units
  • the present invention is directed to an automated and integrated bedside microdialysis platform with automated protocols for moving the perfusate from a reservoir to the microdialysis probe, and collecting and transporting the dialysate from the probe to an analyzer module wherein, in certain implementations, both small and large molecule biomarkers such as lactate, pyruvate, glutamate, glucose and S100B are detected and can be reported continuously for up to 24 hours without user intervention.
  • a disposable dialysate cartridge precludes cross-contamination issues.
  • This platform is applicable, in certain implementations, for early detection of biochemical changes that lead to secondary and comorbid pathologies after moderate to severe traumatic brain injury (TBI).
  • the early biomarkers of these biochemical changes are best tracked with cerebral microdialysis, and continuous online monitoring at bedside provides meaningful medical intervention in clinical settings such as Level 1 trauma centers.
  • Other implementations may be used in conjunction with different types of probes that are designed for detection of biomarkers in other bodily fluids, including but not limited to blood and urine.
  • FIGs. 1A and 1 B show an integrated X-Y slide with a well plate holder.
  • Fig. 2 is an assembly drawing showing the dispensing station consisting of independent multiple Z-direction actuators with fluid delivery lines.
  • FIG. 3 is drawing showing the analyte detection assembly using an optical detection assembly.
  • FIG. 4 shows the storage cartridge for reagents with options for
  • FIG. 5 shows the assembly of the X-Y slide, dispensing station with Z- actuators, analyte detection assembly and reagent cartridge storage system.
  • Fig. 6 shows the assembly of the X-Y slide, dispensing station with Z- actuators, analyte detection assembly, reagent cartridge storage system, and additional peristaltic pumps.
  • Fig. 7 is a drawing of the complete microdialysis platform.
  • Fig. 8 is a schematic drawing of the entire system.
  • Fig.9 is a schematic drawing of the reagent filling station and detection assembly.
  • Fig. 10 is a schematic drawing of the actuation arm operation for
  • Fig. 1 1 is a schematic drawing of the actuation arm operation for
  • Fig. 12 is a graph showing the detection of Lactate in the dialysate in the instrument.
  • Fig. 13 is a graph showing the detection of S100B (protein) in the
  • Fig. 14 is a graph showing the detection of glutamate and lactate (small molecules) in dialysate using electrochemical sensing.
  • Fig. 15 shows one configuration of the dispensing station with multiple Z- actuators.
  • the invention is directed to a microdialysis platform that provides a method of analyzing the dialysate for both small and large molecules in a real-time, continuous manner.
  • the platform is low maintenance and only requires user intervention for reagent/plate placement, which is required only every eight to twelve hours or, in some implementations, up to twenty-four hours.
  • the microdialysis platform is capable of working in combination with a dialysate collection unit, whereby a constant stream of dialysate is fed into the invention from said dialysate collection unit.
  • the invention is not limited to working in combination with a dialysate collection unit, and in certain implementations can work without the dialysate collection unit provided the invention is supplied with dialysate for analysis.
  • FIG. 7 shows a diagram of the complete and assembled microdialysis platform 10, showing the analyte housing for microdialysis platform 10, while a schematic for the overall operation of the microdialysis platform is shown in Fig. 8.
  • the microdialysis platform receives dialysate, which may come from a dialysate collection system or some other provider, which is carried out in one of a 96-well plate or 384-well plate or a similar high density well plate (for example, a 1536-well plate).
  • the microdialysis platform has the option for either an optical or electrochemical method of detection.
  • the microdialysis platform is capable of detecting a variety of molecular analytes, including lactate, pyruvate, glucose, glutamate, urea, and S100B protein.
  • the system performs a continuous detection of small molecules (such as lactate, pyruvate, glucose, and glutamate), and in another implementation, the microdialysis platform adds an additional ability to detect S100B protein or any other proteins which can be detected by immunoassay.
  • Other implementations may use different types of probes to detect biomarkers in, for example, extracellular fluid, blood, urine, or other bodily fluids.
  • Figure 1 B shows an X-Y slide 12 with a well plate 14 (in this example, the plate has 384 wells) mounted in that system, while Figure 1A shows well plate 14 being placed in or removed from X-Y slide 12.
  • the X-Y slide 12 is automated and can be programed to move laterally in an X- direction and/or Y-direction so that individual wells of the X-Y slide can be analyzed, as a specific position will correspond to a specific step of the analysis process. For example, one position will be associated with reagent loading, while another will be associated with detection, as shown in Figure 9.
  • the lateral movement of the X-Y slide 12 allows each individual well of well plate 14 to move to each specific position associated with a specific functionality.
  • the reagents and dialysates are introduced to the individual wells of well plate 14 via a reagent and dialysate dispensing station 16, as shown in Figure 2.
  • the dispensing station 16 comprises multiple individually addressable z-axis actuators 20 which move the associated delivery fluidic line 18 down to the individual wells of the well plate 14.
