CA2201570A1 - Reagent test strip for determination of blood glucose - Google Patents
Reagent test strip for determination of blood glucoseInfo
- Publication number
- CA2201570A1 CA2201570A1 CA002201570A CA2201570A CA2201570A1 CA 2201570 A1 CA2201570 A1 CA 2201570A1 CA 002201570 A CA002201570 A CA 002201570A CA 2201570 A CA2201570 A CA 2201570A CA 2201570 A1 CA2201570 A1 CA 2201570A1
- Authority
- CA
- Canada
- Prior art keywords
- strip
- matrix
- blood
- sample
- dye precursor
- 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
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- 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
- C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
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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
- Y10S435/975—Kit
-
- 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
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
- Y10T436/144444—Glucose
-
- 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
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
Abstract
A reagent test strip is adapted for use in a blood glucose meter. A sample of whole blood L applied to one surface of a matrix on the strip and the meter measures the reflectance of the opposite surface of the matrix at about 635 nm and 700 nm and calculates from the reflectance the concentration of glucose in the sample. The portion of the applied sample that penetrates the matrix and is visible from the testing surface does not absorb to any appreciable extent at 700 nm. Nevertheless, the glucose-containing sample interacts with the components of the reagent-containing matrix to cause a change in reflectance at 700 nm that simulates the effect of the blood color. As a result, the strip can be used in meters that measure glucose concentration in whole blood samples in the presence of optically visible hemoglobin.
Description
RF~ TP Ft~R n~l ~.RMr~ATI~N C~F RT.~n ~.TJC~O~F.
R~r~r ~nfl of ~P T. ~
5 1. Fi~l-l nf tl~ T. ~v.~ n This ir.~ lio,. relates to a dry test strip for measu~lg the co~ a~on of an analyte in a biological fluid; more ya I ;.~ rly, a test strip that calo~ lly ll-easu~es the conc~l~aliu~ of glllrose in whole blood.
f tl~ Rel~ t Many visual test devices have been ~ ope i for ll.easu,~-g ~e co.~.l~dtion of certain analytes in biological fluids. These devices have, for 15 _Yample~ .A~ Cd ~ OSe~ r~o~-~t~ rol, ~Ot~ a~ kelc,~ es, ~l-eli~lalanine, or enzymes in blood, unne, or saliva.
Dry phase reagent strips in.c"~ e,~yll-~based cûll,~osilions are used eAlelraively inl.oay;lals, rlin;~al labol~lo- :es, physician's offlces, andhomes to test sam~ 1.e~ of biological fluids for ~ rose c~ncel~t~alion. In hct, 20 reagent strips have be~Qme an ~v~ ay ~ ~S;Iy for m~ny of the nation's several million ~iabp-tirc~ Since diabetes can cause dangerous anc maliPs in blood . h ~~ cl- ~, it can contrihute to vision loss, Wdney failure, ant other serio~lC m_ 1;CA1 colsequ~.es. To ll~ e the risk of these col~seq-lellces, cul~ll te~rh~ counsels ~_aul~S with diabetes to me~- lre their blood glucose 25 level from two to seven times a day, depending on the nature and seve.il~ of their individual cases. Based on the oL,s..~,ed ~ . n in the mP~Ae lred glucose ~ ~ o ~
levels, the patient and ~l~ysi~al~ lc,~lller make adjusl~ ents in diet, e~-e~se and insulin intake to better manage the ~ se- aearly, this ~rc~ tiQrl should be available to ~e ~alie-,t ;~ Ply, through the use of a si~ lc to-we meter and strip a~sl~. that is rapid, ~P~-L~;ve, and ac~;~ate.
Reagent stdps are hw.. ll that ca,llain an ;.~.~ic~lo~ which tums a .li~
shade of color, d~lg on the c~ ~P~I ~aLoll of ~ c~se in a biological fluid that has been applied to &e stdp. Al&ough some of these stdps use le~ll ~- 1 ;o. .
P~ S, more CQ nm~)rlly ~ey involve an oYi~li7~ dye or dye couple.
Some of the strips include an el~,...e, such as ~ rOSe oY~ which is 10 capable of oYidi7i~ ~l~-~se to g n~ -~ acid and hy&ob~l peroxide. They also COl~ l an ~Yi~li7~ble tye and a sullsldllce having per~Yid~tive activity, which is capable of sele tivel~ catalyzing oY~ tio~l of the oYi~i7~le dye in the~,~s_~e of ll~ob~_l peroxide.
U.S. Pat No. 4,935,346, issued June 19, 1990 to R Phillips et al., ~3i~rloses a 15 meter, strip, and method for ~o~ the glu~e COl '~ tion in a s~ple of whole blood (see also US.P. 5,304,468). The ~ o~ 1 involves simply a~ly~lg a s~mple of whole blood to a first ("s~ple") s?lrfar~ of an inert ~o ls matrLY~ that is ia~.eg"~fl with a l~a~ The s~mplc migrates tunf~d the o~,~osit~, ''l~sLIg'' s~-r~, as the gl.J~ ~se; .l~ra. Ic withthe reagent to 20 ~ cealight~ re~ ~t"o~lu.t. Areadingofrefl~:l--.c~fromthe ~tillgS..~ -al~C~e~lll~seCO~ lio~ ~ ~e ~~.oAc~ ,ellls are made at two Se~a~ ~le ~rd~ in order to ~ b? Llt~.f~es. A
~uf g circuit is triggered by an initial d~ase in refl~ ,.e c~ e~ by w~tling of the leslil,g s--- ra~ by the s~ lc having ~cse~l through the matrix.
US. Pat. No. 5,306,623, issued April 26, 1994 to Kiser et al., ~licrlosPc a visual blood glt~rQ5e test strip that il~volves applying a gl.~ dL~,g L~49 .
whole blood s~mplc to one side of the strip and taking the g~ ose reading on the o~ile side, after red blood cells have been s~aialed out and the s~m~le has rea.t~i with a leZgCnt in the strip. An ~Dtro~ic polysulfone mDmhrane was found e~ ly useful as a single layer matrix for the strip.
