CA2136856A1 - Sensor devices - Google Patents
Sensor devicesInfo
- Publication number
- CA2136856A1 CA2136856A1 CA002136856A CA2136856A CA2136856A1 CA 2136856 A1 CA2136856 A1 CA 2136856A1 CA 002136856 A CA002136856 A CA 002136856A CA 2136856 A CA2136856 A CA 2136856A CA 2136856 A1 CA2136856 A1 CA 2136856A1
- Authority
- CA
- Canada
- Prior art keywords
- membrane
- sensor device
- electrode
- diamond
- sensor
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/308—Electrodes, e.g. test electrodes; Half-cells at least partially made of carbon
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
- G01N27/3274—Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/817—Enzyme or microbe electrode
Abstract
Sensor devices comprising enzyme electrodes incorporating a microporous membrane coated with the carbonaceous material known as "diamond-like carbon" (most conveniently deposited by decomposition of a hydrocarbon, induced by radiation or a high electric field). The membrane material is preferably a polycarbonate and its thickness preferably less than 10 microns, and the coating is preferably 0.01 to 5 µm thick. The preferred porosity is provided by pores of the order of 0.05 to 0.01 microns. The coated membrane imparts high resistance to fouling by contact with whole blood, extends the linearity of the electrode response over a substantially greater range, e.g. in the analytical determination of glucose in blood, and combines a high degree of restriction to passage of interferents while retaining high permeability to hydrogen peroxide and oxygen. Most conveniently used for amperometric measurements, especially using a Clark electrode pair, with an "active"
anode of platinum.
anode of platinum.
Description
SI~ `
.
SENSOR DEVICES.
li, Thls irlvcntlon relates to sensor devices, and more - particularly to improved sensor devices useful for analy.tical -s methods in enzyme-based electrode systems, and especially for use ln biological systems.
It ls known to make and use a varlety of sensor devices wh~ch are based on a form of electrode in which the metal electrode ls surrounded by membranes whlch can exclude interfering materlals from the electrode surface whlle allowing - substances to be determlned by the analytlcal procedure to reach the electrode.
A common form ls that ln which the electrode assembly incorporates an enzyme, whlch acts on the substrate chemical belng evaluated and generates a dlfferent chemical whlch can be determlned, thus provlding means for determinln8 the substrate ~-chemlca1 lndlrectly. An especlally useful ~form of thls procedure ,~
uses gluco e as the substrate and a glucose oxidase enzyme, so that these interact and -- by catalysed oxldatlon of the glucose to gluconic` acld -- produce hydrogen peroxide and oxygen as products. The hydrogen peroxide is very readlly and convenlently 'i det ~mined electrolytically.
A problem encountered wlth such procedures ls that the presence of other materials ln the medium belng analysed can interfere with the operation of the sensor devlce (electrode).
Thls can occur most markedly wlth hi8h molecular weight materlals, as in body flulds (e.g. by~protelns and the llke), but also can occur when one or more of the components of the electrolyte system ls llmlted, ln concentratlon or mobllity, so that the slgnal output of the sensor Celectrode) i~ in turn llmlteci also. Thls effect has the most ;evident effect when it makes the output signal from the sensor (electr~ie> non-linear or reach a llmiting value -- as this restricts the ran8e over which the sensor can be used effectively.
It has been proposed to use varlous materlals as me~brane~, lnterpcsed ~etween the electrode's active worklng surface and th~
medlum under analysis, to prevent lnterferir~ materlals r~achln~
-- SUBSTITUTE SHFET
, . ~
W0 93/24828 ~ 5 ~ - 2 - PCI/GB93/00982 the electrode surface and f~ulin~ it, while still allowing the desired moietles to remain mobile and approach the electrode surface. Although this does produce useful results (controlled permeabllity and blo-compatlblllty~, the presence of any barrier tends to lmpose some limltatlons on mobillty of the moieties present, and those barrlers hltherto proposed have not yet proved to be entlrely satlsfactory.
We have now found that the propertles of such barriers around the worklng surfaces of electrodes in sensor devlces, usually termed "membranes," can be lmproved by appllcation of a coatlng of a carbonaceous material to the material of the membrane. A carbonaceous material whlch we have found to be very effectlve ls already well-known ln itself and described in the art as "dlamond-lilce carbon." It i~ convenie~tly referred to ln the art by the~abbreviation "DLC," and so is referred to ln this manner through thls speciflcatlon.
DLC ls a form of amorphous carbon or a hydrocarbon polymer wlth propertles approaching those of dlamond rather than those of other hydrocarbon polymers. Varlous names have been used for it, for example "dlamond-like hydrocarbon" (DLHC~ and "diamond-like carbon" (DLC), but the term "DLC" appears to be the most c~mmon.
. It pnccPccP~ properties attributablé to a tetrahedral molecular structure of the carbon atoms in it, simllar to that of diamond but wlth some hydrogen atoms attached. It has been descrlb~d in the art as being a designation for "dense amorphous hydrocarbol polymers wlth propertles that differ markedly from those of other hydrocarbon polymers, but which ln many respects resemble dlamond" tJ.C. Angus, EMRS Symposia Proc., 17, 179 (1987)].
~- Surprlslngly, thls "dia~ond-like carbon" coatln~, applied to a membrane, has an unexpectedly beneficial effect on the ran8e over which the sensor can be used.
Thus accordlng to our lnvention we provlde an improved sensor devlce, useful ln the electrolytlc analysis procedures, whlch comprises a worklng electrode surrounded by at least one diffuslon-llmltlng membrane, wherein the said membrane has a coatlng comprlslng a coatlng of a carbonaceous material having structural characterlstlcs com~arable with that of diamond.
.
: SUBSTITU7E SHEET `
W 0 93/24828 ~ 1 u~ S 6 PCT/GB93tO0982 Especially, we prefer to use a form of carbonaceous material known as "diamond-like carbon" ("DLC").
This has ,the advantage of allowing the electrolytic system to respond to the analyte belng determined whlle extending the linear range over which tlle output signal of the sensor ~i.e.
from the working electrode) can be used.
The electrode itself may be any electrode having the properties of a working electrode, especially a metal electrode, and many are known in the art. It is preferably platinum metal, conveniently ln any of the conventional forms for example as a 2 mm dlameter platinum disc mounted in "Perspex" (poly-methyl methacrylate) surrounded by a silver rin8 of 2 cm diameter as a reference electrode. This is commonly referred to as the "Clark electrode assembly."
The membrane materlal may be any whlch is known in the art for the purpose of limiting access of unde ired components, i.e.
a permselective membrane material, but should be one which is of a nature whlch ls compatible with the coating prn~c~ (i.e. is durable enough to survive the coatlng treatment without itself belng degraded or damaged appreciably) and which can retain the deslred coatlng upon its surface. It is preferably a form of mlcroporous membrane wlth low permeability, thou&~l other permselective materlals may be used if desired, operative by their physical and/or chemical properties to give the desired porosity or permeablllty chnracterlstlcs. In chemical terms, it ls preferably a polycarbonate, as this ls a very durable material whlch accepts the coating well, but materials of other chemical constltutlon may be used if desired.
The membrane 1~ preferably made of a thickness less than 10 -30 mlcrons. Such membranes are typically made by conventional methods, for example by rolllng, cutting rom a mass, castin8 from solution, or comblnations of such techniques. The desired mlcroporoslty should be such as to provide pores In the membrane whlch are of the order of 0.05 to 0.01 microns In size. Such porosity may be achieved by known methods, for example by etchlng techniques - especlally the technlque known as "track etching"
using a neutron beam. Such products are obtainable commerclally SU~3STITUTE SHEEl ,~ :
W O 93/24828 ~ - PCT/CB93/00982 ~3~3~ '3 _ 4 _ ,~
,.
under the name "Nuclepore" from Nuclepore, Pleasanton, Callfornla, or the Poretics Corporation (Livermore, U.S.A.). The polymer ltself is impermeable to many hlgher molecular weight specles while remainlng permeable to low-molecular welght specles such a~ hydrogen peroxide.
The formatlon and appllcatlon of the diamond-llke carbon (DLC) to the membrane material as coatlngs or fllms for the purposeis of the present lnventlon may be carried out by ~ethods known in the art. It is usually formed by decompositlon of carbon-contalnlng compounds ln gaseous F vaporlsed form (partlcularly hydrocarbon gases) induced by radiation or electrical fields. ~ ;~
Thus, lt may be prepared from hydrocarbon precursor gases (e.g. propan~, butane or acetylene) by glow-dlscharge deposition, 15 by laser-lnduced chemical vapour decompositlon, by a dual-ion ;
beam technique, or by introduction of the hydrocarbon gases dlrectly lnto a saddle-fleld source. A saddle-field source is a source of lons produced by a colllslon ~etween BaS atoms excited /-by thermlo~lc emlsslon, and thls method ls preferred because lt `~
allows ~heat-sensltlve materials to be coated by a beam that- is uncharged -- so facllltatlng the coatlng of lnsulatlng or non-conductlve materlals.
It~ properties can vary accordlng to the particular raw materlals used and its mode of formation. It can also be made ln other ways, for example by sputtering solid carbon, as an alternatlve to dlssoclating hydrocarbon gases.
Further descrlptlon of DLC -- lncluding lts constitution, nature and properties, and the varlatlons ln its form which can be made -- and modes for its preparation, are to be found for example ln the followlng published references ~among others):-(a) "Diamond-Llke Carbon Applled to Blo-Engineerlng Materials;"
A.C. Evans, J. Franks and P.J. Revell, of Ion Tech Ltd., 2 .
Park Street, Teddington, TW11 OLT, Unlted Klngdom; Medlcal Device Technology, May 1991, pages 26 to 29.
(b) "Preparation and Properties of Dlamondlike Carbon Films;" J.
Franks; J.Vac.Sci.Technol. Vol.A, No.3, May/June 1989, pages 2307-2310;
SUBSTITUTE SHEET
~, ~
WO 93/24828 2 t 3 6 ~ ~ ~ PCT/GBg3/OOg82 .~;
(c) "Blocompatibillty of Diamond-llke Carbon Coating;" L.A.