  • different wells are used to detect different molecular analytes, and thus multiple Z-direction actuators 20 in dispensing station 16 are employed for reagents along with one for the dialysate, although only one actuator 20 is shown in Figure 2 for clarity.
  • the configurations may vary, one such configuration would detect four small molecules (such as lactate, glutamate, glucose, and pyruvate) from the dialysate simultaneously, as shown in Figure 1 1 .
  • four individually addressable actuators 20 are configured to dispensing station 16.
  • the first actuator 20 (Z actuator-1 ) contains fluid delivery lines 18 for twelve individual wells in a three-by-four pattern. These delivery lines comprise standards for each of the four small molecules. For each analyte there are three standards so that a dynamic calibration curve can be generated, against which the sample will be compared to report its concentration in real-time.
  • a second actuator 20 contains fluidic lines 18 for delivering a Reagent A and a Reagent B for both lactate and pyruvate.
  • a third actuator 20 contains fluidic lines for delivering reagent for both glucose and glutamate.
  • the third actuator 20 contains
  • electrochemical sensors 22 for measuring glucose and glutamate, as shown in Figure 1 1 .
  • Some examples of commercially available electrochemical sensors (EC sensors) include sensors from Pinnacle Technology, Inc. and Sarrisa
  • Biomedical These electrochemical sensors are used to detect electrical signal from a reaction between a dialysate fluid and at least one reagent.
  • the fourth actuator 20 (Z actuator-4) connects to an arm that carries the sample dialysate delivery line.
  • additional protein detection immunoassay is integrated with the small molecule detection described previously. This configuration uses three additional actuators 20 to provide a delivery mechanism for secondary antibody and to provide a wash line. Further modification may be possible to have a single line of glucose and glutamate with electrochemical sensors 22 for electrochemical detection. Chemi-luminescence and fluorescence detection may also be employed in various implementations.
  • Figure 15 shows one configuration of the dispensing station 16, this configuration consisting of multiple z-actuator arms 20, each of which may have a unique function as described herein.
  • the invention may also use a hybrid approach, whereby some of the molecules are detected by colorimetric detection and some others are detected by electrochemical sensing, or a hybrid of other forms of detection including chemi-luminescence and fluorescence detection.
  • the optical detection assembly comprises a light source assembly 24, including a filter, steering optics, and collimation optics, and a detector 26.
  • the detector 26 may be a photomultiplier tube, a Photodiode, a CCD camera, or a CMOS based camera in various implementations. Because the X-Y slide 12 is capable of moving laterally in an X-direction and/or Y-direction, each individual well of well plate 14 can be moved inside the optical detection assembly's detection area.
  • the reagents used for this invention are stored in a reagent cartridge 28, which may be fitted with a temperature control unit, as shown in Figure 4.
  • the temperature of the reagents must be kept at a constant temperature for the period of operation, such as eight to twelve hours of operation in certain implementations, in order to ensure optical performance and accurate reporting of concentration.
  • Figure 5 shows the reagent cartridge inserted into the analyte housing, which is shown assembled with the dispensing station and analyte detection assembly on platform base.
  • Figure 6 shows the reagent cartridge inserted into the analyte housing, which is shown assembled with the dispensing station and analyte detection assembly, which is further connected to peristaltic pumps 15 which, in one configuration, may be used to provide dialysate fluids to the detection assembly.
  • the microdialysis platform comprises an on-board electronic control board and software for performing all necessary protocol and final data analysis.
  • An on-board screen or monitor consists of a graphical user interface for operating the invention.
  • This microdialysis platform detects specific concentrations (relevant to clinical range) of different molecules in the presence of all the interferents present in the interstitial fluid.
  • Figure 12 shows the calibration curve for lactate detection from dialysate performed in the instrument as an example. Similarly S100B detection in dialysate performed in the instrument is shown in Figure 13.
  • Figure 14 shows detection of lactate and glutamate in electrochemical sensing mode in dialysate.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Medical Informatics (AREA)
  • Biophysics (AREA)
  • Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne une plate-forme de détection multianalyte pour microdialyse, qui introduit un fluide de dialysat et un ou plusieurs réactifs dans un ensemble de détection et qui analyse le fluide de dialysat quasiment en temps réel en molécules de petite ou de grande taille. La plate-forme utilise des actionneurs actionnables individuellement pour introduire le fluide de dialysat et un ou plusieurs réactifs dans des puits individuels d'une plaque de puits. Un ensemble optique détecte la couleur générée par une réaction entre le fluide de dialysat et un ou plusieurs réactifs. Une carte électrique intégrée exécute les fonctions de l'analyse et un moniteur embarqué fournit à l'utilisateur la possibilité de commander la plate-forme par l'intermédiaire d'une interface graphique utilisateur. La plate-forme peut détecter la concentration en différentes molécules dans le fluide de dialysat.
PCT/US2015/026414 2014-04-17 2015-04-17 Plate-forme de microdialyse Ceased WO2015161219A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201461980983P 2014-04-17 2014-04-17
US61/980,983 2014-04-17

