WO2000064492A1 - Dispositif de surveillance optique de la concentration d'un bioanalyte dans le sang et procedes associes - Google Patents

Dispositif de surveillance optique de la concentration d'un bioanalyte dans le sang et procedes associes Download PDF

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Publication number
WO2000064492A1
WO2000064492A1 PCT/US2000/011268 US0011268W WO0064492A1 WO 2000064492 A1 WO2000064492 A1 WO 2000064492A1 US 0011268 W US0011268 W US 0011268W WO 0064492 A1 WO0064492 A1 WO 0064492A1
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glucose
beads
apparams
sensor body
light
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PCT/US2000/011268
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English (en)
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Jerome S. Schultz
Ralph Ballerstadt
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University Of Pittsburgh Of The Commonwealth System Of Higher Education
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Publication of WO2000064492A1 publication Critical patent/WO2000064492A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose

Definitions

  • the present invention relates to apparatus and an associated method for providing a bioanalyte monitor, such as a glucose monitor, which may be implanted for transdermal use and employs optical means for determining bioanalyte concentration in body tissues. More specifically, it relates to such a system wherein bioanalyte-specific receptors may be bound within the pores of porous beads in the absence of certain levels of bioanalyte in a processing chamber within which they are contained and will emerge from the pores and bind with the bioanalyte when a certain concentration of bioanalyte is received within the chamber.
  • a bioanalyte monitor such as a glucose monitor
  • Accurate monitoring of bioanalyte levels in patients can be vital to the patient's health.
  • Monitoring of glucose in diabetic patients is invaluable in order to prevent blindness, kidney diseases, necrosis of nerve tissue, as well as other complications. This will help to improve the quality of life of those people who are affected with diabetes mellitus type I.
  • a highly specific sensor such as a glucose biosensor, if reliable, is widely thought to assume the glucose-sensing function of the beta cells, the natural organ responsible for the glucose level regulation via insulin in healthy humans.
  • Such a sensor when employed in conjunction with a controllable insulin pump, could function as an artificial pancreas.
  • optical techniques can be used for remote sensing of analytes and other substances.
  • Optical sensors have certain advantages over electrochemical sensors. For example, optical sensors are immune to electromagnetic interferences. Further, the use of optical fibers can be advantageous when the samples are relatively inaccessible, for instance, in case of in vivo tests.
  • Optical fiber wave guides allow the transportation of an optical signal over large distances from the sample to an associated meter, for example. Optical fibers can be exposed to varying environments without suffering substantial destruction or deterioration as a result. For a general discussion of sensors and of optical fiber sensors in particular see Wolfbeis, Fibre-optic Sensors in Biomedical Sciences, Pure and Appl. Chemistry. Vol. 59, No.
  • the intensity of light emitted from or absorbed by the receptor-site/competing ligand complexes or the free competing ligand alone can be measured by a fluorimeter. This measurement gives a quantitative indication of the concentration of plasma constituents in the blood.
  • One limitation of the system of U.S. Patent 4,334,438 is that as the fluorescently-labeled compound is bound to the wall, the optical fiber must be inserted exactly straight inside the hollow fiber so that the amount of baseline fluorescence due to the dye-labeled competing ligand bound to the wall is minimized.
  • the glue seams must form a tight seal because with any leak, the chemical constituents of the sensor can escape.
  • the optical fiber within the hollow fiber configuration can also exhibit lack of stability such that any relative movement between the two fibers while in use affects the signal response.
  • the proteins which are immobilized are pumped through the fiber under the influence of pressure. This flow method results in variations in the amount of immobilized material along the inside wall, due to variations in the spongy surface causing a variability in the calibration curves between sensors during manufacture. There remains a need, therefore, for a sensor which overcomes these disadvantages.
  • U.S. Patent No. 4,892,383 discloses a fiber optic sensor which includes a modular reservoir cell body and a semi-permeable membrane, however, the sensor requires use of a reagent which precludes reversibility. See also U.S. Patent No.
  • United States Patent No. 4,849, 172 discloses an optical sensor having a gas permeable silicone matrix that contains a high concentration of an optical indicator consisting essentially of a mixture of derivatives of a polynuclear aromatic compound.
