WO2000078207A2 - Detection d'analytes - Google Patents

Detection d'analytes Download PDF

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Publication number
WO2000078207A2
WO2000078207A2 PCT/GB2000/002358 GB0002358W WO0078207A2 WO 2000078207 A2 WO2000078207 A2 WO 2000078207A2 GB 0002358 W GB0002358 W GB 0002358W WO 0078207 A2 WO0078207 A2 WO 0078207A2
Authority
WO
WIPO (PCT)
Prior art keywords
skin
glucose
analyte
electroporation
voltage
Prior art date
Application number
PCT/GB2000/002358
Other languages
English (en)
Other versions
WO2000078207A3 (fr
Inventor
Robert Peter Chilcott
Caroline Anne Rowland
Original Assignee
The Secretary Of State For Defence
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
Priority claimed from GBGB9914408.1A external-priority patent/GB9914408D0/en
Application filed by The Secretary Of State For Defence filed Critical The Secretary Of State For Defence
Priority to AU55478/00A priority Critical patent/AU5547800A/en
Publication of WO2000078207A2 publication Critical patent/WO2000078207A2/fr
Publication of WO2000078207A3 publication Critical patent/WO2000078207A3/fr

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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, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A61B2010/008—Interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00747—Dermatology
    • A61B2017/00765—Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation

Definitions

  • This invention relates to the detection of analytes More particularly, the present invention relates to the non-invasive detection of analytes in body fluids.
  • body fluids It is often necessary to analyse body fluids for the qualitative or quantitative detection of analyte.
  • the body fluid most often analysed is blood which is obtained invasively, generally by venepuncture. Obtaining samples in this manner causes problems with the handling of the blood and with the disposal of contaminated equipment Additionally, where a subject has to regularly provide samples the inconvenience and pain associated with the taking of samples is both undesirable and burdensome This is a particular burden on subjects who rely on self monitoring for diagnosis of treatment, such as insulin- dependent diabetics or some epileptics who monitor their treatment following a fit. Problems also arise when blood must regularly be taken from infants, especially neonates, where blood volume is very small.
  • the present invention will now be described with particular reference to its preferred application to the monitoring of blood sugar levels. It is not. however, intended that the invention be limited to such use as ⁇ finds equal utility in other applications such as the detection of electrolytes, alcohol, anti-epileptic drugs, anti-asthmatic drugs such as theophyl ne. lithium, anti-depressants, digoxin. anti-cancer drugs such as fluorouracil, hormones such as vasopressin and especially anabolic steroids, proteins or the like
  • Capillary blood is generally used for assessing blood sugar levels, and is obtained from a "finger-prick" using a lancet or a proprietary blood sampling device. The blood obtained is placed on a reactive st ⁇ p and either allowed to react and the reaction assessed by eye or by a proprietary blood glucose monitoring deuce
  • the present inventors ha ⁇ e found that reverse electroporation of the skin can be used to obtain a sample of interstitial fluid, that is the fluid which bathes the cells of the upper skin layer (epidermis)
  • the interstitial fluid bathing the epidermis is in dynamic equilibrium with the systemic circulation and hence detection of analyte within the interstitial fluid is indicative of its presence in the systemic circulation and hence the quantification of the analyte in the fluid can be used to deduce systemic concentration
  • Iontophoresis employs a constant low voltage current which may be uncomfortable or at least inconvenient for the subject, whereas electroporation employs a rapid, high v oltage pulse, the pulse length of which may be sufficiently short for a pain response not to register
  • Use of electroporation is known for deli ery to cells, but it has not previously been used for extraction of fluid from cells since extraction of solutes at a cellular or tissue level was previously thought j not to yield sufficient quantities tor subsequent detection and
  • electroporation rather than iontophoresis to obtain the sample
  • advantages of using electroporation rather than iontophoresis to obtain the sample include the fact that electroporation is applied for only a short period of time (seconds to minutes) whereas iontophoresis has to be applied for long time periods (20 minutes or more), and the fact that electroporation is less irritating to the subject since it is reversible within a short (30 minute) time span
  • the invention provides apparatus for electroporating the skin in order to obtain a body fluid sample, the apparatus comp ⁇ sing means for applying an elect ⁇ cal charge to the skin, control means for controlling the charge applied to the skin and collecting means for collecting the body fluid obtained
  • the apparatus for electroporating the skin is associated w ith means for detecting the presence of analyte Ideally, the two are w ithin a single piece of apparatus
  • the means for applying an electrical charge to the skin tor example an electrode includes means for controlling the voltage delivered to the skin
  • the electrodes may be commercially av ailable electrodes which minimise the depth of the electric field and thus decrease the risk of stimulating the nerv es in the skin
  • the control means comprises a microprocessor.
  • Such a microprocessor may be commercially available.
  • the control means comprises signal processing means which convert a detector input signal into units of concentration of analyte in addition to controlling the magnitude and frequency of voltage application to the means for applying a charge to the skin and hence to the skin.
  • Control of the voltage may include control of the time for which the voltage is applied and the magnitude of the ⁇ oltage
  • Such means may include the incorporation of an appropnate micro-processing device which will automatically adjust the electrical parameters.
  • the apparatus is capable of being miniaturised, for example to resemble a w ⁇ stwatch.
  • the power unit may be associated with the strap rather than the main body of the watch.
  • a general indication of analyte concentration for example “low “ , "high” or “normal” may be given rather than an absolute value.
  • glucose "normal” may equate to 3 - 10 mmol.l “ ' . "low” to ⁇ 3 mmol.l ' and "high” to > 10 mmol.l ' 1 .
  • the apparatus may be linked to telemetry apparatus to allow remote monitoring of the subject, for example in an intensive care unit, a containment suite or a special care baby unit. Such remote monitoring may also prove advantageous in v etennary medicine.
  • the apparatus is configured to allow automatic sampling at predetermined time intervals.
  • the apparatus is linked to an alarm unit to indicate the presence of an abnormal level of analvte.
  • the analyte to be detected is selected from glucose, electrolytes, alcohol, anti- epileptic drugs, anti-asthmatic drugs such as theophyl ne, lithium, anti-depressants, digoxin. anti-cancer drugs such as fluorouracil. hormones such as vasopressin and especially anabolic steroids and proteins
  • the analyte is glucose
  • the present invention relates to the extraction of chemicals dissolved in the systemic circulation More particularly, in the second aspect the present invention relates to the non-invasi e extraction of solutes dissolved in the interstitial fluid of the skin
  • the present invention further provides a non-invasive method of detecting an analyte in a body fluid, the method including the steps of electroporating the skin to obtain a sample of interstitial fluid and analysing the fluid for the presence of analyte.
  • the skin may be bathed in an osmotically active solution to promote movement of solute from the interstitial tissue
  • the solute may be ionic, such as sodium chloride, or preferably non-ionic, such as glycerol
  • the use of such a solution may be inappropriate where an electrolyte is to be detected by electrochemical means.
  • an osmotically active colloid may be used.
  • the advantage of using a colloid is that it requires replacement less frequently than a solution since it can be washed and reused and would not interfere with the electrochemical detection of solutes.
  • the voltage is applied to the skin as a pulse, preferably for a time pe ⁇ od of between 1 ms and 5 minutes. Most preferably, the pulse is of the order of seconds. More than one pulse may be applied
  • the voltage pulses may be applied at a frequency of 0 01 - 1000 Hz, more preferably at 0.1 - 700 Hz.
  • Detection of the analyte may employ known methods, for example the detection of glucose may employ a glucose electrode.
  • Figure 1 is a graph showing the extraction of glucose from excised human skin by reverse electroporation under isotonic conditions w ith glucose deficiency (condition isotonic A).
  • Figure 2 is a graph show ing the extraction of glucose from excised human skin bv reverse electroporation under isotonic conditions with 4mM glucose added (condition isotonic B).
  • Figure 3 is a graph showing the extraction of glucose from excised human skin by reverse electroporation under isotonic conditions with 4mM glucose added (condition isotonic B) using an alternative pulsing regime to that used for Figure 2.
  • Figure 4 is a graph showing the extraction of glucose from excised human skin by reverse electroporation under hype ⁇ onic conditions, not being in ionic equilibrium (condition hypertonic A).
  • Figure 5 is a graph showing the extraction of glucose from excised human skin by reverse electroporation under hypertonic conditions in ionic equihb ⁇ um (condition hypertonic B),
  • Figure 6 is a graph compa ⁇ ng glucose penetration through a membrane at various intervals after pulsing for isotonic B and hypertonic B conditions
  • FIG. 7 shows schematically electroporation electrodes suitable for use in the present invention
  • Skin preparation Epidermal membranes were prepared bv heat-stripping Briefly, subcutaneous fat was removed from human breast or abdominal skin obtained from reduction surgery that was free of overt pathology The skin was fullv immersed in hot
  • Tritiated water ( ⁇ 2 O, 2ml, l ⁇ Ci.ml " 1 ) was added to the donor chamber of each cell and
  • Control cells had no electrical stimulation. Samples of donor and receptor chamber fluid were taken from all cells immediately before and after pulsing and at regular intervals thereafter, and were placed in 5ml scintillation fluid. To determine specific activity of
  • Liquid Scintillation Counting Samples were counted using a Liquid scintillation counter (Wallac 1409 DSA) using a programme set up for dual measurement of ⁇ and l C . All data obtained were computer analysed.
  • the maximum current that could be obtained by the pulsing apparatus limited the voltage applied to cells and therefore lower voltages than desired ( ⁇ 100V) were utilised.
  • Skin was bathed in a hyper-tonic solution ( 10 x Phosphate buffered saline, pH 7.4). Pulses of 30s, 60s and 300s duration were applied to the skin, via silver electrodes, at 1 hour
  • Figure 6 compares the glucose penetration through the membrane at various time intervals after the application of the pulse for isotonic B and hypertonic B conditions These data were derived from Figures 3 and 5 These data clearly indicate that reverse electroporation tan extract glucose from human skin using hype ⁇ onic conditions The initial rate of glucose mo ement as slower using
  • Two electrodes each contained within plastic tubes filled with saline as shown in Figure 7 are attached to the forearm of a volunteer.
  • the electrodes are connected to a D330 MuIstiStim apparatus.
  • a pulse of electricity [ lOOv. l OHz. 1 ms pulsewidth, 30 second duration] is applied and the saline in the plastic tubes is analysed by a standard colourimetric assay or a glucose electrode to determine the concentration of glucose