Thomson, F.C. Law, J. Franks and N. Rushton; Blomaterials, Vol.12, January 1991 (pages 37-~0);
Cd) "Categorlzatlon of Dense Hydrocarbon Films;" J.C. Angus;
E.M.R.S. Symposium Proo., 1987, Vol. 17, r~e 179; Amorphous Hydrogenated Carbon Fllms, XVII, June 2-5 1987, Edlted by P.Koide & P. Oelhafen. ~
(e) "Properties of Ion Beam Produced Diamondllke Carbon Fllms;"
M.J. Mlrtech; E.M.R.S. Symposium Proc., 1987, Vol. 17, pag~
377;
Cf) "Diamond-llke Carbon - Propertles and Applicatior~s;"
J. Franks, K. Enke and A. Richardt; Metals & Materials (the Journal of the Institute of Netals); and ~g) U.S. Patent No. 4490229; M.J.Mirtich~, J.S.Sorey & B.A.Banks.
Thus, ln brief, our inventi~n can be used as~a method for providin~ a shi;eld, useful or excludin~ interferents from an enzyme lamlnate/electrode assembly, comprlslng a coatlng of a carbonaceous material with~ propérties approachlng those of diamond as a coverlng material. ~The~preferred~carbonaceous ~20 ;~matèrial~ ls that :form: of amorphous carbon or a hydrocarbon $"~polymer~;known~as~ "diamond-like carbon."~ F-cpecially it ~ is used as~ an ~outer~covering material. It can also act as a bloccmpatlble shleld.~ The DLC may also be used~to coat other parts of the electrode~or sensor ~ssembly if desired.
2S Alternatlvely stated, our inventlon;provides Improved sensor devlces inoorpcrating~a coat~lng of ~a~ carbonaceous material kn ~
as "dlamond-l~lke carbon" (DLC) as~an outer shleld, especially when blo-compat~bllity~ is deslred. This coating allows the ~; - pr~cductlon ~of a shleld wi~th tallor-desi8ned desirable dlfusion -i 30 characterlstics. -The~convenient source~ of the carbon is a hydrocarbon gas or vapour, especlally~one which is readlly decomposed by an electric fleld or ~i ~ e. A very convenienit source gas is acetylene, thcuRh~others ~ay be used lf deslred.~ Indlvidual hydrocarbons or 35~ mlxtures thereof may be-used;, and dlluent R~CP~ may be added lf deslred~;and the decomposition/depositl~on prooedure may be carried out~ at prff sures at atmospheric or above o~r below atmospheric, as SUESTITUTE SHEE~' j, . . . . .
,, ,. ~ ..
W093/24828 '~3~b 6 - pcT/Gs93/oo982 found most suitable for particular lnstances.
The coating may be made of a thlckness whlch may ~e varied according to the partlcular requirements desired for the performance of the sensor and the system to be analysed. ~hus, the thlckness of the coating or deposit may-be in the range O.Ol to 5 ~um, but thlcker or thinner coatlngs may be used lf desired.
A typlcal and convenient coating deposit is one approximately O.l ~m thlck, but thls ls not necessarlly the optlmum for all purpo6es. The thickness in nay partlcular case will depend upon such factors as the nature (physical and chemlcal) of the ~aterial upon which the DLC is deposited, and its porosity or permeabillty, and the partlcular characterlstics appropriate tO
the lntended use of the sensor.
The coatlng ls convenlently carried out at a rate which allows the deposlt to adhere to the membrane material and form a coatlng of the deslred thickness - preferably also evenly coated so as to cover substantlally all the surface without leaving any areas too thlnly covered or even un-covered.
When uslng acetylene as a ~ource, for example, the deposltlon may be carrled out at a rate of up to O.5~um per hour, though hlgher or lower rates may bP used lf deslred~
In car~ylng out the coatin~ procedure, lt ls preferred th~t the membrane surface should ~e as clean as practlcable, to ensure that the deposlt has optlmum ablllty to adhere properly.
varlety of cleaning method~ may ~e used. One whlch is very ~ ~sultable ls Fast Atom Bombardment (sometimes referred as "FAB"
- for brevlty); thls comprises sub3ectlng the tar8et material to a neutral atom beam source, and a typical cleanlny tlme ls an exposure to such treatment for about S mlnutes ~ though longer or ?horter tlme may be~used if deslred.
If desired, more than one membrane may be used, and the coatlng may be applied to one or both surfaces of a nembran~ or to~ one or more surfacès of more than one membrane in the electrode ?CcP~bly whlch makes up the sensor device.
35Preferably, the coating is applled to the outer surface of ~ the ~e~brane (l.e. that surface remote from the actlve electrode -~ and nearer to the surrounding ~edia. If more than one me~brane , :~ SUBSTITUTE SHEET
W O 93/24828 21 3 6 ~ ~ ~ P~T/GB93/00982 is used, the most advantageous pOSitiOI~ for the coating of DLC is on that membrane or membrane surface which is rlearest to the medium beir~ studied or analysed.
Thus, for example, the sensor device may comprise an inner and an outer membrane, in which case one may be coated as deflned above and the other may be elther un-coated or may be of another material, coated or un-coated.
For example, the outer membrane may be as deflned above and the lnner may be for example made of a cellulose ester, and especlally any form of cellulose acetate. Such a membrane is preferably made of a thlcknPqq in ttle range O.l to l.O Jum, and may be made by conventional methods, for example by casting from solution, optionally with inclusion of additives (for example by inclusion in the casting solution) to modify the properties of the resultlng cast film or to facilitate the casting process.
The lnvention is applicable to a variety of er~yme systems but is principally applicable to systems in which the enzyme is an oxidase and the hydro~en peroxide formed as a result of its actlon ls measured electrolytically. Especially, it is useful 20 ~for systems, sensors and electrodes lncorporatlng a glucose oxidase enzyme, as the substrate ~lucose is a common component whlch requires to be measured or biochemical and clinical purposes. The use of the coatecl m~mbranes in sensors according to the present inventlon enables the measurement or detection ran8es for 81ucose to be extended considerably beyond those which are easlly measurable by the sensors known bitherto, and also for the degree of linearity of re~ponse (i.e. the relationshlp between the sensor output slgnal and the amount of the substrate glucose3 to be extended, which makes the sensors much more useful ln practical cllnical or laboratory condltlons. Thus, as an -- lllustration, ranges of 81ucose detection up to 25-30 m~ of glucose are advantageous ln practlce and the pre ent lnvention allows the range of detection to be extended even beyond this, -~ for example to lOO mM or even more. Such hl8~ concentrations can be of ~alue for measurlng glucose concentratlon in media assoclated wlth products in the food and fermentatlon lndustries.
.
~ -SUBSTITUTE SHEE~.
W093/24828 c~,~3~ 5b 8 - PCI/GB93/00982 - ~
The enzyme may be incorporated in the sensor by conventional means, for example by being immoblllsed on the membrane by a fixlng agent whlch does not impalr its enzymlc activity (for '' example glutaraldehyde and albumin), and a very convenlent form 5 'of constructlon of the sensor ls that ln whlch the enzyme is held -in place between two membranes -- sometimes termed a "laminated"
form of membrane. In such "laminates" one membrane layer (termed ' the outer layer) ls the one exposed to the meidlum under study or ~' analysis, and this ls the one on which the diamond-llke coatir~
ls of most value, though the coating can be on any or all membrane surfaces as desired.
The mode of electrolytlc analysis to be used is especlally amperometric analysis, which is well known and used in the art.
The prlncipal advantage of our sensors ls that they can be i`
used in the reagent-less analysis o a wide variety of body 1uids (e.g. blood or serum) and other biological m~dla without dllutlon and' without significant interference from endogenous or ~-exo~enous agents whlch may be present in a patient's blood. It '~
enhances any membrane-based sensor system, whether enzyme-based or not.
Diamond-llke carbon coatings have the advantages of a high 1' degree of inertness and also a hlgh degree of haemo-compatlblllty ' (ccmpatlblllty with blood). ,~' Further advantages of the present lnvention include~
25 Cl) providing of a strong, flexlble coating on the sensor; ~' (2) allowin~ the precise flne-tuning of the poroslty to the outer membrane of a sensor, thus extending the linearity range; ,~
~3) exclusion, by the coatlng, of large macromolecular and some smaller electrochemicai'lly actlve interferents,~so preventin8 - 30 blo-fouling oÇ the enzyme electrode assembly and enhanclng the selectlvlty of the electrode, even to the extent that an outer membrane can provide the propertles otheirwise requiring the use of another, lower, underlying permselective membrane.
An especial advanta8e of the sensor of the present lnventlon ls that lt wlll permlt the reliable analysis of glucose concentratlons ln whole undiluted blood. This is usually not .
SU8STITUTE SHEEr. `
W O 93t24828 ~ 6 ~ PCT/GB93/00982 _ 9 _ possible with the known forms of sensor. Of course, the value of the invention is not restrlcted to belng solely a~plicable to the analysls of blood t and it may be applied to analysls o~ other media contalnlng qulte hi8h concentratlons of glucose or other S electrochemically active species at levels which comm,only present cor~lderable problems for analysls. Such other medla include a varlety of a media of organlc or non-organlc orlgin, for example plant and frult Juices, chemlcal process liquids, and the llke.
Thus according to our invention we also provlde a method for the electrolytic analysis, especlally of biological fluids, which comprises applying them to a sensor device or electrode system in whlch there is used a sensor electrode as defined above.
The preferred form of electrolytic analysis is amperometric detection.
Usually, the electrode of our invention will be used as the anode.
In use, the electrode of our lnvention can be used to carry out the method of our invention by immersion (together with an associated cathode) in a predetermined volume of a buffer solution to be analysed, and applying a polarlsing voltage so that the amperometric measurements can be made and compared before and after the addltlon of the blood or serum sample under test. The procedure may also be `callbrated ~y use of solutions containing known amounts of the substances sought, and lts accuracy thls c,hecked and conflrmed. Llkewlse, the procedure may -~ ~be carrled out uslng known amounts of compounds which are ~-considered to be potentlally troublesome by `their expected abillty to lnterfere wlth the measurement of the paracetamol, so that the degree of interference (lf any) can be established~
Conventlonal apparatus n~y be used, for the cell, electrodes a~ld the measurement ~and recordlng of , the current-voltage relationships for the samples under test. Measurements may be made contlnuously or intermlttently, as desired.
In operatlng the procedure, it ls convenient to use a '~ 35 polarlsing ,volta~e in the range I 0.~ to 0.8 volts Cpreferably at -~approxlmately ~ 6.S volt) against a sllver/silver chloride .
S~ '8STITUTE SHEET
WO 93/24828 PCT/GB93/00982 ~
.. , s~ -- 10 -- :~:
2~
electrode. The liquid medium may be at a pH which c~n vary over a conslderable ran8e, but is especially ln the pH range 6 to 8 and preferably at approximately 7.4 (or physiologlcal use).
The sample under examinatlon may be stlrred or unstlrred, as desired or convenient.