  • U.S. Patent No. 4,857,273 discloses another type of sensor involving enhancement of a light signal response by incorporating a partially reflecting, partially transmitting medium between a coupling structure and an optically dense body.
  • Optical sensors based on generating a resonance signal in a metallic medium have also been known. See U.S. Patent No. 4,877,747.
  • Other sensors based on detection of refractive index changes in gaseous liquids, solids or porous samples have been known. See U.S. Patent No. 4,815,843 and U.S. Patent No. 4,755,667.
  • United States Patent No. 4,577, 106 discloses a remote multi-position information gathering system for obtaining thermometric information from remote locations using fiber optics.
  • United States Patent No. 4,861,727 discloses a luminescent oxygen sensor using a lanthanide complex.
  • U.S. Patent 4,558,014 discloses assay apparatus employing fluorescence.
  • No. 3,785,772 discloses a device having a pair of syringes to withdraw blood from a patient, and a dialysis membrane to separate a particular blood constiment from the blood, a reactant which reacts with the chosen blood constiment to form a reactant- blood constiment complex the concentration of which is proportional to the concentration of the blood constiment.
  • This system requires replacement of the reactant after each measurement because the reactant and the blood constiment form an irreversible complex.
  • the system cannot measure an instantaneous change in the concentration of the blood constiment because of the time taken to remove the blood from the body and obtain a reaction with the reactant.
  • United States Patent No. 3,638,639 also discloses measurement of blood constituents outside the body. In this system, a catheter is inserted into the blood and lipids are passed through a membrane in the catheter and are dissolved in a solvent which is removed from the body to be analyzed.
  • United States Patent No. 3,939,350 shows a system for carrying out immunoassays using fluorescence to indicate the presence of a ligand to be detected.
  • oximeters which are photoelectric photometers, to non-invasively estimate the extent of blood oxygenation.
  • oximeters which are photoelectric photometers
  • a probe housing has an optical fiber associated therewith and has a membrane which is permeable to the analyte being studied.
  • the housing has a reflective surface member disposed between the optical fiber and membrane to define a dark chamber which does not allow light from the optical fiber to enter or exit the chamber.
  • a dye-labeled analog- analyte can pass through the reflective member to permit it to enter an adjacent light chamber where measurements related to the concentration of the analyte may be made. Excitation light from an optical fiber is received within the light chamber.
  • Immobilized receptors are provided within the housing preferably in the dark chamber.
  • the dye-labeled analog-analyte and analyte compete to bind with the immobilized receptors.
  • the dye-containing analog-analyte molecules which do not bind to immobilized receptors pass through the reflective surface member to the light chamber.
  • a light source acting through the optical fiber creates responsive fluorescent light to be emitted by the dye-containing analog-analyte with such responsive light being carried to the detector means.
  • the detector means employ this fluorescent light to determine concentration of the analyte in the sample.
  • an ]n vivo sensor which may be placed under the skin is employed. This system, however, employs two chambers alone with fiber optic means and a reflective divider between the two chambers.
  • the apparatus includes a sensor capsule having a processing chamber defined by a wall which has a membrane permeable to the analyte and receptor material disposed within the chamber and capable of chemically interacting with the analyte.
  • at least a portion of the sensor is translucent.
  • a light source which may be an optical fiber, causes light to impinge on the translucent portion of the capsule and pass therethrough. Responsive fluorescent light is generated and emitted.
  • Detector means receive and process the light to determine concentration of the analyte.
  • a dye-labeled analog-analyte may be provided within the chamber.
  • the sensor is said to be implantable and can be placed underneath the skin.
  • the apparatus and method of the present invention preferably provides a porous hollow sensor body which has a processing chamber containing one or a plurality of porous beads that are constructed to block or reduce the emission from a fluorescent dye contained therein and analyte-specific receptors which may be bound to helper molecules located within the porous beads.
  • the porosity of the hollow sensor body is such as to resist passage of the beads, receptors and helper molecules therethrough while permitting passage of the glucose component of the blood therethrough.
  • a light source causes excitation light to impinge on the processing chamber and when no glucose or glucose not reaching a certain level is present emitted responsive fluorescent light will be at a low level.