US. Pat. No. 5,453,360, issued _.~t~.. her 26,1995 to Y. S. Yu, ~;SC1QSDS a dye couple useful in dry reagent strips for r1~ , analytes, such as ~ ose, inbiological fluids. The dye couple ~""l" ;~P5 ~ll-etl~1-2-l,efLcG~ 7~Qli~one >O1~D and 8 anilino 1-~ l,ll.alenesulfonate and is used as an indir~tnr in a ~e~ . cascade ~,~o.l.l~.g a strong oYi~i7irlg agent, such as l~ydrog~
10 peroxite. An adv.ullage of the couple is that it is soluble in aq.leo.ls sollltiorl, but becomes ;- .~11-l ~ie upon oYirl~tive cotlr~ ~n~y llL~u~.g fading and proviting a stable e~d~ Lt.
A meter that has come into widespread use for self-m~lulo,m~, of blood glll~e is the One Touch~!D Il meter, which uses a strip that is ~l~rrihed in U.S.
Pat. Nos. 4,935,346 and 5,304,468, ~ lcse~l above. The meter and strip permit a user to . . . ~P~C. . ~ ~ ~3 E c~,- .c~ r~ ~ ;o. l in a whole blood sAmrle qui~ly, easily, and a-~c~ y. The s~mple is applied to one sulraoe of the strip and the measu~lent made on the o~l,osile s... r~e. A portion of the whole blood sa~lrle ~ les from the sample sLu~ace to the testing s..~ r~ , and the blood 20 color canbe ol,~l from the testing ~ r~
~.lrnmary o~ *IP ~
The ~ nt i~ lLon provides a reagent test strip for use in an a~ al~ls for ~l~le....;.~g a co ~lràLion of ~ ose in a s~mple of whole blood. The 4 2 2 0 1 5 7 ~
a~ lus co~ . ;sec optical means for ~1Dtec*~ ~ of light at wa~,ele.~ s of about 635 nm and about 700 nm rPfl~ from at least a p~liol~ of a mat~Y ~ ~ near one end of the strip, which m~hi y CO ~ es (a) a s~mrle r~vil-g s- -- r~ for le ~ivL.g the who!e blood S?~ and S ~as~L~, a portion of it board a l~ti~lE, s~l~fare o~ile ll-~Elo, (b) a s~ e that sel~tiv~ly retards the p~Csa~e of red blood cells ll~rougll the matrhY and ~ c the lysing of the cells in the m~h~iY, wl-er~y any portion of the sample that is visible from the testing --- race does not - absorb light to any appreciable extent at about 7DO nm, and (c)areagentfor;~.die~ the~ by~eal;ngatthe testing su~a~ a ~g~ n~ I ~ . ~e at about 700 nm that is sul,skulLally equivalent to ~at y~l~d by the al~r, 1. - ~e of h~mnglobin in blood and a ~.~ in r~ ~ at about 635 nm that is; .~ ;ve of the gl~ ose In the~ ~.~nt ~ ;o ~ and the appPn~ ce to the fact that "sA~ le that is visible from the lesling ~ ce does not absorb light to any a~r~ ;~hl~ extent at about 700 nm" means that 700 nm abso.L,an~e by the sample, as seen ll,ro.lgll the I~LI.g s~,~ r, ~, is less than about 20% of the 700 nm ~l,so.l,a~ ~ ~.1 by the reaction of the sample w.ith the reag~nt-Another e-~ ent of the ~.esP~ vel-L~ also provides a reagent test strip for use in an aEJ~"~t"c for ~1~, ...ini.~E, a c~ ~ of gll~cose in a sample of whole blood. The ay~ c ~ s optical means for delc~li..
il~t~s;l~ of light at ~vav~ gtlls of about 635 nm and about 700 nm from at least a ~ iG~ of a matnx disposed near one end of the strip, which 25 matrix ec ~ s 2 2~ 7 ~
(a) a sPm, le receivi~ s~aee for r~ving the whole blood sAmple and p&ssin~; a portion of it to.. ~rd a testing surface Gyyosile ll~erelo, the testing s~ a~ ~ l~avil~ a rf nPc~ c~ at about 700 nm that, when the tesling surface l~c ~.~~s wet, undergoes a change that LC s~sla-llially equivalent to that S y~o~ r~d by the al~so,l,~e of l-~...og!okill in blood, (b) a structure that selectively retardc the pacsa~e of red blood ceLc l1UO~ the matrix and ~--;--;~.; ~ the lysing of the cells in the matniY, ~vl-er any portion of the sample that is visible from the testing surface does not absorb light to any ayy~eciable extent at about 700 nm, and (c) a reagent for ~ the ~ c~se eo ~ aLon by ~eaLing at the testing SIJ~ ~r~ a .1 ~a- 1~ in rf~fl~ ~ at about 635 nm.
The L~ lion providec a reagent test strip that is suihble for use in a One - Touch~l9 whole blood gl~-~se meter. Since the sh~.ture of the strip selectively l~lards the passage of red blood cells through the matrix and ~L~ es their lysing, the ~ .;. ,aLon is less dependent on the hPmatnrrit of the ~ whole blood samrle.
R iPf n~ . ,~t;. . I ~f t1 IP r~r~w~
Fig. 1 is a ~ e view of an embodilnenL of a test strip of this U 1~ _. ItiUI L
nPtailP 1 T)PC.. ~1;nn~f t~lP T~v~ It;r~.l This iLIv~lliGll provides a rapid and simr!P ~elllG.l, employing a reliable and easy to o~dle a~ ue, for the ~let .~ aLon of ~ cose in whole blood.
The method in~lves applying to one s--- r~ce (~e "sam~le" surface) of an inert ~o~o.,s matrix a small s~ of whole blood, s~rn~ It to salulale the matrix.
25 The matTix is typically ~les~t in a r~n~ ~me~ rillg ap~ardllls when blood is applied. At least a ~, liGl~ of the liquid s~mple penetrates the matrix, -resulting in an initial change in rPfl~l ~ at the o~yosite ("testing") surface.
The ~lu~ose in the s~mple reacts with one or more reagents bound to the matnx to form a produ* that changes the r~flec~-~e of the mAhiy A reading is then taken at one or more times after the initial change in refl~l~. ~e to relate theS further change in r~ ,ce at the tesli,-~ surface or in the matrix to the c~llc~lha~ion of g]ll~ ose in the sAmr'e.