The electrolytic procedure for use of the sensors of our invention may be carried out over a considerable range of temperatures, for example ln the range 20 to ~0 degrees C.. It is usually important that the tempeirature used for callbration is wlthln approximately 4 degrees C. of the assay temperature.
For calibratlon, an isotonic or other other buffer may be used, but it ls preferable to use one which has an ionic strength similar to blooci (i.e. approximately O.lS M).
The medium ls commonly aqueous, but need not necessarlly be so, and an organic solvent may be used if desired (as such, or in admixture with each other and~or water) provlded it is an electrolyte and dissolves any desired reagents, but is not medlcally relevant to the assay carried out.
Typically, a procedure for calibration uses a treatment in isotonic phosphate buffer at pH 7.4. Following this, the buffer is~ removed, the serum or blood ls added, and the response is awalted thls lllustrates how much the pro edure can become a simpllfied analysls.
For thls purpose, the electrode may be lmmersed in a sample of the fluid (e.g. blood) and then llnked wlth a suitable reference electrode Cfor example a silver electrode or a calomel ;~ - electrode~ in conventional manner. Measurement of the voltage, - current and the llke may be taken and the measurements taken and recorded as deslred, lntermittently or contlnuously. For this, conventlonal apparatus may be used.
Samples of the mexila for examinatlon Cfor example bloKxi or serum) may be obtalned by standard methods. The quantity of blo~d~serum should be sufflcient to ccver the electrode and the current measured at a flxed tlme or after a stable response has been achleved. Likewlse, samples of other m~iia may be obtained ln any convenlent manner and brought lnto contact wlth the sensor of the present lnventlon for the purpose of component detectic-n.
SUBSTITUTE SHEET
.
W O 93/24828 ~ 1 3 ~ ~ ~i S PC~r/G B93/00982 The membrane and/or anode may be prepared for use in the analytical proces~ of the inventlorl by soaking it, when it ls in place around the anode, in a solution correspondln~ to the electrolyte medlum before the blood~serum sample ls added.
Simllar procedure~ and conditions may be used for analysis of other medla of a biologlcal or blochemical nature, with modifications as wlll appear appropriate to an expert in the art having regard for the nature of the media, the components sought, and the conditions and requirements of the measurement.
The inventlon is lllustrated, but not limlted, by the followin; Examples.
EXAMPLES. ", ~ ., Chemic,als:
Glucose oxidase from A~,pergillus niger (75Y. protein, 150,000 unlts/g solld), and bovine serum albumin (fraction V), were obtalned from the Sl~ma Chemical Company Llmlted (Poole, Dorset), D-glucose, di-sodium hydrogen phosphate, di-hydrogen sodium phosphate, sodlum benzoate and sodium chloride ('`AnalaR" grade) were obtalned from BDH (Poole, Dorset)~ All chemlcals were used without further preparatlon.
Buffer:
A bufer (pH 7.~j of 5.28 x 10 2~ Na2HP0~, 1.3 x 10 2M
NaH2P04, 5.1 x 10 3M sodium chlorlde, 6.24 x 10 3M sodium benzoate was prepared in dlstllled water. Thls buffer was used for all enzyme preparatlons and diffus~onal studies.
, .
DLC Coated PolYcarbonate Membranes:
Polycarbonate membranes for DLC coating were purchased from Poretlc~ Corporatlon (Llvermore, USA~ and the DLC coatln8 procedure performed by Atom Tech Ltd. (Teddln8ton~ Mlddlesex, En8land - formerly Ion Tech Limlted) as has been described (J.
Franks; J. Vac. Sci. A71 (1989), page 2307). Polycarbonate membranes of pore radll 0.01, 0.05 and 0.1~um were prepared with deposltlon duratlons of DLC of 1 minute, 3 minutes 30 seconds, SUBSTITUTE S~lEET
W O 93/24828 PCT~GB93/00982 ~ 2 -and 7 minutes and compared with un-coated membranes. Membranes were cleaned by a 5 mlnute Fast Atom Bombardment (FAD) within an argon or other gaseous saddle fleld source. Control membranes were similarly treated.
DLC coatlng times quoted define deposltion tlmes, so single-sided cc~ted membranes had all of the depositlon of DLC applled to one surface, whlle double-sided coated membranes had 50%
applled to each surface. In this way it was lntended that single and double sidecl coated membranes could be directly compared wlth regard to coating durations. The deposition rate of DLC was 0.45 um per hour, so } minute, 3 minutes 30 seconds, and 7 minutes coating corresporld to 0.0075, 0.0225 and 0.05 ~um thickness respectlvely. These membranes had a quoted thic~ness of 6~um, so the maximum coating of DLC was less than 170 of the membrane thlckness to whlch lt was applled. It was therefore assumed to have a negllglble effect on the thlckness of the membranes used ln the calculation of the P values.
~: .
Apoàratus: i An oxygen electrode assembly (Rank Brothers, Bottisham, Ca~bridge, U.K.) as prevlously used (W.H.Mullen, S.J.Churchouse, F.H.Keady and P.M.Vadgama; Anal. Chlm. Acta. 183 (1986), page S9) was utllised for glucose oxidase enzyme electrodes. The working electrode (anode) was polarlsed at +650 mv (vs Ag~AgCl) for the `~
oxidatlon of hydrogen peroxide. The cell was comprised of a central 2 mm dlameter platlnum dlsc wlth an outer~pre-anodised 12 mm dlameter 1 mm silver ring (Ag~AgCl) a~ a combined reference and counter electrode. The purpose-built voltage polarisation source and potentlostat ware constructed by the Chemistry workshops (Unlverslty of Newcastle, U.K.), and a x-t chart recorder-(Lloyd Instruments plc, Fareham, Hants., U.K.) was used `~
to record amperometric responses of the electrode assembly from the potentiostat current follower. A blood gas analyser CInstrumentatlon Lab Model IL 1802 - Hope Hospltal, Clinical Biochemistry Laboratory) was used for the analysis Of P02 within buffer aliquots.
i ;~ SUBSTITUTE SHEEr W O 93/24828 2 t 3 5 ~ PCT/GB93/00982 .~Fabrication of En2vme Electrodes:
Glucose oxidase ~GOD) (2560 unlts/ml) and bovine serum albumin (BSA) (O.1 g/ml) were dissolved in buffer solution. 6~ul of GOD/BSA solutlon and ~ul of glutaraldehyde (5% v/v) were mixed S rapidly and placed on a 1 cm2 portion Or O.OS ~m ~olycarbonate ~e~brane. A 1 cm2 portion of DLC-coated polycarbonate membrane was~then pl;aced Oll top and gl~ass slides;were used to compress the enzyme and membrane ;lamirlate under finger pressure for approxlmately S minutes. $he resulting cross-linked enzyme 10~ ~laminate was placed~ over the~worklng electrode, pr~lor to flnal electrode assembly and~f~ixation by an "O" rlr~.
Methodolo~v~:~Determlnat~lon~of Fermeablll~tv CQeff1clents:
Sol~ute~mass trans~fer~ measuremene;s across DLC-coated polycarbonate membranes to~assess their permeability were performed at 22 + 1 de W C. ln a Classical diffusion chamber apparatus~consistir~lg of~two chaDbers~. Both chaqhers were of 170 ml volume~and~were`~separated~by two~ stainl~ess steel di ~ and two sealing~rubber~"O"-~rings~clamped together~to hold the n~lbrarle~f ; 20 lnterest~wlth;~a~cross-sectional area~avai~labIe ~for~mass transport o 7.07~ The~solute of~lnterest~wa~added to one chamber and mass~ trans~fer ~was~thèn~det~ermined ~by measuring solute concentratlons~l;n~both~chamberS~ at ~periodlc lntervals. For the determinatlon~ of~ pO2~ levels~ al~lquoes~were extract~dl by a syrlnge and sealed;~wlthln~small~glass~;vessels~So`~prev~nt ~m~lxin8 wlth the atmospb~re,~prior~to~ ~ lysls.~ Oxygen~ wlthin one chamber was consuméd~by~ placl~ng~cross-l~inked~ GODJ~BSA fllms ln excess, to create oxy8en~grad~1ents~across t~he~membrane of interest.~ PO2 -levels we-re~determi~ned~;by~the blood~ gas~analyser. Permeabillty coef~1clènts~were ~calculated using ~th~e~expresslon derived by Sun et~al. (Blotech. Bloeng., 34!~ (1989),~page 55).
alvsls`of Blood Glucose Concentratlons:
Blood;~samples~previously ~tested for 8lucose conce~ltrations ; 35 ~Hope Hospltal Cl~i~nlcal Bl;ochemlstry laboratory)~were used for the~assessment of~enzyme~e1ectrodes for whole blood analysis.
Blo~d samples~were use`d on the same ~ay as the hospltal analysls : ~
~ '. ' , 1 :
SUBSi-lTUTE SHEE~
''~' .', '': ~ - '`' W O 93/24828 f ~ 14 - PCT/CB93/00982 and stored under refrigeration in tubes containing fluoride oxalate prlor to use to prevent the lowering of blood glucose levels wlth time due to c~ll metabolism.
Results:
Polycarbonate membranes (Poretlcs Corporation) lncorporate near cylindrical channels, formed by a well established neutron beam track-etched method. The relatlvely low thickness (approx.
11 ~um) of these membranes has enabled minimlsatlon of dlffusional dlstances, whlle facilitatln8 a hlgh degree of control over dlffuslonal re lstance. The glucose/O2 permeablllty coefficlent, P, ratlo is of critlcal signiflcance lf the membrane is to be used as a substrate dlffusion limitlng outer membrane over oxidase enzymes. By mlnimising the glucose/O2 P ratio for membranes, enzyme electrodes were constructed that became dlffuslon controlled rather than reflectlng lntrlnsic enzyme klnetics.
DLC-coated polycart~nate membranes have now allowed further extenslon of llnearity for glucose analysls wlthln in vitro samples c,ao mM), and also enabled minlmlsatlon of bio-fouling to the sensor. A series of experlments was performed to determine the P values for 2 and glucose acroOEs a spectrum of DLC single and double slded coated membranes, uslng a diffu~lon chamber ~apparatus (A.C. Evans, J. Franks and P.J. Revell; Medlcal Devlce 25 Technol., 26 (1991) page 26). On each nr~lon three membranes of each type were independentIy tested wlthln the diffusion chamber, and a mean value for each P value calculated. To aid clarity, only this value ls u~ed ln descrlblng permeabillty coefficlents trends.