  • the glucose-specific receptors bound to the helper molecules will be positioned within pores of the beads with the beads preferably being made of opaque material or being dye-labeled so as to minimize florescence background light.
  • the bonds between the glucose-specific receptors and helper molecules will be severed as glucose binds to the glucose-specific receptors and the latter will freely diffuse out of the beads thereby increasing the level of responsive emitted fluorescent light emerging from the sensor body.
  • the beads will be dye-labeled chemically cross-linked dextran beads and the glucose- specific receptors will be fluorochrome-labeled Concanavalin A and the helper molecules will be dextran.
  • the porous bead is made of a material that blocks the emission of light from fluorescent dyes when they reside within the bead.
  • glucose-specific receptors are placed within the processing chamber. These fluorescently labelled receptors will be bound within the porous beads in the absence of certain levels of glucose in the processing chamber, and will not respond to excitation when they reside within this region. When a certain concentration of glucose is received within the processing chamber the receptors will emerge from the porous beads and will fluoresce when the processing chamber is exposed to an appropriate excitation light source.
  • Figure 1 is a partially schematic cross-sectional illustration of a porous hollow sensor for optical glucose monitoring of the present invention.
  • Figure 2 is a schematic cross-sectional illustration of the beads and associated receptors when the sensor has no glucose present.
  • Figure 3 is a figure substantially identical to Figure 2 except illustrates the condition of a certain level of glucose being present.
  • Figure 4 is a plot of absorption and fluorescence versus wavelength for chromophoric components of the particle-based affinity sensor of the present invention.
  • Figure 5 is a plot of time versus fluorescence with fluorescence given in arbitrary units and the glucose concentration indicated adjacent to the arrows.
  • Figure 6 is a plot of glucose concentration versus fluorescence response of the sensor.
  • Figure 7 is a plot of fluorescence response of the sensor versus time in the presence of a predetermined amount of glucose.
  • Figure 8 is a plot of fluorescence versus time for a sensor of the present invention in the absence of glucose. DESCRD7TION OF THE PREFERRED EMBODIMENTS
  • patient as used herein means members of the animal kingdom including human beings.
  • a porous hollow sensor body which may be a hollow body 2 which may be a hollow dialysis fiber, defines a processing chamber 4.
  • the sensor body 2 is, in the form shown, introduced under the skin 6 of a patient, preferably a distance D, which might be on the order of about 0.1 to 5 mm and preferably about 1 to 2 mm.
  • the porous hollow sensor body 2 is disposed adjacent to blood vessel 10 and communicates therewith due to the porosity of interstitial tissue.
  • the sensor body 2 contains a large volume of porous beads 14 which occupy about 50 to 80 percent of the volume of chamber 4.
  • the so bound glucose-specific receptors are disposed within pores in the porous beads 14 which are open to the exterior.
  • a suitable light source 20 which may be an optical fiber source, causes light beam 22 to impinge upon the porous hollow sensor body 2 which is either translucent or transparent, at least in part, so as to facilitate passage of the excitation light beam 22 through the skin 6 and sensor body 2.
  • This excitation light beam 22 when it impinges upon the glucose-specific receptors bound to glucose will create responsive fluorescent light to be emitted.
  • the chamber 4 substantially completely filled with beads so as to minimize gaps of a length significantly larger than the particle diameter which is about 20 to 50 ⁇ m.
  • the photodetector 26 receives the emitted fluorescent light 28 and converts the same into corresponding electrical signals which are delivered to processor 30 which may be in the form of a microprocessor or other computer means.
  • the processor 30 makes a determination of the glucose concentration which may be provided through any output apparatus 32 in hard copy, a visual display, such as a
  • CRT screen may be stored on magnetic storage media or in either the processor 30 or output device 32.
  • sensor body 2 contains another fluorescent dye, 12, which serves to calibrate for intensity of light that actually impinges on the sensor body.
  • the preferred location for the dye is within the sensor chamber 4.
  • Light source 20 provides a light beam 23 that excites the fluorescent dye 12 and causes the emission of light beam 29.
  • Fluorescent dye 12 is chosen so that the color of the light beam is different than light beam 28.