FIG. 1 shows one em~ t of the ~resenl ~ A thin l~r~utlllilic m~h iy reagent pad 11 is positi~ned at one end of a plastic holder12 by means of an adhesive 13, which &eclly and firmly attaches the reagent pad to the holder. The holder, which is optional, provides physical form and rigidity to the strip. A hole 14 is ~ s~nt in the pl_stic holder 12 in the area to which reagent pad 11 is attached, so that s~ulpl~ canbe applied through hole 14 to the 5Ample side of the reagent pad and light r~fl~cterl from the other, g side.
A whole blood s~mple to be tested is applied to pad 11. Gene~ally, the reagent pad s~urace area is about 10 m~2 to 100 mm2~ especially 10 mm2 to 50 mm2, which ~ lly provides a volume that 5-10 ~LL of sample will more th~
salu~le.
Al detils le~ the struchlre of the strip a~ear in the above .~r~l~d US. Pats. Nos. 4,935,346, ('346) and 5,304,468 ('468)-The an~lysis ~.elllod of this ~vel~LG~ relies on a change in absorb_nce, as measured by diffuse rPfl~(~ Ice, which is ~ep~lPllt upon the ~lYrose ~nc~.~ation ~es~t in a sAmrle being tested. This change may be 25 ~ ;ned by measLuillg the rPflPcta. ~e rh~nf~P over on,e or more time intervals.
2 2 0 ~ ~ 7 ~
~ n o~.ation, the test strip is first mo~ ed in an ~,sl~ent for reading light ~1 ~s~Mb~cei e.g., color ~ ensil~, by rPfl~--~ce, prior to a~ of thes~ Then, a ~ ~se co.~lail~ing blood s~m~e - o~tait ed by a finger stick, for ~ le - is a~lied to the matnx of the test strip. ~felably, the ~molunt S ~s that I eP~l~ i to sal~te the matrDc in the area wherP rPflP~ ce will be ,leasu~ed (i.e., about ~10 ~L). After the s~ k is applied, li~lg of the ~ t iS in;ti~d :-t~ ir;~lly wh~n fluid ~ ales the m~h iy, and the a~-al ~t. ~c ~letech the resulting ~ilge in rPnp~ Ire of the testing s~ ace.~he l 1 .a.~F in refle~la~ ,~ over a pre~l?l~ ~ ~ .; . ~e l tiime, as a result of fc~rm~ti~n of 10 reaction ~.od~i~l, is then rPl~te l to the gluc~se co~ aLon in the sAmple Refl~iux refers in this s~;r;ra~ Q and in the s~el~ied claims both to the visible ~vav~ igth range and to i~ra~ed and ultraviolet r~ic3i~ti~
Asuitable ilwt.~ilent, such as a di~-lse refl~a.~e pholQ...elel withi 8~ J~ te sofl~. a~e, can be made to All~m-tir~lly read r~nP.t~Q~e at one or 15 more timie L~ ls, c~ t,? the refle~la.~ r h~ng~, and, using CalilJldiliiCi~l factors, o~ l the g]l~ ose col--~-.l-~ J~i in the blood sample. Details of such an insl~ ing the me~ gy used by the instrumient to CC~l~vc~
n~~ ~ m~c- ~ ~c~ into blood gl . ~rose c~,n~cr 1 . ~ l ;on.c, are provided in '346 and '468. In ~ ~ular, eQmm erc ially available One Touch~) meters are 20 s~-_Lle for use in co~ :- .al;~l with the reagent strip of th,e present ~IvenLo l to ~leasl~re ~ c~se C~1ICC1~ I;')~C in whole blood S~ ~~1eS. These meters read r~fl?~ ~ of the strip lesL,Ig sllrfA~ .~? at about 635 nm and about 700 nm.
The matrix of the ~~ccl,t invc,Lo ~ is ~ ,~ly a membrane that efrc~ivcly sc~aralcs the red blood cells _nd l~~loglobin from a whole blood 25 s~mrle to leave the gl.~ a~ g plAsmA- The sep~ R~ll takes place as the sg~ k moves through the mc~ .alle from the sAmple surface to the tesli~
- - -- 2 2 0 ~ ~ 7 0 rfarP, A mPmhrane to a~o~ )li~ that s~y~ , may have pores that trap ~e red blood ceDs, generally pore sizes in the range from about 0.1 ~um to about 5 ~m P~ele.aL.ly, the ~,e.nl)ra~Le is ~wol~:c, wi~ a range of pore sizes; more yle~dbly~ a broad range of pore sizes. Wl~ the matrix c~.l~,~es 5 an ~ isD~pic meLI~ane, the sample site is p.ef~dL.ly the large-pore side.
For e ~ r'~, a gratient of pore sizes from about 0.1 ~m to about 150 ~lm may extend through the me~ ule. C~n the large-pore side, pore size is ~ .ably in the range from about 30 ~m to about 40 ~ On the side of the me~ r~
where the pores are sm~ll~t (i.e., the b2aLll~; a ~ f. c~), the void volul-le is10 relatively small, and the m~ of the membrane is generally quite dense, within a layer that can typically ~.,sLlule up to 20% of the ~ "al~'s ~ickness. Within this layer, pore size is l"ef..dbiy in the range from about 0.1to about 0.8 ~m, with a ~ 1 pore size ~,~f~ly about 0.3 ~m.
When the whole blood sample is ay~lied to the 5~mrl~ side, the s- , 'e 5 e~ itw..7~ gly sm-ller pores as it penclrales the ml ~.h~
I ~- Ql ~IAlly~ soads such as red blood cells reac h a ~;1;~,- . in ~e membrane,generally near the sample s~ ra.~P~ where they can ~nel~ale no rullller~ The m~ .h,a, le not o~ly kaps red blood cells near the s-9-mp~? s~lrfAr~o~ but also ...;..;..~;,~c lysing of the cells, so that any portion of the ssmrl~ that is visible 20 from the testing slura~e does not absorb light to any ~e~i9~!e extent at about 700 nm. The balP~l~P of the s- -~e, still ro- ~1~;. .;. 1~, the dissd~d gll)c~5e, e~dles through to the t~ , side. As it passes ~rough the memhrane~
glll~ose in the sample reacts with the reagent, ~lsin~ a light-aL,sc~ lg dye to be formed near the lesL~g side, L~ sul~al~lLally arre.~lg refl ce from 25 the testing sllrfAc~. The a~ isohol,:c nature of the merïbrane and/or use of a LPS~9 S~y;i~dLng CQ ~I~-t (~i.c~vcse~l below) 1J~; .nil.4 relaLvely rapid flow rates through the membrane, even while s~y~aL;on of the solids is taking place.