We studled how the P values for 81ucose and 2 are reiated to polycarbonate membranes of O.Ol, O.OS and O.l ~um pore radll, with dlfferent durations of slngle and double sided DLC coatlng.
Thls demonstrated that, typlcally, P values across three membranes prepared by the same procedure may be attalned to -~ 35 withln a margln of around 5%. The productlon of membranes, the coatln~ procedure and methodology for the valuatlon of P values ls therefore shown to be reproducible.
.
~. ~
~ SUBSTITUTE SHEET
_ . , . .. . , . . . . . ... . .. . .. . . . . .. .. _ W O 93/24828 2 ~ ~ ~ 5 ~ PCT/GB93/00982 , .
We founcl that the P values for both glucose and 2 decrease with decr~ing pore radius and with increasing DLC coating time, whlch is conslstent with the flndlng that as the pore area is encroached the diffusior,al reslstance to solute trans-membrane s transport lncrec~ses. In partlcular, we found that P values for glucose progressively diminish as the DLC coating thickne~s is lncreased, due to the pore area belng progressively diminishecl.
No previous technique used by us (e.g. organic solvent depositlon) has allowed such "fine tuning" of membrane permeability at small pore radii. Our results indicated that, for a slmilar application of DLC, whether lt is to a single surface or to both membrane surfaces has little influence on the diffusing species' behaviour across the membrane.
0.01 ~m pore. racllt p~ly~rbc-nate membranes were founcl to be blcx~ to sducose trc~r~c-rt when ~reater than 1 mlnul.e ~ul~lor coatings of DLC are applied. However, single sided coated membranes become blocked at c1 mlnute DLC coating duratlons, whereas diffusion of glucose is permitted for double sided coated membranes of 1 mlnute DLC coatlng duration. This blocking difference is believed to be due to the build-up of DLC at very small pores ln slngle sided coatings, whereas the pore aperture ls spared if thls is distributed across two membrane surfaces.
Of particular interest, however, is the findlng that 2 transport ls much less affected by DLC appllcation, and that when glucose is fully obstruGted 2 trans-membrane transport ls stlll malntalned. The P ratlo values are very slmllar for slngle or double slded DLC-coated membranes. The flrst application of DLC
Cl mlnute) re~ults ln th~ greatest reciuctlon of the glucose/O2 P
ratlos. Further coatings of DLC result in contlnued reduction in this ratio, although the effect is less promin~nt. The membranes showlng the smallest glucose/02 P ratlos are those for 0.05 ~um pore radil membranes with 7 mlnutes DLC coatlng, for both single and double slded coated membranes.
- We carrled out the calibratlon of glucose oxldase enzyme electrodes with upper double sided 0.01 Jum pore radil membranes and the correspondlng control. Llnear ranges of analysls were SUBSTITUTE SHEET
c~ 3 ~S~ ~ ;
found to possible to in excess of 80 mM concentratlons, which are vastly in excess of those that may be attalned with un-coated membranes.
Further work was carried out on calibratlon curves for S enzyme electrode~ employir~ upper 0.05 ~um pore radll membranes.
The almost identlcal behaviour shown by enzyme electrodes utllising single and double slded DLC-coated membranes conflrms that, for both types of membrane, the same coatlng tlmes impart almost identical ~ropertles. In addition, as the DLC coatlng tlme ls increased, the enzyme electrode llnearity range is progressively extended.
Simllar findlngs are shown for 0.1 ~um pore radil upper membrane enzyme electrodes and the calibration curves for sensors utlllsing 0.1 ~um pore radil DLC-coated upper polycarbonate membranes. Agaln, longer durations of DLC coating result in extended linearity ranges.
A ma~or constralnt to the commercialisation of prevlously ~nown sensors for whole blood measurements ha~ been the lntractable problem of signal drift as a result of blo-foullng.
20A series of experiments was designed so that the enzyme electrodes, all wlth inner 0.05 ~um pore radll un-coated polycarbonate me~branes, and varying pore radil DLC-coated outer polycarbonate membranes (together wlth controls) were exposed to heparlnised whole blood and then rinsed wlth non-anticoagulated buffer solutlon. Responses to S mM glucose solutlons, before and after blood exposure, were recorded and percentage losses of response were calculated.
The percentage l~eP~ of slgnal followlng exposure to whole blood for 30 mlnutes was calculated. Results showed a typical loss of response to a standard 5mM buffered glucose solutlon, followlng increasing tlme exposure to whole blood. Agaln, very few dlfferences were ohRPrved betwee~l sln~ie or double slded DLC-coated membranes. However, the reslstance to bio-foullng appears to lncrease wlth greater deposltlon of DLC for all membranes.
35The greatest change ls seen between un-coated membranes and the flrst deposltlon of DLC (1 minute). The polycarbonate SUBSTITUTE SHEET
WO 93/24828 2 ¦ ,? ~ ~ 5 ~ PCT/GB93/00982 x~
~ , .
membrane pore radius also appears to be critlcal, as smaller pore radli membranes always exhlblt lower losses followlng blood exposure than enzyme electrodes with simllar DLC-coated membranes of larger pore radil. It therefore appears that both smaller S pore radii and longer durations of DLG coatlng contrlbute to lncreased functlonal bio-compatlblllty.
As before, only double sided DLC-coat~d membrane of 0.01~um pore radli could be tested for bio-foulin~ as single sided DLC-coated O.O1 ~lm pore radii membranes were all blo~ked to 81ucose.
However, 0.01 ~m pore radii polycarbonate membranes wlth 1 minute depositlon DLC double-sided coatlngs as the upper membrane of an enzyme laminate exhibited extreme reslstance to blo-fouling, showing a los~ of only 6æ signal followlng 30 minutes exposure to whole blood. This is considerably better than has been achieved to date with other membrane ~ystems to our knowledge.
An enzyme laminate with an upper nominal pore radius of 0.1 ~um and 7 minutes double-sided DLC coating was exposed to blood, w hed with ~distilled water, and buffer placed in the cell for conti~nued washing for one hour. The buffer was then replaced 20 ~wlth a 5 mM glucose buffer and the response recorded. The final response was found to be ~% higher than previously noted, believed to be because some surface bio-fouling had been ~echanically dislodged.
As linearity ranges for glucose analysis over clinically ZS useful ranges had been attained, and the effects of bio-foulin~
assessed following whole blood exposure, two sensors for comparison were constructed -- both wlth lower o .as ~um pore radii polycarbonate me~b anes; outer rembranes were of O.Ol and 0.1 ~lm pore radii double sidad 1 minute duratlon DLC-coated membranes.
Th cP two enzyme ele trodes were calibrated followlng exposure to whole blood, and individual blood c~mples previously tested for 81ucose le~els wlthln a Cllnlcal Blo~hemlstry Laboratory (at Hope Hospltal) were analysed and the correlatlons between the two ~- electrodes and the Clinical Laboratory results were studled. The 3S 0~.01 ~um pore radll upper membrane glucose electrode yielded results~ which were ln close a8reement wlth those of the .
~ SUBSTITUTE SHEEr WO 93/24828 ,~ PCT/GB93/00982 '~3 6 `~ 18 -Biochemistry Laboratory, though the results for 0.1 ~m pore radli membranes showed a poorer correlation. Thls has two important consequPn~es. The correlati~ns show that this enzyme electrode is capable of yieldin8 conslstently reliable results for the analysis of blood glucose concentration~ desplte repeated exposure to whole blood. Secondly, although no permselectlve membrane has been used, the electrode appears to show little sign of electroactive lnterferents reaching the working electrode, indicatlng that the upper membrane is uniquely acting as a barrier to electroactlve interferents.
Conclusions:
A comprehensive serles of DLC-coated microporous polycarbonate membranes have been ~cP~ced in terms of porosity and permeabillty coefficlents calculated for glucose and oxygen uslng the classical diffusion chamber.
Glucose electrodes have been constructed utilislng DLC-coated outer coverlng membranes, and linearity ranges assessed for sensors possesslng a ~eries of ~LC-coated membranes.
Comparisons have hPPn made between the permeablllty coefficient of glucose and oxygen, and P ratios related to linearity ranges attained using these membranes. Lower glucose/O2 ratios were found to be associated wlth extended linearity ranges. Linearity ranges ln excess of 80 mM glucose concentratlons were attalned uslng 0.01 ~um, 1 minute duration DLC-coated, polycarbonate membranes as outer coverlng membranes. The enzyme electrode utilicP~ the membrane showing the greatest diffuslonal resistance to glucose, suggestlng that the glucose/02 P ratlo and the a~solute P value for glucose are both critlcal for linearising a glucose enzyme electrode. The same enzyme electrode exhibited a good resistance to blo-fouling, wlth losses in response of only 67. followlng repeated exposure to whole blood as well as showing close correlatlon to glucose analysls uslng conventional Clinical Blochemlstry technlques, desplte the ab ence of an underlying selectlve membrane.
.
:
SUBSTITUTE SHEET
.
SENSOR DEVICES.
li, Thls irlvcntlon relates to sensor devices, and more - particularly to improved sensor devices useful for analy.tical -s methods in enzyme-based electrode systems, and especially for use ln biological systems.
It ls known to make and use a varlety of sensor devices wh~ch are based on a form of electrode in which the metal electrode ls surrounded by membranes whlch can exclude interfering materlals from the electrode surface whlle allowing - substances to be determlned by the analytlcal procedure to reach the electrode.
A common form ls that ln which the electrode assembly incorporates an enzyme, whlch acts on the substrate chemical belng evaluated and generates a dlfferent chemical whlch can be determlned, thus provlding means for determinln8 the substrate ~-chemlca1 lndlrectly. An especlally useful ~form of thls procedure ,~
uses gluco e as the substrate and a glucose oxidase enzyme, so that these interact and -- by catalysed oxldatlon of the glucose to gluconic` acld -- produce hydrogen peroxide and oxygen as products. The hydrogen peroxide is very readlly and convenlently 'i det ~mined electrolytically.
A problem encountered wlth such procedures ls that the presence of other materials ln the medium belng analysed can interfere with the operation of the sensor devlce (electrode).
Thls can occur most markedly wlth hi8h molecular weight materlals, as in body flulds (e.g. by~protelns and the llke), but also can occur when one or more of the components of the electrolyte system ls llmlted, ln concentratlon or mobllity, so that the slgnal output of the sensor Celectrode) i~ in turn llmlteci also. Thls effect has the most ;evident effect when it makes the output signal from the sensor (electr~ie> non-linear or reach a llmiting value -- as this restricts the ran8e over which the sensor can be used effectively.