  • the relative intensities of light beam 28 and 29 can be used to compensate for changes in the intensity of light received by chamber 2.
  • the hollow fiber may have a length of about 0.2 to 1 cm and an external diameter of about 0.2 to 0.3 mm.
  • the ends of the hollow fiber may be sealed with a glue, such as cyanoacrylate, that is activated by water.
  • the geometry of the sensor is not limited to the shape of hollow fibers.
  • Dialysis fibers have shown an excellent history in kidney dialysis, are biocompatible, and have a short diffusion pathway which provides short response time.
  • the porous bead 50 may be of generally spherical configuration and have an external diameter of about 10 to 150 microns and preferably about 70 to 120 microns.
  • the beads 50 have a plurality of pores which are in communication with the exterior surface 52 of the bead 50.
  • the glucose-specific receptors such as 56, 58, 60 and 62, for example, will be bound to the helper molecules and positioned within the pores of the bead 50.
  • the excitation light beam 22 which has passed through the patient's skin and the outer wall of the porous hollow sensor body 2 which may be a hollow dialysis fiber, for example, will not create substantial responsive fluorescence.
  • the beads 50 are darkly colored with dyes to establish a broad spectrum light absorption band which includes the excitation and emission wavelengths of the fluorescence label on the glucose- specific receptors.
  • the emission light beam 28 which would normally contain glucose-induced fluorescence be either of small magnitude or non-existent.
  • the beads 50 may be made of an opaque material, such as porous carbon, for example.
  • a suitable bead for use in the present invention is that sold under the trade designation Sephadex G150 which has a high helper molecule density per unit weight of beads. This permits a high number of receptor molecules to be bound to them. Also, the beads can be very efficiently labeled with dyes. This promotes the production of a very high glucose-dependent fluorescence signal. Furthermore, this provides beads which are efficiently labeled with dyes. This provides efficient blockage of light passing into the beads thereby strongly attenuating the background fluorescence of the glucose-specific receptors bonded to the helper molecules and disposed within the pores of the beads. This serves to effect the desired reduction in background fluorescence thereby making the monitor more accurate.
  • Suitable dyes which could be used for this purpose are any dyes showing a substantial overlap of their absorption spectra with the excitation and emission spectra of the fluorochrome.
  • fluorescein and or similar fluorochromes are covalently linked to Con- A the combination of Pararosanilin and
  • Safranin O can be utilized to color the beads.
  • Sephadex beads (a trade designation of Pharmacia, Sweden) are microscopic beads of Dextran, (i.e. the helper molecules) containing terminal glucose residues. The dextran chains are cross-linked to give a three dimensional network.
  • a suitable glucose-specific receptor is the fluorochrome-labeled "Concanavalin A,” designated “Con A, " which is bonded to the helper molecule which may be Dextran attached to the beads 50.
  • Con-A is a mannose and glucose-specific protein that is extracted, and affinity-purified from seeds of the plant Canavalis ensiformis. It consists of two to four glucose-binding sites.
  • fluorescein described herein is only an example.
  • Other fluorochromes such as Alexa dyes may be beneficial as they have improved photostability and pH-independence.
  • Another aspect that has to be considered is the interference of auto skin fluorescence with the one of the fluorochrome in the wavelength range between 500 and 600 nm.
  • near-infrared fluorochromes may be preferred. In this wavelength region from 600 to 800 nm skin fluorescence is very low.
  • the dyes attached to the beads to block the fluorescence emission of the receptor should be changed as well, preferably showing a reasonably high absorption coefficient in this aforementioned wavelength region.
  • the bead 50 having a generally spherical outer surface 52.
  • the glucose concentration within chamber 4 has reached the desired or certain level and the glucose specific receptors, such as 70, 72, 74, 76, for example, have emerged from the pores of bead 50 and/or bonded to the glucose rather than the dextran helper molecules thereby creating fluorescent emission from the fluorochrome labeled glucose-specific receptors in chamber 4 to product fluorescent emission light beam 80 which is of greater intensity than that shown in Figure 2 and provides an accurate indication of glucose-concentration.
  • the fluorescence sensor response time may be on the order of about 300 to 500 seconds.