The matrix is a hy~o~l~ilic ~Of~ IS memhrarle to which reagents may be covalently or non-covalently bound. The matrix allows for the flow of an 5 a(lueo ls ~ throughit. Italsoallowsfor binriinf~ of y~oleulc~",posilio"~
to the matcvc willloul a~iably adversely a~f~ting the biological activity of the yrot~ e.g. enzymatic a.livilr of an e~ e. To the extent that ~,ole~,s are to be covalently bound, the matrix will have active sites for covalent l o,,~lu.g or may be a.Lv.~led by means ~.~1l to the art. The ~;c....l~s;t;on ofthe matdx is reflective, and it has slluici~nt tl~ ess to y~ ul the form~ti~ of a light absorbing dye in the void ~/olu,ne or on the surface to substAnti~lly affect the n~ .- ~ from the m~ x- The matdx maybe of a ~--);f~.--.
~il;~ or a a~a~ , on a s~ s! ~gle ~ro.~i~.g the ll~cecs~- y s~u lu~e and physical p .Les, such as h~.lrot)l.il ity.
Polyslllf ~nes and poly~mi-3Ds (nylons) are e. _ rl~r of sllit~Akle matrK
m~tPriAlq Other polymers having c~ -A~ le ~,c,~lLes may also be used.
The polymers maybe m~ifi~ l to il.lr~l,lce other fun~tio~,al glO.l~S which provide for .l~ ,ed sl,u.l~es, so that the s~l~fA~ of the matrK may be nP1ltrAI, ~osilive, or l~gaLv~
A ~ ~ed ll,etllod of ~rel-A. ;. .~ the ~o~ ls mAtPriAl that forms the matrix is to cast the polymer without a su~,til~g core. Such a matrK is, for .ple, the al,iso~opic polysulfone ~,e l~l~ule available from ~ , Inc., T;..-o-.i.-..~, MD. The terms "matnxn and u"~ ne" are used angeably herein. Each term is understood to not be ~ it~l to a single 25 layer and may in~ ?, for P~AmrlD, an absorbent layer. A matrix of less than about 500 ~m thickness is usually employed, with about 115 to 155 ~m being 2 2 0 ~ 5 ~ ~
~d. A thickness of about 130 to 140 ~m is most ~.ef~ed, parti~ll~rly when the matrix is nylon or a~soh~ic polysulfone. ~he matnx generally does not ~1 ~f~rm on wetLng, thua ~e1~ its o.~7n~1 confo~ ti~ and size, and has 5~rr~ t wet al~ to allow for routine mal~ra,cl~e.
The m~ r~ has ~.~~ into it~ pores a testing reagent that is çap~ of rea~ g with gl~J~se to ~O~l~ a light-al~sc,.l ~~ reaction product.
The m ~ ~hr~LLe may be keat#~d with rea~ t by di~plLIg it into a ...;~ of the cQml~o~ ~,LlL~ sa~ t;~themembrane. Excessreagentmaybe r~nu.ei by mechanical means such as, for e~ c, an air knife, doctor blade, 10 or glass rod. The mPmbrane is then dried. Reagent tends to cu~L.~ltrale near the small-pore (t~sLLLL~,) side of the ~P.~ nP Other methods that are suitable for a~ LL~g reagent to the memhr~np will occur readily to a ~ having oldiLIar~r skill in the art.
The leaLiLLg reagent ro-~ r~s a co-~ ~nt for c~ ~LLng gll~ ose to 15 lL~.Log~Lperoxideandac..-..~ tfor~lcl~;-LglL~o~nperoxide.The rca~$~ntmayol~LoLLallyfuLLlLerco~ ~ a ~.a~_l;"~ whichcauses solids, such as red bloo ,d cells, to bPC~ e eLIh..~ed in the m~h ix, eLl~;LLvely removing the solids from the whole blood. ~ r~al c~ U~L euLa may also be included as described below.
I~e~ ico---~-o-LeQLsforc~l.,~LLE;~ aeto1I~U,~.LpProYiliP
in~lt~ -rOaP oYi~i~cP~ an eLL~R that is usually ~tai~d from Aspergillus niger or Pe~irillillm ~l~rose ~Yi~4P reacts with gl~se and oArgeL~ to ~c~iuce gl-~rono~ onP and lI~o~l per~Yide. Opti,LI~L~ g~ USP oY~ 4e co. u~ ~ d~ls on the cc -..~ io-~ of the indir~tor s~ral~L; ho~
~ oae oy~ ce in the range from about 500-10,000 U./mL L ge~erally sl~it~
more ~r~ l ly from about 700-2000 U./mL. Generally, higher c~nceL~ lhons LFS~9 of ~ ose oY~ ce cause the re~i~ to ~.ooeed more rapidly and lower a;lIc~haliO~s, less rapidly. O~ c~ alio.. can be ~l~t~ ed by ~uLIe ~ latiorL
- The llr~c,g~ peroxide so ~ ed reacts wi~ the cc"l,po~ for S ~rt~t; ~ peroxite,whichro ~ Saper~ ethatreleclively catalyzes a reactionl~et~ the llr~Gg~ peroxide and an ~dica~r. The peroYi~l~ce uses hydrog~l pcro~d~ as an oxidant which is rap~h~e of re~
h~L.,g_~ atoms from various s~l,shales. A s~ Ahle peroxi~lAce may c~nlain ,.o~o~..t)llr,i." a red hemin ~ained from plants. Peroxi~l~cec o~a,~led from _-lim~lc~ for P~ lc from the thyroid glands of animals, are also suitable.
Horseradich per~Yi~ ~ee ff~PO) is eS~-;~lly ~f~ed as a c~ n~ of the r~ v -.~for~e~;u~h~ o,~ peroxide. Thehy~oge~l pel'OYi~D, f~ ly catalyzed by a peroy~ ce~ reacts either di~lly or i~ itLClly to form an ir~dira~or dye that redu.~ 635 nm ,en~a~ Ice at the testing sllrhre Testing s ~ race reflecku~e is measLIted at two waveleng~s - about 635 nm and about 700 nm.