It has been proposed to use varlous materlals as me~brane~, lnterpcsed ~etween the electrode's active worklng surface and th~
medlum under analysis, to prevent lnterferir~ materlals r~achln~
-- SUBSTITUTE SHFET
, . ~
W0 93/24828 ~ 5 ~ - 2 - PCI/GB93/00982 the electrode surface and f~ulin~ it, while still allowing the desired moietles to remain mobile and approach the electrode surface. Although this does produce useful results (controlled permeabllity and blo-compatlblllty~, the presence of any barrier tends to lmpose some limltatlons on mobillty of the moieties present, and those barrlers hltherto proposed have not yet proved to be entlrely satlsfactory.
We have now found that the propertles of such barriers around the worklng surfaces of electrodes in sensor devlces, usually termed "membranes," can be lmproved by appllcation of a coatlng of a carbonaceous material to the material of the membrane. A carbonaceous material whlch we have found to be very effectlve ls already well-known ln itself and described in the art as "dlamond-lilce carbon." It i~ convenie~tly referred to ln the art by the~abbreviation "DLC," and so is referred to ln this manner through thls speciflcatlon.
DLC ls a form of amorphous carbon or a hydrocarbon polymer wlth propertles approaching those of dlamond rather than those of other hydrocarbon polymers. Varlous names have been used for it, for example "dlamond-like hydrocarbon" (DLHC~ and "diamond-like carbon" (DLC), but the term "DLC" appears to be the most c~mmon.
. It pnccPccP~ properties attributablé to a tetrahedral molecular structure of the carbon atoms in it, simllar to that of diamond but wlth some hydrogen atoms attached. It has been descrlb~d in the art as being a designation for "dense amorphous hydrocarbol polymers wlth propertles that differ markedly from those of other hydrocarbon polymers, but which ln many respects resemble dlamond" tJ.C. Angus, EMRS Symposia Proc., 17, 179 (1987)].
~- Surprlslngly, thls "dia~ond-like carbon" coatln~, applied to a membrane, has an unexpectedly beneficial effect on the ran8e over which the sensor can be used.
Thus accordlng to our lnvention we provlde an improved sensor devlce, useful ln the electrolytlc analysis procedures, whlch comprises a worklng electrode surrounded by at least one diffuslon-llmltlng membrane, wherein the said membrane has a coatlng comprlslng a coatlng of a carbonaceous material having structural characterlstlcs com~arable with that of diamond.
.
: SUBSTITU7E SHEET `
W 0 93/24828 ~ 1 u~ S 6 PCT/GB93tO0982 Especially, we prefer to use a form of carbonaceous material known as "diamond-like carbon" ("DLC").
This has ,the advantage of allowing the electrolytic system to respond to the analyte belng determined whlle extending the linear range over which tlle output signal of the sensor ~i.e.
from the working electrode) can be used.
The electrode itself may be any electrode having the properties of a working electrode, especially a metal electrode, and many are known in the art. It is preferably platinum metal, conveniently ln any of the conventional forms for example as a 2 mm dlameter platinum disc mounted in "Perspex" (poly-methyl methacrylate) surrounded by a silver rin8 of 2 cm diameter as a reference electrode. This is commonly referred to as the "Clark electrode assembly."
The membrane materlal may be any whlch is known in the art for the purpose of limiting access of unde ired components, i.e.
a permselective membrane material, but should be one which is of a nature whlch ls compatible with the coating prn~c~ (i.e. is durable enough to survive the coatlng treatment without itself belng degraded or damaged appreciably) and which can retain the deslred coatlng upon its surface. It is preferably a form of mlcroporous membrane wlth low permeability, thou&~l other permselective materlals may be used if desired, operative by their physical and/or chemical properties to give the desired porosity or permeablllty chnracterlstlcs. In chemical terms, it ls preferably a polycarbonate, as this ls a very durable material whlch accepts the coating well, but materials of other chemical constltutlon may be used if desired.
The membrane 1~ preferably made of a thickness less than 10 -30 mlcrons. Such membranes are typically made by conventional methods, for example by rolllng, cutting rom a mass, castin8 from solution, or comblnations of such techniques. The desired mlcroporoslty should be such as to provide pores In the membrane whlch are of the order of 0.05 to 0.01 microns In size. Such porosity may be achieved by known methods, for example by etchlng techniques - especlally the technlque known as "track etching"
using a neutron beam. Such products are obtainable commerclally SU~3STITUTE SHEEl ,~ :
W O 93/24828 ~ - PCT/CB93/00982 ~3~3~ '3 _ 4 _ ,~
,.
under the name "Nuclepore" from Nuclepore, Pleasanton, Callfornla, or the Poretics Corporation (Livermore, U.S.A.). The polymer ltself is impermeable to many hlgher molecular weight specles while remainlng permeable to low-molecular welght specles such a~ hydrogen peroxide.
The formatlon and appllcatlon of the diamond-llke carbon (DLC) to the membrane material as coatlngs or fllms for the purposeis of the present lnventlon may be carried out by ~ethods known in the art. It is usually formed by decompositlon of carbon-contalnlng compounds ln gaseous F vaporlsed form (partlcularly hydrocarbon gases) induced by radiation or electrical fields. ~ ;~
Thus, lt may be prepared from hydrocarbon precursor gases (e.g. propan~, butane or acetylene) by glow-dlscharge deposition, 15 by laser-lnduced chemical vapour decompositlon, by a dual-ion ;
beam technique, or by introduction of the hydrocarbon gases dlrectly lnto a saddle-fleld source. A saddle-field source is a source of lons produced by a colllslon ~etween BaS atoms excited /-by thermlo~lc emlsslon, and thls method ls preferred because lt `~
allows ~heat-sensltlve materials to be coated by a beam that- is uncharged -- so facllltatlng the coatlng of lnsulatlng or non-conductlve materlals.
It~ properties can vary accordlng to the particular raw materlals used and its mode of formation. It can also be made ln other ways, for example by sputtering solid carbon, as an alternatlve to dlssoclating hydrocarbon gases.
Further descrlptlon of DLC -- lncluding lts constitution, nature and properties, and the varlatlons ln its form which can be made -- and modes for its preparation, are to be found for example ln the followlng published references ~among others):-(a) "Diamond-Llke Carbon Applled to Blo-Engineerlng Materials;"
A.C. Evans, J. Franks and P.J. Revell, of Ion Tech Ltd., 2 .
Park Street, Teddington, TW11 OLT, Unlted Klngdom; Medlcal Device Technology, May 1991, pages 26 to 29.
(b) "Preparation and Properties of Dlamondlike Carbon Films;" J.
Franks; J.Vac.Sci.Technol. Vol.A, No.3, May/June 1989, pages 2307-2310;
SUBSTITUTE SHEET
~, ~
WO 93/24828 2 t 3 6 ~ ~ ~ PCT/GBg3/OOg82 .~;
(c) "Blocompatibillty of Diamond-llke Carbon Coating;" L.A.
Thomson, F.C. Law, J. Franks and N. Rushton; Blomaterials, Vol.12, January 1991 (pages 37-~0);
Cd) "Categorlzatlon of Dense Hydrocarbon Films;" J.C. Angus;
E.M.R.S. Symposium Proo., 1987, Vol. 17, r~e 179; Amorphous Hydrogenated Carbon Fllms, XVII, June 2-5 1987, Edlted by P.Koide & P. Oelhafen. ~
(e) "Properties of Ion Beam Produced Diamondllke Carbon Fllms;"
M.J. Mlrtech; E.M.R.S. Symposium Proc., 1987, Vol. 17, pag~
377;
Cf) "Diamond-llke Carbon - Propertles and Applicatior~s;"
J. Franks, K. Enke and A. Richardt; Metals & Materials (the Journal of the Institute of Netals); and ~g) U.S. Patent No. 4490229; M.J.Mirtich~, J.S.Sorey & B.A.Banks.
Thus, ln brief, our inventi~n can be used as~a method for providin~ a shi;eld, useful or excludin~ interferents from an enzyme lamlnate/electrode assembly, comprlslng a coatlng of a carbonaceous material with~ propérties approachlng those of diamond as a coverlng material. ~The~preferred~carbonaceous ~20 ;~matèrial~ ls that :form: of amorphous carbon or a hydrocarbon $"~polymer~;known~as~ "diamond-like carbon."~ F-cpecially it ~ is used as~ an ~outer~covering material. It can also act as a bloccmpatlble shleld.~ The DLC may also be used~to coat other parts of the electrode~or sensor ~ssembly if desired.
2S Alternatlvely stated, our inventlon;provides Improved sensor devlces inoorpcrating~a coat~lng of ~a~ carbonaceous material kn ~
as "dlamond-l~lke carbon" (DLC) as~an outer shleld, especially when blo-compat~bllity~ is deslred. This coating allows the ~; - pr~cductlon ~of a shleld wi~th tallor-desi8ned desirable dlfusion -i 30 characterlstics. -The~convenient source~ of the carbon is a hydrocarbon gas or vapour, especlally~one which is readlly decomposed by an electric fleld or ~i ~ e. A very convenienit source gas is acetylene, thcuRh~others ~ay be used lf deslred.~ Indlvidual hydrocarbons or 35~ mlxtures thereof may be-used;, and dlluent R~CP~ may be added lf deslred~;and the decomposition/depositl~on prooedure may be carried out~ at prff sures at atmospheric or above o~r below atmospheric, as SUESTITUTE SHEE~' j, . . . . .
,, ,. ~ ..
W093/24828 '~3~b 6 - pcT/Gs93/oo982 found most suitable for particular lnstances.
The coating may be made of a thlckness whlch may ~e varied according to the partlcular requirements desired for the performance of the sensor and the system to be analysed. ~hus, the thlckness of the coating or deposit may-be in the range O.Ol to 5 ~um, but thlcker or thinner coatlngs may be used lf desired.
A typlcal and convenient coating deposit is one approximately O.l ~m thlck, but thls ls not necessarlly the optlmum for all purpo6es. The thickness in nay partlcular case will depend upon such factors as the nature (physical and chemlcal) of the ~aterial upon which the DLC is deposited, and its porosity or permeabillty, and the partlcular characterlstics appropriate tO
the lntended use of the sensor.
The coatlng ls convenlently carried out at a rate which allows the deposlt to adhere to the membrane material and form a coatlng of the deslred thickness - preferably also evenly coated so as to cover substantlally all the surface without leaving any areas too thlnly covered or even un-covered.