  • the relationship between fluorescence as contained in the emission light beam 80 and the glucose concentration is substantially linear from about 0 to 20 mM glucose concentration.
  • Light may be delivered and withdrawn from the skin by fiberoptic means or by a portable apparatus incorporating a light source, such as a focused laser beam using a lens, and a light modulating and amplifying unit, such as filters and photomultiplier, for example.
  • a light source such as a focused laser beam using a lens
  • a light modulating and amplifying unit such as filters and photomultiplier
  • the intensity of the glucose-induced fluorescence signal of a novel particle-based affinity hollow fiber sensor was optimized in order to be able to detect minimal fluorescence changes in a miniature hollow fiber sensor for optical transdermal glucose monitoring.
  • the glucose-sensing bioelements were Concanavalin- A (Con-A) labeled with Alexa 488 (a fluorescein substitute) and dyed Sephadex beads (G150).
  • the dyes were Safranin O and Pararosanilin which were chemically attached via divinyl sulphone to the beads. This procedure rendered the color of beads red- violet with an absorption peak at 530 nm.
  • Con A-loaded beads were enclosed into a short segment of a hollow fiber.
  • the beads occupied more than 50 % of the total volume of the hollow fiber lumen.
  • the binding reaction of Alexa 488-labeled Con-A inside the porous beads resulted in a reduction of fluorescence due to the intense light absorption of the dye-labeled beads at the excitation and emission wavelength of 490 and 520 nm respectively.
  • Alexa 488- Con A dissociates from the glucose-residues of the Sephadex beads and diffuses out of the beads into the field of view of the excitation light, leading to large increase in fluorescence (up to 8 times of the background fluorescence).
  • the matrix is represented by Sephadex beads, which are dyed with chromophores.
  • the absorption spectrum of the chromophore overlaps with the fluorescence excitation and emission spectra of the fluorochrome.
  • fluorochrome labeled Con A is dissociated from the beads and able to diffuse towards the extra-particle space where it can uninhibitedly fluoresce.
  • the performance of the fluorescence-altering binding reaction was tested inside a small segment of a hollow dialysis fiber, the envisaged encasement of the biosensing elements for future in- vivo studies.
  • Dialysis hollow fibers were from Kunststoffseidewerk (Pima, Germany).
  • the spectrophotometer (Turner, model 340, Bamstead, Indiana, USA) was used for measuring optical density.
  • Fluorescence measurements were done with the fluorescence spectrophotometer (LS50B, Perkin Elmer, Beaconsfield, UK).
  • the excitation and emission wavelengths of the spectrophotometer were set at 495 and 520 nm respectively.
  • the microcell adaptor Perkin Elmer part No. L225 0139
  • the flow-through cell LC cell accessory, Perkin Elmer part no. L225 0138
  • the fiber optic assembly Perkin Elmer part No. L225 0137
  • a bundled fiber cable length 1 m
  • the divinyl sulfone method was done according to a method previously reported by (Porath, et al., (1975) Agar derivatives for chromatography, electrophoresis and gel-bound enzymes.
  • H. Rigid agarose gels cross-linked with divinyl sulphone (DVS), J Chromatography 103, 49-62). This method was employed as a chemical linker between the Sephadex matrix and the amine groups of the dyes.
  • Sephadex G150 250 mg were pre-swollen in 20 ml distilled water overnight. The beads were washed over a sieve with several volumes of distilled water.
  • the bead suspension (12 ml) was then mixed with 12 ml of a 1 M sodium carbonate buffer solution (Na 2 C0 3 , pH 11.4) in a beaker. During the entire period of the procedure, the suspension was intensively stirred on a magnetic stirrer. DVS (300 ul) was added to the suspension and allowed to proceed for 1 hour. The beads were washed over a sieve with distilled water to remove non-bound DVS and equilibrated again with sodium carbonate buffer (pH 11.4). Safranin O and
  • Pararosanilin (each 30 mg) were dissolved in DMSO (1 ml). This solution was then added to the bead suspension and allowed to proceed for overnight. Glycine (1 g) was introduced to the mixture to neutralize remaining active DVS groups. After 1 hour the beads were transferred into a 15 ml plastic vial and centrifuged in order to remove non-bound dye molecules. The supernatant was discarded. The beads were re- suspended in DMSO, shaken, and centrifuged again. This procedure was repeated three more times. Distilled water was then used as extraction solvent. When the supernatant became color-free, the violet beads were dissolved in PBS and stored at room temperature.