R~flPC~ P mPacLll~~~lb are made in a timed sequence. The sequence is ;at~l by the refle~ e ~ I at 635 nm that results from the arrival of a ~. l;ol~ of ~e sAmrl~ at the Leslin~ s~ ~. ra-~ We denote this initiA*~ of timing as "rPfl~1~ wil~LL ~g". The ~n S~l~nc~ at 700 nm is ~~P~c~ed 15 seconds later. By that time, the blood will have s~lLualed the reagent pad, and the . a~;~ of the ghlrose cc."lai,~,~; blood s~m~l~ with the reagent~c..,~il~,E~, ,~,e will have ~~ll~i a reduction in r~fl~~ e at 700 nm that is SL~ hntially equivalent to the ~ o~ e~ by blood color being visible 25 at the testing ~!'- r''AP. Thus, although any s~mI~le that is visible from the testing sLurace does not absorb light to any ayyleciable extent at 700 nm, ~e LF~9 meter ~l~t~t-C the lQ''l~ rl in 700 nm rpn~l;on that it ~C~tPs with a~ oe by the blood color, and that causes it to then make refl?ct~-lce ements at about 635 nm. The gl.~ se CO~ tion in the s~m, 'e is r~ Pt~ from the 635 nm refle.l~~, using the 700 nm LF n~ ~ to S r~ be a co,le~1io~ factor. Note that since blood absorbs at 635 nm, so too should the blood;cimyl~ting 700 nm a~ r. Ideally, the blood~im~ ti~g m~tPri~l cllo~lld have the same ratio of a~ .r~ at 700 nm to aL.s~,L,anc~ at 635 nm as does whole blood, but for l,~vil~ we refer to the blood~imlll~ti~
mAtp~ S ~l ~su ba~rD at 700 nm only. Details of the ral~ll~tio~, iru luding the 10 c~ LG.~ for the "blood" r~n~u~p at 700 nm, ay~eal in the aforPm~ti~
'346 The re~ P~l lesLIg-s--- r~ n~l ..~? at 700 nm that cimlllatPc the blood color can be ~rr~1~ in four Al~ at;ve ways. First, the meml~r~e may C~
a ro~ -.,- ~l that absorbs 700 nm radiaLo.~ and the l~xL-~ s~rfAce may be S ~1~S~ 11Y opaque until it ~ -.DC more ~ya~ t to 700 nm light when wet The cc,~ ~n~t that ~t~sorbs at 700 nm may be a ~IO ~WO~ for ~
that is not visible from the dry t~sl;ng a ~ -'P- The C~I~G~lt could also be a su~.l onto which the ~ ~e is cast, a coating on the sAmpl~ suLracP of the m~mhrane~ or the lL~e.
~eco l~i, the memhrane may in~ude a water SO1~1JI~ dye thathas light a~so~d.ue at 700 nm that is slll~sl~ lly in~eased wh_n the dye goes into sol~l;on For PYAmple~ the dye could initiallybe in the forrn of finely divided ~vale. soluble crystals, a~ylied to the ...~ ule as ~1;4~ solids that appear white and provide no sl~hsl~Lal absorbance at 700 nm. The aqueous s~mple 25 dissolves the dye, at which point it l~-c -.~ colored and Ahsorhs at 700 nm. An ~.~.. .pl~ of such a dye is ~;c yp~ phthal~;ral~e.
LFS~9 --Third, the ;..l ~ ;~bet~veen gl.~cose and the reagent in the me,~
can res~t in a ~l~ro~.v~l~re that pl ~sc;.bs light at both 635 nm and 700 nm, ;. A~ ose ac,,.~x,.~aL~ and, at the same time, sim~ ng the ~res~e of blood.
S Fin~lly, the blood-rca~-l ;- .t.~ ~1 can yield two cl~o~lophores, one of which ~hso~bs at 635 nm and the other of which absorbs at 700 nm. F~ulllel, since a¢lly ~f o~ 700 nm refle~ ~ re~ltl~i~n is needed to simtll~te the p,es~-ce of blood color, ~Lf~a~ly only a small ~-OUnl of the ~luo,~.u~llore that ~bsorbs at 700 nm is ~ l. In the first two cases, in which 700 nm Pl-s."ba~ ce (i.e., le~-r~1 refle~ e) results from ~ .el me~ne ~- "l~'~' .l, the 700 nm abso~L,&b~e does not r~ e a ~uv~Llv~llvle.
In the third and fourth cases, the rP~~ ~ in 700 nm rPflP~ e is Pff~*~l by a ~o~v~l v~e. The third case re~ es that the ~ ~se reagent ;~1 g~dt~ a ~hro~lv~lv.e whose ~l-~-l~a- ,~e at 700nm simtll~tP~c lS whole blood and whose ~ .Z~-~P at 635 nm r~ i*~ ly meAcllres the ~ gl~ osecO~ .'haliv~lintheblood. t~ ally,themagritt~i?ofthere~ n in rPfl~ - ~ce at 635 nm, adj. sled as ~ rlo-ce~l in '346, at a sui~hle tim-e after l;zl;o,~of the timing s~~ ~, is a u.easu~e of the ~ r~se c~l~-haLon in the whole blood s~ , le Dye couples that are suitable as in~ tQrs indude z~ ne (AAP) and ~uo~.otrc,l ic acid; AAP and ~anilino 1-alenesulf~nate (ANS); AAP and N~thyl-N~2 l~yd~Ar-~sulfo~rû~.yl) m-tohli~lin~P (TOOS); 3-methyl-2~. ~ l;na~ ~ hy ir~7~P l-~ oride (MBI~ and ANS; and MBTH w~ -ed with its fc~rmalA~~yde azine.
The last case involves ~al ale ~hromo~ es, one to in~lirate ~ Qse 25 w~ alion by dev~ ir~ ~so l,al,~e at 635 nm that is a m~Cllre of g~ ose w ~c~ I ;o~ ~ in the blood ~amrle and the other to cimlllate blood (by matrhing - -2 ~ O ~ 5 7 0 whole blood's ~t~;.L,~ at 700 nm). A suitable dye y~ or to indicate ose co~ tio.n iS MBTH combined with3 ~ .P!l~y~ n~ic aad (DMAB).