When uslng acetylene as a ~ource, for example, the deposltlon may be carrled out at a rate of up to O.5~um per hour, though hlgher or lower rates may bP used lf deslred~
In car~ylng out the coatin~ procedure, lt ls preferred th~t the membrane surface should ~e as clean as practlcable, to ensure that the deposlt has optlmum ablllty to adhere properly.
varlety of cleaning method~ may ~e used. One whlch is very ~ ~sultable ls Fast Atom Bombardment (sometimes referred as "FAB"
- for brevlty); thls comprises sub3ectlng the tar8et material to a neutral atom beam source, and a typical cleanlny tlme ls an exposure to such treatment for about S mlnutes ~ though longer or ?horter tlme may be~used if deslred.
If desired, more than one membrane may be used, and the coatlng may be applied to one or both surfaces of a nembran~ or to~ one or more surfacès of more than one membrane in the electrode ?CcP~bly whlch makes up the sensor device.
35Preferably, the coating is applled to the outer surface of ~ the ~e~brane (l.e. that surface remote from the actlve electrode -~ and nearer to the surrounding ~edia. If more than one me~brane , :~ SUBSTITUTE SHEET
W O 93/24828 21 3 6 ~ ~ ~ P~T/GB93/00982 is used, the most advantageous pOSitiOI~ for the coating of DLC is on that membrane or membrane surface which is rlearest to the medium beir~ studied or analysed.
Thus, for example, the sensor device may comprise an inner and an outer membrane, in which case one may be coated as deflned above and the other may be elther un-coated or may be of another material, coated or un-coated.
For example, the outer membrane may be as deflned above and the lnner may be for example made of a cellulose ester, and especlally any form of cellulose acetate. Such a membrane is preferably made of a thlcknPqq in ttle range O.l to l.O Jum, and may be made by conventional methods, for example by casting from solution, optionally with inclusion of additives (for example by inclusion in the casting solution) to modify the properties of the resultlng cast film or to facilitate the casting process.
The lnvention is applicable to a variety of er~yme systems but is principally applicable to systems in which the enzyme is an oxidase and the hydro~en peroxide formed as a result of its actlon ls measured electrolytically. Especially, it is useful 20 ~for systems, sensors and electrodes lncorporatlng a glucose oxidase enzyme, as the substrate ~lucose is a common component whlch requires to be measured or biochemical and clinical purposes. The use of the coatecl m~mbranes in sensors according to the present inventlon enables the measurement or detection ran8es for 81ucose to be extended considerably beyond those which are easlly measurable by the sensors known bitherto, and also for the degree of linearity of re~ponse (i.e. the relationshlp between the sensor output slgnal and the amount of the substrate glucose3 to be extended, which makes the sensors much more useful ln practical cllnical or laboratory condltlons. Thus, as an -- lllustration, ranges of 81ucose detection up to 25-30 m~ of glucose are advantageous ln practlce and the pre ent lnvention allows the range of detection to be extended even beyond this, -~ for example to lOO mM or even more. Such hl8~ concentrations can be of ~alue for measurlng glucose concentratlon in media assoclated wlth products in the food and fermentatlon lndustries.
.
~ -SUBSTITUTE SHEE~.
W093/24828 c~,~3~ 5b 8 - PCI/GB93/00982 - ~
The enzyme may be incorporated in the sensor by conventional means, for example by being immoblllsed on the membrane by a fixlng agent whlch does not impalr its enzymlc activity (for '' example glutaraldehyde and albumin), and a very convenlent form 5 'of constructlon of the sensor ls that ln whlch the enzyme is held -in place between two membranes -- sometimes termed a "laminated"
form of membrane. In such "laminates" one membrane layer (termed ' the outer layer) ls the one exposed to the meidlum under study or ~' analysis, and this ls the one on which the diamond-llke coatir~
ls of most value, though the coating can be on any or all membrane surfaces as desired.
The mode of electrolytlc analysis to be used is especlally amperometric analysis, which is well known and used in the art.
The prlncipal advantage of our sensors ls that they can be i`
used in the reagent-less analysis o a wide variety of body 1uids (e.g. blood or serum) and other biological m~dla without dllutlon and' without significant interference from endogenous or ~-exo~enous agents whlch may be present in a patient's blood. It '~
enhances any membrane-based sensor system, whether enzyme-based or not.
Diamond-llke carbon coatings have the advantages of a high 1' degree of inertness and also a hlgh degree of haemo-compatlblllty ' (ccmpatlblllty with blood). ,~' Further advantages of the present lnvention include~
25 Cl) providing of a strong, flexlble coating on the sensor; ~' (2) allowin~ the precise flne-tuning of the poroslty to the outer membrane of a sensor, thus extending the linearity range; ,~
~3) exclusion, by the coatlng, of large macromolecular and some smaller electrochemicai'lly actlve interferents,~so preventin8 - 30 blo-fouling oÇ the enzyme electrode assembly and enhanclng the selectlvlty of the electrode, even to the extent that an outer membrane can provide the propertles otheirwise requiring the use of another, lower, underlying permselective membrane.
An especial advanta8e of the sensor of the present lnventlon ls that lt wlll permlt the reliable analysis of glucose concentratlons ln whole undiluted blood. This is usually not .
SU8STITUTE SHEEr. `
W O 93t24828 ~ 6 ~ PCT/GB93/00982 _ 9 _ possible with the known forms of sensor. Of course, the value of the invention is not restrlcted to belng solely a~plicable to the analysls of blood t and it may be applied to analysls o~ other media contalnlng qulte hi8h concentratlons of glucose or other S electrochemically active species at levels which comm,only present cor~lderable problems for analysls. Such other medla include a varlety of a media of organlc or non-organlc orlgin, for example plant and frult Juices, chemlcal process liquids, and the llke.
Thus according to our invention we also provlde a method for the electrolytic analysis, especlally of biological fluids, which comprises applying them to a sensor device or electrode system in whlch there is used a sensor electrode as defined above.
The preferred form of electrolytic analysis is amperometric detection.
Usually, the electrode of our invention will be used as the anode.
In use, the electrode of our lnvention can be used to carry out the method of our invention by immersion (together with an associated cathode) in a predetermined volume of a buffer solution to be analysed, and applying a polarlsing voltage so that the amperometric measurements can be made and compared before and after the addltlon of the blood or serum sample under test. The procedure may also be `callbrated ~y use of solutions containing known amounts of the substances sought, and lts accuracy thls c,hecked and conflrmed. Llkewlse, the procedure may -~ ~be carrled out uslng known amounts of compounds which are ~-considered to be potentlally troublesome by `their expected abillty to lnterfere wlth the measurement of the paracetamol, so that the degree of interference (lf any) can be established~
Conventlonal apparatus n~y be used, for the cell, electrodes a~ld the measurement ~and recordlng of , the current-voltage relationships for the samples under test. Measurements may be made contlnuously or intermlttently, as desired.
In operatlng the procedure, it ls convenient to use a '~ 35 polarlsing ,volta~e in the range I 0.~ to 0.8 volts Cpreferably at -~approxlmately ~ 6.S volt) against a sllver/silver chloride .
S~ '8STITUTE SHEET
WO 93/24828 PCT/GB93/00982 ~
.. , s~ -- 10 -- :~:
2~
electrode. The liquid medium may be at a pH which c~n vary over a conslderable ran8e, but is especially ln the pH range 6 to 8 and preferably at approximately 7.4 (or physiologlcal use).
The sample under examinatlon may be stlrred or unstlrred, as desired or convenient.
The electrolytic procedure for use of the sensors of our invention may be carried out over a considerable range of temperatures, for example ln the range 20 to ~0 degrees C.. It is usually important that the tempeirature used for callbration is wlthln approximately 4 degrees C. of the assay temperature.
For calibratlon, an isotonic or other other buffer may be used, but it ls preferable to use one which has an ionic strength similar to blooci (i.e. approximately O.lS M).
The medium ls commonly aqueous, but need not necessarlly be so, and an organic solvent may be used if desired (as such, or in admixture with each other and~or water) provlded it is an electrolyte and dissolves any desired reagents, but is not medlcally relevant to the assay carried out.
Typically, a procedure for calibration uses a treatment in isotonic phosphate buffer at pH 7.4. Following this, the buffer is~ removed, the serum or blood ls added, and the response is awalted thls lllustrates how much the pro edure can become a simpllfied analysls.
For thls purpose, the electrode may be lmmersed in a sample of the fluid (e.g. blood) and then llnked wlth a suitable reference electrode Cfor example a silver electrode or a calomel ;~ - electrode~ in conventional manner. Measurement of the voltage, - current and the llke may be taken and the measurements taken and recorded as deslred, lntermittently or contlnuously. For this, conventlonal apparatus may be used.
Samples of the mexila for examinatlon Cfor example bloKxi or serum) may be obtalned by standard methods. The quantity of blo~d~serum should be sufflcient to ccver the electrode and the current measured at a flxed tlme or after a stable response has been achleved. Likewlse, samples of other m~iia may be obtained ln any convenlent manner and brought lnto contact wlth the sensor of the present lnventlon for the purpose of component detectic-n.
SUBSTITUTE SHEET
.
W O 93/24828 ~ 1 3 ~ ~ ~i S PC~r/G B93/00982 The membrane and/or anode may be prepared for use in the analytical proces~ of the inventlorl by soaking it, when it ls in place around the anode, in a solution correspondln~ to the electrolyte medlum before the blood~serum sample ls added.
Simllar procedure~ and conditions may be used for analysis of other medla of a biologlcal or blochemical nature, with modifications as wlll appear appropriate to an expert in the art having regard for the nature of the media, the components sought, and the conditions and requirements of the measurement.
The inventlon is lllustrated, but not limlted, by the followin; Examples.
EXAMPLES. ", ~ ., Chemic,als:
Glucose oxidase from A~,pergillus niger (75Y. protein, 150,000 unlts/g solld), and bovine serum albumin (fraction V), were obtalned from the Sl~ma Chemical Company Llmlted (Poole, Dorset), D-glucose, di-sodium hydrogen phosphate, di-hydrogen sodium phosphate, sodlum benzoate and sodium chloride ('`AnalaR" grade) were obtalned from BDH (Poole, Dorset)~ All chemlcals were used without further preparatlon.
Buffer:
A bufer (pH 7.~j of 5.28 x 10 2~ Na2HP0~, 1.3 x 10 2M
NaH2P04, 5.1 x 10 3M sodium chlorlde, 6.24 x 10 3M sodium benzoate was prepared in dlstllled water. Thls buffer was used for all enzyme preparatlons and diffus~onal studies.
, .