  • a small volume of bead suspension (100 ⁇ l) was mixed with 2 to 3 times the volume of FITC-Con-A solution (see Table 1 for concentrations). After the binding equilibrium was reached, the tube was centrifuged, the supernatant discarded, and 200 ⁇ l of PBS was added. Hollow fibers (i.d. 195 ⁇ m) were cut to a length of 3-5 cm and glued into the tip of 10- ⁇ l pipette tip (Loctite 410, Rocky Hill, CT, USA). This served as a loading device. The particle suspension was aspirated into a 100- ⁇ l pipette tip by means of an adjustable pipette (Oxford, St.
  • the 10-fiber assembly was introduced into translucent tubing (length 6 cm) which diameter (0.4 cm) was slightly smaller than the width of the assembly plastic base, resulting in a snug fit of the sensor assembly inside the tubing (sensor holder).
  • the sensor holders were stored in PBS buffer under ambient light at room temperature (20-23 °C).
  • the sensor holder was incorporated into a flow system which was comprised of a waste beaker and pump for pushing glucose solutions through the sensor holder.
  • the head of the fiber bundle linked to the fluorescence spectrophotometer was positioned and held with a clamp holder.
  • the optical path length was 2 mm.
  • the out-coming excitation light covered the full width of the sensor fibers (core diameter of fiber bundle head 0.4 cm).
  • the whole assembly was covered with black felt to keep stray light out during the fluorescence measurements.
  • the fluorescence change in response to 0 and 20 mM glucose was monitored at various intervals.
  • the fluorescence signal in absence of glucose was maximized by slight changes of the fiber head above the sensor fiber in order to obtain comparative results.
  • the relative fluorescence response which is expressed as the percentage of the fluorescence change upon 20 mM glucose from the base line fluorescence in the absence of glucose, was normalized as percentage of the initial sensor response at the first day.
  • Sephadex beads (G150, diameter 20-50 ⁇ m) were intensively colored using a combination of two dyes, Safranin O and Pararosaniline.
  • the dyes were chemically attached to the beads via divinyl-sulphone (DVS).
  • the dyed beads showed a broad absorption shoulder at the wavelength of 540 nm (see Fig. 4).
  • Curve A is the excitation spectrum of fluorescein
  • Curve B is the emission spectrum of fluorescein
  • Curve C is the absorption spectrum of Safranin O and Pararosaniline.
  • the fluorochrome Alexa 488 has been chosen as a substitute for the more common fluorochrome fluorescein, because it is less prone to photo bleaching and inner-filter effect due to high fluorochrome concentration.
  • the binding capacity of the modified beads was 25 mg Con-A per ml wet bed volume twice as high as the original material (11 mg/ml wet bed volume). The increase in binding capacity can be explained by a better accessibility of Con A to glucose residues of the dextran matrix which are usually hidden inside unmodified beads.
  • FIG. 5 A typical time-response curve of a 1 week old sensor fiber which was positioned inside the flow-through cuvette is shown in Figure 5. Strong attenuation of the background fluorescence is noted. In the presence of 20 mm glucose, the fluorescence increased up to 4 times. The average time for the fluorescence change in response to glucose was 5 min. In Figure 6 the plot of fluorescence vs. glucose concentration is displayed. The graph is almost linear within the physiological concentration range of glucose (0 to 20 mM). The beads were loaded with different concentrations of Alexa 488-labeled Con-A by exposing them to various feed concentrations to find out the optimal change. It was noticed that the reproducibility of concentration measurements varied depending on the history of the sensor fiber assembly.
  • the change of fluorescence in response to 20 mM glucose was highest at around 0.15 mg/ml FITC-Con-A (see Table 2).