The blood~imtll-o-tit~ dye canbe ~ a ~ in a va~;ely of ways. First, it 5 canbe b~ l~ by a redox 1~~ ~;~n, pmilor to ~atwhich ;g~.~ales the aL,s~;,L an~e at 635 nm that intlicatPs the ~ iO., ~y~"~yt~ of such dyes are MBTH ~..~ ~1 with primoqttin~P ~ l ale (PDP), AAP
c~"1~:.~1withPDP,and com~ al;.~. LC ll.e~eof.~,thebloo~d-~,cimtll~t dye can be g. f~r ~l~l by a pH ~ .~ The high pH of blood means that the rcag~t pH increases from about 4.2 to about 7, or more, when blood ~ .uh ~s the m~t i-c. Dyes that develop blood~imtll~ti~ color in r~ e to that pH
~hange include ali7at in red S (an ~- .io~ anthr; q ~ e dye) and phenol red (phenal~ fo~ al~in). Third, the dye canbe g~.a~ by a ~7~1;0n with a n~l-r ~lly o ~ blood ~ ent (other than g~ se)- For ~ le, metallo~.ro~ ic dyes can de ~ . Iop color by co ~ , with metals ~s_~t in the blood. 1~ ~oI~ alein complexone will E,~lale blood~imul~ting color by complexing with cAl~itlm in the blood. RO~lti~ a~ can yield the ~ ~ dye or dye co ~ :n~;~ to ~imtll~t~ the Absc.ba~c~ of whole blood at 700 nm.
,~ltl n~I~h the ~- ~;CG~ "1~"~e that is the ~ ed m~triy filters out red blood cells and holds them away from the t~tu-~, side, ~tiol.ally the testing r~ag~_~t may also c~ . a sey~ , c.,-~ p~ (see, for PYamrl~, the a~ ino~ U.S. Pat. No. 5,~06,6'~-~, to Kiser et aL) The se ~
ro-..~n~.t should be Ca~ IP of produ~ng a relatively clear colorless fluid 2~ from fluid co- ~ red blood cells, e.g., whole blood, by s~uest~.i.~ red blood cells in the matrL~c and, ~lef~ly, also seq~ ~g any small amounts LFS~L9 of free hemoglobirL Sr~ cc -~~J~ s for use in the itbl~lt ~l~r~,lion inrll~de but are not l;---ile-l to ~ yl~l2 glycol, poly (metllylvi~
ether/m~leir) al.hy~;de, poly~,ro~lene glycol, polysl~ r~ e sulfonic acid, ~lya~rlic acid, polyv-i~lyl alcohol, and polyv~lyl sulfonic acid at a pH of 5 about 4.0~Ø Such s~a- ~ P- .I~ are ~ l in thP matnx in amounts that will vary ,l~ upon their charge and molecular weight, the other co~l~or~e~ Ic ;---~ in the m~t iY, the matnx pH and pore size, and the resi~ l-.ni~ e of the matrix after &~-g. Such par~mPPrs are readily d~te.~ able by one S~ 1P~1 in the art. For ~A.~ le, when poly~,opyl~e glycol is employed as the 5~pa~1;~ CO~ O~ (e.g., PPG 410 from BASF, Wya~dotte, MI~, it is l.~ably ~.~s_ll at about 2-30% weight to volume (w/v), and more ~.- fe; ~l -ly 8-10% w/v. Other ~ g CQ- -.l~ - ~ can also be employed in a ~r~ l;~ of about 2-30% w/v. The polyll ~;c lillg col--l~ may be ~I~ ~ or im~ ~ in the matrix or cast 15 in the membrane .1--. I~ m~ ra~ 2.
Some water soluble salts can also effect blood s~r~ ;~ Among salts slli~hl~ for s~aLi..E; blood ro--.l~~ ls are ~ s, f~ t~s, and slllf~t~s, as well as ~.lain acids, such as amino acids, citric acid, phytic acid, and malic acid. (See, e.g., U.S. Pat 3,552,928, issued Jan~ ~ 5, 1971, to M.C. Fetter.) ~ I;.gco~ ,-,~~ areyr~ hlyinrll~ inthetestingreagent,1~
~ey i~l.,ease d e ~_liv~ness of the me--lh~ e in e~ ~at no ay~al~le amount of red blood gets through They thus ensure that samrle that is visible from the testing surface does not absorb light to any a~re ~ hle extent at 700 nm. , Other com~l~lts may be imhe~ into the matrix to enhance the cclcratis~ and reaA~hility of the reagent strips and to p~ese..~e the ~iro~ it~
and illle~;l;ty of the m~triy For e~mrle, the testing reagent may indude salts and/or b~,~ to aid in the seyard~on of the dye in the m~triY Such 1,~
rnay c~llail~ for PY~mple~ citrate, ~es~ll in soltlti~n at from about 0.01M to about 1.0 M, and ~.efe dl,ly at about 0.1M O~er 1,~ may also be S employed.
Co~.lyo~ds that make the matrix l-r~ llilic or c~.uyo~nds that can act as stabilizers, such as hydrolyzed ~ olehls, may also be employed. Such compounds include but are not li...i~P l to for PYAmrle l,o~ ,e serum albumin, tides and the low molec~ r weight ~.u~e~l available as Crotein* SPA
10 (CRODA, Inc. New York, N. Y.). Such co.,l~u,lds are used at cu.~ll.ations of for example about 1 mg/mL to about 100 mg/mL. In the case of Crotein, about 30 mg/mL is ~r~.~
Other sPhili7prs and ~ ives may also be irlrl~ e 1 in the coA~ for the m~triY. For e~ le ethylene diamine tetraacetic acid (EDTA), die~ylene 15 triamine per t~~~etic acid (DTPA) and related com~ mds may be employed, for e~ lc, at c~ dli~. s of about 0.01 mg/mL to about 10 mg/mL.