DLC Coated PolYcarbonate Membranes:
Polycarbonate membranes for DLC coating were purchased from Poretlc~ Corporatlon (Llvermore, USA~ and the DLC coatln8 procedure performed by Atom Tech Ltd. (Teddln8ton~ Mlddlesex, En8land - formerly Ion Tech Limlted) as has been described (J.
Franks; J. Vac. Sci. A71 (1989), page 2307). Polycarbonate membranes of pore radll 0.01, 0.05 and 0.1~um were prepared with deposltlon duratlons of DLC of 1 minute, 3 minutes 30 seconds, SUBSTITUTE S~lEET
W O 93/24828 PCT~GB93/00982 ~ 2 -and 7 minutes and compared with un-coated membranes. Membranes were cleaned by a 5 mlnute Fast Atom Bombardment (FAD) within an argon or other gaseous saddle fleld source. Control membranes were similarly treated.
DLC coatlng times quoted define deposltion tlmes, so single-sided cc~ted membranes had all of the depositlon of DLC applled to one surface, whlle double-sided coated membranes had 50%
applled to each surface. In this way it was lntended that single and double sidecl coated membranes could be directly compared wlth regard to coating durations. The deposition rate of DLC was 0.45 um per hour, so } minute, 3 minutes 30 seconds, and 7 minutes coating corresporld to 0.0075, 0.0225 and 0.05 ~um thickness respectlvely. These membranes had a quoted thic~ness of 6~um, so the maximum coating of DLC was less than 170 of the membrane thlckness to whlch lt was applled. It was therefore assumed to have a negllglble effect on the thlckness of the membranes used ln the calculation of the P values.
~: .
Apoàratus: i An oxygen electrode assembly (Rank Brothers, Bottisham, Ca~bridge, U.K.) as prevlously used (W.H.Mullen, S.J.Churchouse, F.H.Keady and P.M.Vadgama; Anal. Chlm. Acta. 183 (1986), page S9) was utllised for glucose oxidase enzyme electrodes. The working electrode (anode) was polarlsed at +650 mv (vs Ag~AgCl) for the `~
oxidatlon of hydrogen peroxide. The cell was comprised of a central 2 mm dlameter platlnum dlsc wlth an outer~pre-anodised 12 mm dlameter 1 mm silver ring (Ag~AgCl) a~ a combined reference and counter electrode. The purpose-built voltage polarisation source and potentlostat ware constructed by the Chemistry workshops (Unlverslty of Newcastle, U.K.), and a x-t chart recorder-(Lloyd Instruments plc, Fareham, Hants., U.K.) was used `~
to record amperometric responses of the electrode assembly from the potentiostat current follower. A blood gas analyser CInstrumentatlon Lab Model IL 1802 - Hope Hospltal, Clinical Biochemistry Laboratory) was used for the analysis Of P02 within buffer aliquots.
i ;~ SUBSTITUTE SHEEr W O 93/24828 2 t 3 5 ~ PCT/GB93/00982 .~Fabrication of En2vme Electrodes:
Glucose oxidase ~GOD) (2560 unlts/ml) and bovine serum albumin (BSA) (O.1 g/ml) were dissolved in buffer solution. 6~ul of GOD/BSA solutlon and ~ul of glutaraldehyde (5% v/v) were mixed S rapidly and placed on a 1 cm2 portion Or O.OS ~m ~olycarbonate ~e~brane. A 1 cm2 portion of DLC-coated polycarbonate membrane was~then pl;aced Oll top and gl~ass slides;were used to compress the enzyme and membrane ;lamirlate under finger pressure for approxlmately S minutes. $he resulting cross-linked enzyme 10~ ~laminate was placed~ over the~worklng electrode, pr~lor to flnal electrode assembly and~f~ixation by an "O" rlr~.
Methodolo~v~:~Determlnat~lon~of Fermeablll~tv CQeff1clents:
Sol~ute~mass trans~fer~ measuremene;s across DLC-coated polycarbonate membranes to~assess their permeability were performed at 22 + 1 de W C. ln a Classical diffusion chamber apparatus~consistir~lg of~two chaDbers~. Both chaqhers were of 170 ml volume~and~were`~separated~by two~ stainl~ess steel di ~ and two sealing~rubber~"O"-~rings~clamped together~to hold the n~lbrarle~f ; 20 lnterest~wlth;~a~cross-sectional area~avai~labIe ~for~mass transport o 7.07~ The~solute of~lnterest~wa~added to one chamber and mass~ trans~fer ~was~thèn~det~ermined ~by measuring solute concentratlons~l;n~both~chamberS~ at ~periodlc lntervals. For the determinatlon~ of~ pO2~ levels~ al~lquoes~were extract~dl by a syrlnge and sealed;~wlthln~small~glass~;vessels~So`~prev~nt ~m~lxin8 wlth the atmospb~re,~prior~to~ ~ lysls.~ Oxygen~ wlthin one chamber was consuméd~by~ placl~ng~cross-l~inked~ GODJ~BSA fllms ln excess, to create oxy8en~grad~1ents~across t~he~membrane of interest.~ PO2 -levels we-re~determi~ned~;by~the blood~ gas~analyser. Permeabillty coef~1clènts~were ~calculated using ~th~e~expresslon derived by Sun et~al. (Blotech. Bloeng., 34!~ (1989),~page 55).
alvsls`of Blood Glucose Concentratlons:
Blood;~samples~previously ~tested for 8lucose conce~ltrations ; 35 ~Hope Hospltal Cl~i~nlcal Bl;ochemlstry laboratory)~were used for the~assessment of~enzyme~e1ectrodes for whole blood analysis.
Blo~d samples~were use`d on the same ~ay as the hospltal analysls : ~
~ '. ' , 1 :
SUBSi-lTUTE SHEE~
''~' .', '': ~ - '`' W O 93/24828 f ~ 14 - PCT/CB93/00982 and stored under refrigeration in tubes containing fluoride oxalate prlor to use to prevent the lowering of blood glucose levels wlth time due to c~ll metabolism.
Results:
Polycarbonate membranes (Poretlcs Corporation) lncorporate near cylindrical channels, formed by a well established neutron beam track-etched method. The relatlvely low thickness (approx.
11 ~um) of these membranes has enabled minimlsatlon of dlffusional dlstances, whlle facilitatln8 a hlgh degree of control over dlffuslonal re lstance. The glucose/O2 permeablllty coefficlent, P, ratlo is of critlcal signiflcance lf the membrane is to be used as a substrate dlffusion limitlng outer membrane over oxidase enzymes. By mlnimising the glucose/O2 P ratio for membranes, enzyme electrodes were constructed that became dlffuslon controlled rather than reflectlng lntrlnsic enzyme klnetics.
DLC-coated polycart~nate membranes have now allowed further extenslon of llnearity for glucose analysls wlthln in vitro samples c,ao mM), and also enabled minlmlsatlon of bio-fouling to the sensor. A series of experlments was performed to determine the P values for 2 and glucose acroOEs a spectrum of DLC single and double slded coated membranes, uslng a diffu~lon chamber ~apparatus (A.C. Evans, J. Franks and P.J. Revell; Medlcal Devlce 25 Technol., 26 (1991) page 26). On each nr~lon three membranes of each type were independentIy tested wlthln the diffusion chamber, and a mean value for each P value calculated. To aid clarity, only this value ls u~ed ln descrlblng permeabillty coefficlents trends.
We studled how the P values for 81ucose and 2 are reiated to polycarbonate membranes of O.Ol, O.OS and O.l ~um pore radll, with dlfferent durations of slngle and double sided DLC coatlng.
Thls demonstrated that, typlcally, P values across three membranes prepared by the same procedure may be attalned to -~ 35 withln a margln of around 5%. The productlon of membranes, the coatln~ procedure and methodology for the valuatlon of P values ls therefore shown to be reproducible.
.
~. ~
~ SUBSTITUTE SHEET
_ . , . .. . , . . . . . ... . .. . .. . . . . .. .. _ W O 93/24828 2 ~ ~ ~ 5 ~ PCT/GB93/00982 , .
We founcl that the P values for both glucose and 2 decrease with decr~ing pore radius and with increasing DLC coating time, whlch is conslstent with the flndlng that as the pore area is encroached the diffusior,al reslstance to solute trans-membrane s transport lncrec~ses. In partlcular, we found that P values for glucose progressively diminish as the DLC coating thickne~s is lncreased, due to the pore area belng progressively diminishecl.
No previous technique used by us (e.g. organic solvent depositlon) has allowed such "fine tuning" of membrane permeability at small pore radii. Our results indicated that, for a slmilar application of DLC, whether lt is to a single surface or to both membrane surfaces has little influence on the diffusing species' behaviour across the membrane.
0.01 ~m pore. racllt p~ly~rbc-nate membranes were founcl to be blcx~ to sducose trc~r~c-rt when ~reater than 1 mlnul.e ~ul~lor coatings of DLC are applied. However, single sided coated membranes become blocked at c1 mlnute DLC coating duratlons, whereas diffusion of glucose is permitted for double sided coated membranes of 1 mlnute DLC coatlng duration. This blocking difference is believed to be due to the build-up of DLC at very small pores ln slngle sided coatings, whereas the pore aperture ls spared if thls is distributed across two membrane surfaces.
Of particular interest, however, is the findlng that 2 transport ls much less affected by DLC appllcation, and that when glucose is fully obstruGted 2 trans-membrane transport ls stlll malntalned. The P ratlo values are very slmllar for slngle or double slded DLC-coated membranes. The flrst application of DLC
Cl mlnute) re~ults ln th~ greatest reciuctlon of the glucose/O2 P
ratlos. Further coatings of DLC result in contlnued reduction in this ratio, although the effect is less promin~nt. The membranes showlng the smallest glucose/02 P ratlos are those for 0.05 ~um pore radil membranes with 7 mlnutes DLC coatlng, for both single and double slded coated membranes.
- We carrled out the calibratlon of glucose oxldase enzyme electrodes with upper double sided 0.01 Jum pore radil membranes and the correspondlng control. Llnear ranges of analysls were SUBSTITUTE SHEET
c~ 3 ~S~ ~ ;
found to possible to in excess of 80 mM concentratlons, which are vastly in excess of those that may be attalned with un-coated membranes.
Further work was carried out on calibratlon curves for S enzyme electrode~ employir~ upper 0.05 ~um pore radll membranes.
The almost identlcal behaviour shown by enzyme electrodes utllising single and double slded DLC-coated membranes conflrms that, for both types of membrane, the same coatlng tlmes impart almost identical ~ropertles. In addition, as the DLC coatlng tlme ls increased, the enzyme electrode llnearity range is progressively extended.