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Medical Informatics (AREA)
  • Surgery (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Optics & Photonics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Ink Jet Recording Methods And Recording Media Thereof (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un procédé et un dispositif de détection non invasive d'analytes dans le sang. Ce procédé repose sur l'électroporation de la peau afin d'obtenir un échantillon de fluide interstitiel pour analyse.
PCT/GB2000/002358 1999-06-22 2000-06-15 Detection d'analytes WO2000078207A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55478/00A AU5547800A (en) 1999-06-22 2000-06-15 Analyte detection

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9914408.1 1999-06-22
GBGB9914408.1A GB9914408D0 (en) 1999-06-22 1999-06-22 Analyte detection
GB0009970A GB0009970D0 (en) 1999-06-22 2000-04-25 Analyte detection
GB0009970.5 2000-04-25

Publications (2)

Publication Number Publication Date
WO2000078207A2 true WO2000078207A2 (fr) 2000-12-28
WO2000078207A3 WO2000078207A3 (fr) 2001-06-28

Family

ID=26244159

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/002358 WO2000078207A2 (fr) 1999-06-22 2000-06-15 Detection d'analytes

Country Status (2)

Country Link
AU (1) AU5547800A (fr)
WO (1) WO2000078207A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010094131A1 (fr) 2009-02-20 2010-08-26 Abdeltif Essalik Détection biomédicale non invasive et systèmes de suivi

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5730714A (en) 1988-01-29 1998-03-24 The Regents Of The University Of California Method for the iontophoretic non-invasive determination of the in vivo concentration level of glucose
EP0889703A1 (fr) 1996-02-05 1999-01-13 Diasense, Inc. Procedes et appareil de detection non invasive du glucose: sonde non invasive

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5547467A (en) * 1988-01-21 1996-08-20 Massachusettes Institute Of Technology Method for rapid temporal control of molecular transport across tissue
ATE131081T1 (de) * 1988-01-21 1995-12-15 Massachusetts Inst Technology Molekültransport durch gewebe mit der verwendung von elektroporation.
US5458140A (en) * 1993-11-15 1995-10-17 Non-Invasive Monitoring Company (Nimco) Enhancement of transdermal monitoring applications with ultrasound and chemical enhancers
US5551953A (en) * 1994-10-31 1996-09-03 Alza Corporation Electrotransport system with remote telemetry link
US5911223A (en) * 1996-08-09 1999-06-15 Massachusetts Institute Of Technology Introduction of modifying agents into skin by electroporation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5730714A (en) 1988-01-29 1998-03-24 The Regents Of The University Of California Method for the iontophoretic non-invasive determination of the in vivo concentration level of glucose
EP0889703A1 (fr) 1996-02-05 1999-01-13 Diasense, Inc. Procedes et appareil de detection non invasive du glucose: sonde non invasive

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010094131A1 (fr) 2009-02-20 2010-08-26 Abdeltif Essalik Détection biomédicale non invasive et systèmes de suivi
US9986979B2 (en) 2009-02-20 2018-06-05 Invafree Hms, Inc. Non-invasive biomedical detection and monitoring systems

Also Published As

Publication number Publication date
AU5547800A (en) 2001-01-09
WO2000078207A3 (fr) 2001-06-28

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