  • the relative exclusion volume of Sephadex G150 beads was estimated to be at circa 40% of the total fiber segment volume which the beads occupied. As a result, the volume accessible to the displaced
  • FITC-Con-A molecules was only around 60% of the total, yielding a molar FITC concentration 1.7 times as high. This translates into the end concentration around 12 ⁇ M FITC which is based on the molar labeling efficiency of 3.6 FITC per Con-A (Sigma data sheet). This optimal value is in agreement with the optimum fluorescence yield obtained by a fluorescence titration curve of pure FITC-labeled Con-A which showed a saturation at around 11M FITC (data not shown). At a higher lectin concentration (0.35 mg/ml), the relative and absolute change of the fluorescence was slightly decreased due to self-quenching. A molar FITC concentration of 21 ⁇ M was estimated at this Con-A concentration.
  • Sephadex G150 beads were pre-loaded with FITC-labeled Con-A and filled into glass capillaries (W. I mm, length 5 cm).
  • the background fluorescence which refers to glass capillaries either filled with non-modified or dye-modified beads in the absence of FITC-Con-A, was subtracted from the fluorescence emission data obtained in presence of FITC-Con-A. TABLE 2 Glucose-induced fluorescence change of the particle-based sensor system as a function of feed concentration of FITC-labeled Con-A.
  • the Con-A loaded beads were encased inside a hollow fiber segment.
  • the ratio of volume of beads to free space was about 3: 1.
  • Glucose solutions of 0 mM and 20 mM were alternately pumped through the quartz flow-through cell of the fluorescence spectrophotometer, and the fluorescence response was detected.
  • the present invention has provided an improved apparams and method for optically monitoring the concentration of glucose in blood. It provides a reversible glucose monitor wherein a hollow fiber contains porous beads which receive within its pores glucose-specific receptors bonded to dextran when the glucose in the sensor is at the zero level or below a certain level and the fluorescein-labeled bioligand in the form of the glucose-specific receptors bond to glucose when it is present above a certain level, thereby producing responsive fluorescence to excitation light introduced transdermally and producing fluorescent emission light which can be measured and processed by appropriate sensors.
  • the invention is not so limited and may be employed to determine concentration in a body fluid, such as blood, other analytes, such as Thyroxine, which is a hormone, Methotrexate, an anticancer agent, Gentamicin, an antibiotic, and Phenytoin, an anticonvulsive, for example, with appropriate helper molecules and receptors as will be known to those skilled in the art.
  • Thyroxine which is a hormone, Methotrexate, an anticancer agent, Gentamicin, an antibiotic, and Phenytoin, an anticonvulsive, for example, with appropriate helper molecules and receptors as will be known to those skilled in the art.
  • helper molecule such as dextran
  • a fluorescently-tagged receptor such as Con-A
  • the receptors such as Con-A
  • a fluorescently-tagged helper molecule such as dextran

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Abstract

L'invention concerne un dispositif et un procédé associé, qui servent à surveiller la concentration de récepteurs spécifiques d'analyte, tel que le glucose, dans le sang. Le dispositif comporte un corps de détecteur creux poreux qui définit une chambre de traitement contenant plusieurs billes poreuses, et un analyte, tel que des récepteurs spécifiques du glucose liés à des molécules assistantes. Une source lumineuse permet d'appliquer de la lumière d'excitation sur le corps de détecteur. Lorsque le glucose est présent selon une certaine concentration dans la chambre du corps de détecteur, de la lumière fluorescente émise en réaction apparaît et peut être détectée afin de déterminer la concentration de l'analyte. Les récepteurs spécifiques d'analyte peuvent être liés initialement aux molécules assistantes à l'intérieur des pores des billes lorsqu'un certain taux d'analyte présent dans la chambre du corps de détecteur n'est pas atteint. La présence de taux accrus d'analyte dans la chambre provoque la liaison des récepteurs spécifiques d'analyte à celui-ci, ce qui accroît l'intensité de la lumière fluorescente émise et fournit une indication sur la quantité d'analyte présent dans le sang. Lorsqu'ils sont liés à l'analyte, les récepteurs spécifiques d'analyte sont positionnés à l'extérieur des pores des billes de façon à être en contact plus sensible avec la lumière d'excitation. Les billes poreuses sont de préférence en matière opaque, ou peuvent être marquées à l'aide d'un colorant de manière à réduire au minimum les taux de lumière fluorescente en arrière-plan, afin de réduire au minimum la détection du récepteur spécifique du glucose marqué par un fluorochrome lorsque la substance se situe à l'intérieur des billes poreuses. L'invention peut être utilisée dans un détecteur de glucose et avec d'autres analytes.