Simllar findlngs are shown for 0.1 ~um pore radil upper membrane enzyme electrodes and the calibration curves for sensors utlllsing 0.1 ~um pore radil DLC-coated upper polycarbonate membranes. Agaln, longer durations of DLC coating result in extended linearity ranges.
A ma~or constralnt to the commercialisation of prevlously ~nown sensors for whole blood measurements ha~ been the lntractable problem of signal drift as a result of blo-foullng.
20A series of experiments was designed so that the enzyme electrodes, all wlth inner 0.05 ~um pore radll un-coated polycarbonate me~branes, and varying pore radil DLC-coated outer polycarbonate membranes (together wlth controls) were exposed to heparlnised whole blood and then rinsed wlth non-anticoagulated buffer solutlon. Responses to S mM glucose solutlons, before and after blood exposure, were recorded and percentage losses of response were calculated.
The percentage l~eP~ of slgnal followlng exposure to whole blood for 30 mlnutes was calculated. Results showed a typical loss of response to a standard 5mM buffered glucose solutlon, followlng increasing tlme exposure to whole blood. Agaln, very few dlfferences were ohRPrved betwee~l sln~ie or double slded DLC-coated membranes. However, the reslstance to bio-foullng appears to lncrease wlth greater deposltlon of DLC for all membranes.
35The greatest change ls seen between un-coated membranes and the flrst deposltlon of DLC (1 minute). The polycarbonate SUBSTITUTE SHEET
WO 93/24828 2 ¦ ,? ~ ~ 5 ~ PCT/GB93/00982 x~
~ , .
membrane pore radius also appears to be critlcal, as smaller pore radli membranes always exhlblt lower losses followlng blood exposure than enzyme electrodes with simllar DLC-coated membranes of larger pore radil. It therefore appears that both smaller S pore radii and longer durations of DLG coatlng contrlbute to lncreased functlonal bio-compatlblllty.
As before, only double sided DLC-coat~d membrane of 0.01~um pore radli could be tested for bio-foulin~ as single sided DLC-coated O.O1 ~lm pore radii membranes were all blo~ked to 81ucose.
However, 0.01 ~m pore radii polycarbonate membranes wlth 1 minute depositlon DLC double-sided coatlngs as the upper membrane of an enzyme laminate exhibited extreme reslstance to blo-fouling, showing a los~ of only 6æ signal followlng 30 minutes exposure to whole blood. This is considerably better than has been achieved to date with other membrane ~ystems to our knowledge.
An enzyme laminate with an upper nominal pore radius of 0.1 ~um and 7 minutes double-sided DLC coating was exposed to blood, w hed with ~distilled water, and buffer placed in the cell for conti~nued washing for one hour. The buffer was then replaced 20 ~wlth a 5 mM glucose buffer and the response recorded. The final response was found to be ~% higher than previously noted, believed to be because some surface bio-fouling had been ~echanically dislodged.
As linearity ranges for glucose analysis over clinically ZS useful ranges had been attained, and the effects of bio-foulin~
assessed following whole blood exposure, two sensors for comparison were constructed -- both wlth lower o .as ~um pore radii polycarbonate me~b anes; outer rembranes were of O.Ol and 0.1 ~lm pore radii double sidad 1 minute duratlon DLC-coated membranes.
Th cP two enzyme ele trodes were calibrated followlng exposure to whole blood, and individual blood c~mples previously tested for 81ucose le~els wlthln a Cllnlcal Blo~hemlstry Laboratory (at Hope Hospltal) were analysed and the correlatlons between the two ~- electrodes and the Clinical Laboratory results were studled. The 3S 0~.01 ~um pore radll upper membrane glucose electrode yielded results~ which were ln close a8reement wlth those of the .
~ SUBSTITUTE SHEEr WO 93/24828 ,~ PCT/GB93/00982 '~3 6 `~ 18 -Biochemistry Laboratory, though the results for 0.1 ~m pore radli membranes showed a poorer correlation. Thls has two important consequPn~es. The correlati~ns show that this enzyme electrode is capable of yieldin8 conslstently reliable results for the analysis of blood glucose concentration~ desplte repeated exposure to whole blood. Secondly, although no permselectlve membrane has been used, the electrode appears to show little sign of electroactive lnterferents reaching the working electrode, indicatlng that the upper membrane is uniquely acting as a barrier to electroactlve interferents.
Conclusions:
A comprehensive serles of DLC-coated microporous polycarbonate membranes have been ~cP~ced in terms of porosity and permeabillty coefficlents calculated for glucose and oxygen uslng the classical diffusion chamber.
Glucose electrodes have been constructed utilislng DLC-coated outer coverlng membranes, and linearity ranges assessed for sensors possesslng a ~eries of ~LC-coated membranes.
Comparisons have hPPn made between the permeablllty coefficient of glucose and oxygen, and P ratios related to linearity ranges attained using these membranes. Lower glucose/O2 ratios were found to be associated wlth extended linearity ranges. Linearity ranges ln excess of 80 mM glucose concentratlons were attalned uslng 0.01 ~um, 1 minute duration DLC-coated, polycarbonate membranes as outer coverlng membranes. The enzyme electrode utilicP~ the membrane showing the greatest diffuslonal resistance to glucose, suggestlng that the glucose/02 P ratlo and the a~solute P value for glucose are both critlcal for linearising a glucose enzyme electrode. The same enzyme electrode exhibited a good resistance to blo-fouling, wlth losses in response of only 67. followlng repeated exposure to whole blood as well as showing close correlatlon to glucose analysls uslng conventional Clinical Blochemlstry technlques, desplte the ab ence of an underlying selectlve membrane.
.
:
SUBSTITUTE SHEET
Claims (20)
1. A sensor device, useful for electrolytic analytical procedure, incorporating a carbonaceous material having characteristic comparable with that of diamond, especially that known as diamond-like carbon, which can series as a shield to exclude interferents.
2. A sensor device as claimed in Claim 1 in which a working electrode is surrounded by at least one diffusion-limiting membrane, wherein the said membrane has a coating comprising a a carbonaceous material having characteristics comparable with that of diamond, especially that known as diamond-like carbon.
3. A sensor device as claimed in Claim 1 or Claim 2 wherein the working electrode is a metal, preferably platinum.
4. A sensor device as claimed in any of Claims 1 to 3 wherein the working electrode is in the form of a platinum disc surrounded by a silver ring as reference electrode (a "Clark electrode assembly").
5. A sensor device as claimed in any of Claims 1 to 4 wherein the membrane is made of a permaselective membrane material, especially a microporous membrane with low permeability, and preferably a polycarbonate.
6. A sensor device as claimed in any of Claims 1 to 5 wherein the membrane has a thickness less than 10 microns.
7. A sensor device as claimed in any of Claims 1 to 6 wherein the membrane has pores which are of the order of 0.05 to 0.01 microns in size.
8. A sensor device as claimed in any of Claims 1 to 7 wherein the coating of diamond-like carbon is of a thickness in the range 0.01 to 5 µm.
9. A sensor device as claimed in any of Claims 1 to 8 wherein the membrane is cleaned before coating e.g. by Fast Atom Bombardment.
10. A sensor device as claimed in any of Claims 1 to 9 wherein the coating of "diamond-like carbon" is applied to the outer surface of the membrane (i.e. that surface remote from the active electrode and nearer to the surrounding media) or, if more than one membrane is used, the coating of diamond-like carbon is on that membrane or membrane surface which is nearest to the medium being studied or analysed.
11. A sensor device as claimed in any of Claims 1 to 10 wherein the sensor contain an enzyme system, and especially one using an oxidase (especially a glucose oxidase) and the hydrogen peroxide formed as a result of its action is measured electrolytically.
12. A sensor device as claimed in any of Claims 1 to 11 wherein the enzyme is held in place between two membranes --conveniently termed a "laminated" form of membrane.
13. A sensor device comprising diamond-like carbon, substantially as described.
14. A method for electrolytic analysis, 3specially of biological fluids, which comprises applying them to a sensor device or an electrode system in which there is used a sensor electrode as defined in any of Claims 1 to 13.
15. A method for electrolytic analysis as claimed in Claim 14 wherein the electrolytic analysis is amperometric detection.
16. A method for electrolytic analysis as claimed in Claim 14 or Claim 15 applied to the reagent-less analysis of a body fluid, especially blood.
17. A method for electrolytic analysis as claimed in any of Claims 14 to 16 wherein there is used a polarising voltage in the range + 0.4 to 0.8 volts (preferably at approximately + 6.5 volt) against a silver/silver chloride electrode.
18. A method for electrolytic analysis as claimed in any of Claims 14 to 17 wherein the sensor is calibrated at a temperature within approximately 4 degrees C. of the assay temperature.
19. A method for electrolytic analysis as claimed in any of Claims 14 to 18 wherein the sensor is first treated with a buffer solution.
20. A method for electrolytic analysis using a sensor as claimed in any of Claims 1 to 14, substantially as described.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929211402A GB9211402D0 (en) | 1992-05-29 | 1992-05-29 | Sensor devices |
| GB9211402.4 | 1992-05-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2136856A1 true CA2136856A1 (en) | 1993-12-09 |
Family
ID=10716218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002136856A Abandoned CA2136856A1 (en) | 1992-05-29 | 1993-05-13 | Sensor devices |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5531878A (en) |
| EP (1) | EP0647318B1 (en) |
| JP (1) | JPH08501144A (en) |
| AT (1) | ATE177202T1 (en) |
| AU (1) | AU676678B2 (en) |
| CA (1) | CA2136856A1 (en) |
| DE (1) | DE69323747T2 (en) |
| DK (1) | DK0647318T3 (en) |
| ES (1) | ES2131579T3 (en) |
| GB (1) | GB9211402D0 (en) |
| GR (1) | GR3030177T3 (en) |
| NZ (1) | NZ252235A (en) |
| WO (1) | WO1993024828A1 (en) |
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|---|---|---|---|---|
| US3979274A (en) * | 1975-09-24 | 1976-09-07 | The Yellow Springs Instrument Company, Inc. | Membrane for enzyme electrodes |
| GB8522834D0 (en) * | 1985-09-16 | 1985-10-23 | Ici Plc | Sensor |
| GB2209836A (en) * | 1987-09-16 | 1989-05-24 | Cambridge Life Sciences | Multilayer enzyme electrode membrane and method of making same |
| DE4014109A1 (en) * | 1990-05-02 | 1991-11-07 | Siemens Ag | ELECROCHEMICAL DETERMINATION OF THE OXYGEN CONCENTRATION |
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| AU676678B2 (en) | 1997-03-20 |
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