Publications (1)

Publication Number Publication Date
WO2015161219A1 true WO2015161219A1 (fr) 2015-10-22

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Application Number Title Priority Date Filing Date
PCT/US2015/026414 Ceased WO2015161219A1 (fr) 2014-04-17 2015-04-17 Plate-forme de microdialyse

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WO (1) WO2015161219A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106202944A (zh) * 2016-07-15 2016-12-07 鼎泰生物科技（海南）有限公司 一种血糖仪用户界面显示控制方法和装置

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6498010B1 (en) * 1997-04-21 2002-12-24 Randox Laboratories, Ltd Method for making a device for the simultaneous detection of multiple analytes
US20070020152A1 (en) * 2005-07-20 2007-01-25 Costello John J Iii Kinematic wellplate mounting method
US20070116600A1 (en) * 2005-06-23 2007-05-24 Kochar Manish S Detection device and methods associated therewith
US20110256630A1 (en) * 2010-04-19 2011-10-20 Clinton Charles M Assay apparatuses, methods and reagents
US20120270305A1 (en) * 2011-01-10 2012-10-25 Illumina Inc. Systems, methods, and apparatuses to image a sample for biological or chemical analysis
US20130137166A1 (en) * 2010-07-23 2013-05-30 Beckman Coulter, Inc. System and method including analytical units
CA2883413A1 (fr) * 2012-08-29 2014-03-06 Sfc Fluidics, Llc Dispositifs microfluidiques actionnes de facon electrochimique
US20140093908A1 (en) * 2012-09-28 2014-04-03 Sysmex Corporation Sample preparation apparatus and sample preparation method

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6498010B1 (en) * 1997-04-21 2002-12-24 Randox Laboratories, Ltd Method for making a device for the simultaneous detection of multiple analytes
US20070116600A1 (en) * 2005-06-23 2007-05-24 Kochar Manish S Detection device and methods associated therewith
US20070020152A1 (en) * 2005-07-20 2007-01-25 Costello John J Iii Kinematic wellplate mounting method
US20110256630A1 (en) * 2010-04-19 2011-10-20 Clinton Charles M Assay apparatuses, methods and reagents
US20130137166A1 (en) * 2010-07-23 2013-05-30 Beckman Coulter, Inc. System and method including analytical units
US20120270305A1 (en) * 2011-01-10 2012-10-25 Illumina Inc. Systems, methods, and apparatuses to image a sample for biological or chemical analysis
CA2883413A1 (fr) * 2012-08-29 2014-03-06 Sfc Fluidics, Llc Dispositifs microfluidiques actionnes de facon electrochimique
US20140093908A1 (en) * 2012-09-28 2014-04-03 Sysmex Corporation Sample preparation apparatus and sample preparation method

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106202944A (zh) * 2016-07-15 2016-12-07 鼎泰生物科技（海南）有限公司 一种血糖仪用户界面显示控制方法和装置

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