PCT/US2000/011268 1999-04-27 2000-04-27 Dispositif de surveillance optique de la concentration d'un bioanalyte dans le sang et procedes associes WO2000064492A1 (fr)

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US10251776B2 (en) 2014-01-10 2019-04-09 Geelux Holding, Ltd. Devices configured to monitor biological parameters, and to provide treatment, at an Abreu brain thermal tunnel
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US10780222B2 (en) 2015-06-03 2020-09-22 Pacific Diabetes Technologies Inc Measurement of glucose in an insulin delivery catheter by minimizing the adverse effects of insulin preservatives
US11497405B2 (en) 2013-10-11 2022-11-15 Brain Tunnelgenix Technologies Corp. Method and apparatus for biological evaluation
US11872018B2 (en) 2015-03-10 2024-01-16 Brain Tunnelgenix Technologies Corp. Devices, apparatuses, systems, and methods for measuring temperature of an ABTT terminus

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US8774885B2 (en) 1996-09-04 2014-07-08 Geelux Holdings, Ltd. Device for generating a detectable signal based upon concentration of at least one substance
US7809417B2 (en) 1996-09-04 2010-10-05 Marcio Marc Abreu Contact lens for collecting tears and detecting analytes for determining health status, ovulation detection, and diabetes screening
US7756559B2 (en) 1996-09-04 2010-07-13 Marcio Marc Abreu Device for generating a detectable signal based upon antibody/antigen interaction
US6681127B2 (en) 1999-08-26 2004-01-20 Novartis Ag Ocular analyte sensor
US6850786B2 (en) 1999-08-26 2005-02-01 Novartis Ag Ocular analyte sensor
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US7403805B2 (en) 2001-02-23 2008-07-22 Marcio Marc Abreu Apparatus and method for noninvasive measurement of analytes from the conjunctiva using mid-infrared radiation
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US7187960B2 (en) 2002-04-22 2007-03-06 Marcio Marc Abreu Apparatus and method for measuring biologic parameters
US8328420B2 (en) 2003-04-22 2012-12-11 Marcio Marc Abreu Apparatus and method for measuring biologic parameters
US8834020B2 (en) 2003-04-22 2014-09-16 Geelux Holdings, Ltd. Thermal imaging system
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US8364217B2 (en) 2003-09-02 2013-01-29 Biotex, Inc. System, device and method for determining the concentration of an analyte
US7236812B1 (en) * 2003-09-02 2007-06-26 Biotex, Inc. System, device and method for determining the concentration of an analyte
US10227063B2 (en) 2004-02-26 2019-03-12 Geelux Holdings, Ltd. Method and apparatus for biological evaluation
US8502167B2 (en) 2004-04-26 2013-08-06 Sensors For Medicine And Science, Inc. Systems and methods for extending the useful life of optical sensors
WO2005106435A1 (fr) * 2004-04-26 2005-11-10 Sensors For Medicine And Science, Inc. Systemes et procedes permettant de prolonger la duree de vie de capteurs optiques
US7375347B2 (en) 2004-04-26 2008-05-20 Sensors For Medicine And Science, Inc. Systems and methods for extending the useful life of optical sensors
US9445767B2 (en) 2005-10-24 2016-09-20 Geelux Holdings, Ltd. Apparatus and method for measuring biologic parameters
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US9119530B2 (en) 2005-10-24 2015-09-01 Geelux Holdings, Ltd. Apparatus and method for measuring biologic parameters
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US11497405B2 (en) 2013-10-11 2022-11-15 Brain Tunnelgenix Technologies Corp. Method and apparatus for biological evaluation
US10251776B2 (en) 2014-01-10 2019-04-09 Geelux Holding, Ltd. Devices configured to monitor biological parameters, and to provide treatment, at an Abreu brain thermal tunnel
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