V~ri~ti-~ns of the detail ~ .l~ herein may be made ~illlout d~ lg from the scope and spirit of the ~ esellt .ll~/el li~rL
* Trade-mark
R~r~r ~nfl of ~P T. ~
5 1. Fi~l-l nf tl~ T. ~v.~ n This ir.~ lio,. relates to a dry test strip for measu~lg the co~ a~on of an analyte in a biological fluid; more ya I ;.~ rly, a test strip that calo~ lly ll-easu~es the conc~l~aliu~ of glllrose in whole blood.
f tl~ Rel~ t Many visual test devices have been ~ ope i for ll.easu,~-g ~e co.~.l~dtion of certain analytes in biological fluids. These devices have, for 15 _Yample~ .A~ Cd ~ OSe~ r~o~-~t~ rol, ~Ot~ a~ kelc,~ es, ~l-eli~lalanine, or enzymes in blood, unne, or saliva.
Dry phase reagent strips in.c"~ e,~yll-~based cûll,~osilions are used eAlelraively inl.oay;lals, rlin;~al labol~lo- :es, physician's offlces, andhomes to test sam~ 1.e~ of biological fluids for ~ rose c~ncel~t~alion. In hct, 20 reagent strips have be~Qme an ~v~ ay ~ ~S;Iy for m~ny of the nation's several million ~iabp-tirc~ Since diabetes can cause dangerous anc maliPs in blood . h ~~ cl- ~, it can contrihute to vision loss, Wdney failure, ant other serio~lC m_ 1;CA1 colsequ~.es. To ll~ e the risk of these col~seq-lellces, cul~ll te~rh~ counsels ~_aul~S with diabetes to me~- lre their blood glucose 25 level from two to seven times a day, depending on the nature and seve.il~ of their individual cases. Based on the oL,s..~,ed ~ . n in the mP~Ae lred glucose ~ ~ o ~
levels, the patient and ~l~ysi~al~ lc,~lller make adjusl~ ents in diet, e~-e~se and insulin intake to better manage the ~ se- aearly, this ~rc~ tiQrl should be available to ~e ~alie-,t ;~ Ply, through the use of a si~ lc to-we meter and strip a~sl~. that is rapid, ~P~-L~;ve, and ac~;~ate.
Reagent stdps are hw.. ll that ca,llain an ;.~.~ic~lo~ which tums a .li~
shade of color, d~lg on the c~ ~P~I ~aLoll of ~ c~se in a biological fluid that has been applied to &e stdp. Al&ough some of these stdps use le~ll ~- 1 ;o. .
P~ S, more CQ nm~)rlly ~ey involve an oYi~li7~ dye or dye couple.
Some of the strips include an el~,...e, such as ~ rOSe oY~ which is 10 capable of oYidi7i~ ~l~-~se to g n~ -~ acid and hy&ob~l peroxide. They also COl~ l an ~Yi~li7~ble tye and a sullsldllce having per~Yid~tive activity, which is capable of sele tivel~ catalyzing oY~ tio~l of the oYi~i7~le dye in the~,~s_~e of ll~ob~_l peroxide.
U.S. Pat No. 4,935,346, issued June 19, 1990 to R Phillips et al., ~3i~rloses a 15 meter, strip, and method for ~o~ the glu~e COl '~ tion in a s~ple of whole blood (see also US.P. 5,304,468). The ~ o~ 1 involves simply a~ly~lg a s~mple of whole blood to a first ("s~ple") s?lrfar~ of an inert ~o ls matrLY~ that is ia~.eg"~fl with a l~a~ The s~mplc migrates tunf~d the o~,~osit~, ''l~sLIg'' s~-r~, as the gl.J~ ~se; .l~ra. Ic withthe reagent to 20 ~ cealight~ re~ ~t"o~lu.t. Areadingofrefl~:l--.c~fromthe ~tillgS..~ -al~C~e~lll~seCO~ lio~ ~ ~e ~~.oAc~ ,ellls are made at two Se~a~ ~le ~rd~ in order to ~ b? Llt~.f~es. A
~uf g circuit is triggered by an initial d~ase in refl~ ,.e c~ e~ by w~tling of the leslil,g s--- ra~ by the s~ lc having ~cse~l through the matrix.
US. Pat. No. 5,306,623, issued April 26, 1994 to Kiser et al., ~licrlosPc a visual blood glt~rQ5e test strip that il~volves applying a gl.~ dL~,g L~49 .
whole blood s~mplc to one side of the strip and taking the g~ ose reading on the o~ile side, after red blood cells have been s~aialed out and the s~m~le has rea.t~i with a leZgCnt in the strip. An ~Dtro~ic polysulfone mDmhrane was found e~ ly useful as a single layer matrix for the strip.
US. Pat. No. 5,453,360, issued _.~t~.. her 26,1995 to Y. S. Yu, ~;SC1QSDS a dye couple useful in dry reagent strips for r1~ , analytes, such as ~ ose, inbiological fluids. The dye couple ~""l" ;~P5 ~ll-etl~1-2-l,efLcG~ 7~Qli~one >O1~D and 8 anilino 1-~ l,ll.alenesulfonate and is used as an indir~tnr in a ~e~ . cascade ~,~o.l.l~.g a strong oYi~i7irlg agent, such as l~ydrog~
10 peroxite. An adv.ullage of the couple is that it is soluble in aq.leo.ls sollltiorl, but becomes ;- .~11-l ~ie upon oYirl~tive cotlr~ ~n~y llL~u~.g fading and proviting a stable e~d~ Lt.
A meter that has come into widespread use for self-m~lulo,m~, of blood glll~e is the One Touch~!D Il meter, which uses a strip that is ~l~rrihed in U.S.
Pat. Nos. 4,935,346 and 5,304,468, ~ lcse~l above. The meter and strip permit a user to . . . ~P~C. . ~ ~ ~3 E c~,- .c~ r~ ~ ;o. l in a whole blood sAmrle qui~ly, easily, and a-~c~ y. The s~mple is applied to one sulraoe of the strip and the measu~lent made on the o~l,osile s... r~e. A portion of the whole blood sa~lrle ~ les from the sample sLu~ace to the testing s..~ r~ , and the blood 20 color canbe ol,~l from the testing ~ r~
~.lrnmary o~ *IP ~
The ~ nt i~ lLon provides a reagent test strip for use in an a~ al~ls for ~l~le....;.~g a co ~lràLion of ~ ose in a s~mple of whole blood. The 4 2 2 0 1 5 7 ~
a~ lus co~ . ;sec optical means for ~1Dtec*~ ~ of light at wa~,ele.~ s of about 635 nm and about 700 nm rPfl~ from at least a p~liol~ of a mat~Y ~ ~ near one end of the strip, which m~hi y CO ~ es (a) a s~mrle r~vil-g s- -- r~ for le ~ivL.g the who!e blood S?~ and S ~as~L~, a portion of it board a l~ti~lE, s~l~fare o~ile ll-~Elo, (b) a s~ e that sel~tiv~ly retards the p~Csa~e of red blood cells ll~rougll the matrhY and ~ c the lysing of the cells in the m~h~iY, wl-er~y any portion of the sample that is visible from the testing --- race does not - absorb light to any appreciable extent at about 7DO nm, and (c)areagentfor;~.die~ the~ by~eal;ngatthe testing su~a~ a ~g~ n~ I ~ . ~e at about 700 nm that is sul,skulLally equivalent to ~at y~l~d by the al~r, 1. - ~e of h~mnglobin in blood and a ~.~ in r~ ~ at about 635 nm that is; .~ ;ve of the gl~ ose In the~ ~.~nt ~ ;o ~ and the appPn~ ce to the fact that "sA~ le that is visible from the lesling ~ ce does not absorb light to any a~r~ ;~hl~ extent at about 700 nm" means that 700 nm abso.L,an~e by the sample, as seen ll,ro.lgll the I~LI.g s~,~ r, ~, is less than about 20% of the 700 nm ~l,so.l,a~ ~ ~.1 by the reaction of the sample w.ith the reag~nt-Another e-~ ent of the ~.esP~ vel-L~ also provides a reagent test strip for use in an aEJ~"~t"c for ~1~, ...ini.~E, a c~ ~ of gll~cose in a sample of whole blood. The ay~ c ~ s optical means for delc~li..
il~t~s;l~ of light at ~vav~ gtlls of about 635 nm and about 700 nm from at least a ~ iG~ of a matnx disposed near one end of the strip, which 25 matrix ec ~ s 2 2~ 7 ~
(a) a sPm, le receivi~ s~aee for r~ving the whole blood sAmple and p&ssin~; a portion of it to.. ~rd a testing surface Gyyosile ll~erelo, the testing s~ a~ ~ l~avil~ a rf nPc~ c~ at about 700 nm that, when the tesling surface l~c ~.~~s wet, undergoes a change that LC s~sla-llially equivalent to that S y~o~ r~d by the al~so,l,~e of l-~...og!okill in blood, (b) a structure that selectively retardc the pacsa~e of red blood ceLc l1UO~ the matrix and ~--;--;~.; ~ the lysing of the cells in the matniY, ~vl-er any portion of the sample that is visible from the testing surface does not absorb light to any ayy~eciable extent at about 700 nm, and (c) a reagent for ~ the ~ c~se eo ~ aLon by ~eaLing at the testing SIJ~ ~r~ a .1 ~a- 1~ in rf~fl~ ~ at about 635 nm.
The L~ lion providec a reagent test strip that is suihble for use in a One - Touch~l9 whole blood gl~-~se meter. Since the sh~.ture of the strip selectively l~lards the passage of red blood cells through the matrix and ~L~ es their lysing, the ~ .;. ,aLon is less dependent on the hPmatnrrit of the ~ whole blood samrle.
R iPf n~ . ,~t;. . I ~f t1 IP r~r~w~
Fig. 1 is a ~ e view of an embodilnenL of a test strip of this U 1~ _. ItiUI L
nPtailP 1 T)PC.. ~1;nn~f t~lP T~v~ It;r~.l This iLIv~lliGll provides a rapid and simr!P ~elllG.l, employing a reliable and easy to o~dle a~ ue, for the ~let .~ aLon of ~ cose in whole blood.
The method in~lves applying to one s--- r~ce (~e "sam~le" surface) of an inert ~o~o.,s matrix a small s~ of whole blood, s~rn~ It to salulale the matrix.
25 The matTix is typically ~les~t in a r~n~ ~me~ rillg ap~ardllls when blood is applied. At least a ~, liGl~ of the liquid s~mple penetrates the matrix, -resulting in an initial change in rPfl~l ~ at the o~yosite ("testing") surface.
The ~lu~ose in the s~mple reacts with one or more reagents bound to the matnx to form a produ* that changes the r~flec~-~e of the mAhiy A reading is then taken at one or more times after the initial change in refl~l~. ~e to relate theS further change in r~ ,ce at the tesli,-~ surface or in the matrix to the c~llc~lha~ion of g]ll~ ose in the sAmr'e.
FIG. 1 shows one em~ t of the ~resenl ~ A thin l~r~utlllilic m~h iy reagent pad 11 is positi~ned at one end of a plastic holder12 by means of an adhesive 13, which &eclly and firmly attaches the reagent pad to the holder. The holder, which is optional, provides physical form and rigidity to the strip. A hole 14 is ~ s~nt in the pl_stic holder 12 in the area to which reagent pad 11 is attached, so that s~ulpl~ canbe applied through hole 14 to the 5Ample side of the reagent pad and light r~fl~cterl from the other, g side.
A whole blood s~mple to be tested is applied to pad 11. Gene~ally, the reagent pad s~urace area is about 10 m~2 to 100 mm2~ especially 10 mm2 to 50 mm2, which ~ lly provides a volume that 5-10 ~LL of sample will more th~
salu~le.
Al detils le~ the struchlre of the strip a~ear in the above .~r~l~d US. Pats. Nos. 4,935,346, ('346) and 5,304,468 ('468)-The an~lysis ~.elllod of this ~vel~LG~ relies on a change in absorb_nce, as measured by diffuse rPfl~(~ Ice, which is ~ep~lPllt upon the ~lYrose ~nc~.~ation ~es~t in a sAmrle being tested. This change may be 25 ~ ;ned by measLuillg the rPflPcta. ~e rh~nf~P over on,e or more time intervals.
2 2 0 ~ ~ 7 ~
~ n o~.ation, the test strip is first mo~ ed in an ~,sl~ent for reading light ~1 ~s~Mb~cei e.g., color ~ ensil~, by rPfl~--~ce, prior to a~ of thes~ Then, a ~ ~se co.~lail~ing blood s~m~e - o~tait ed by a finger stick, for ~ le - is a~lied to the matnx of the test strip. ~felably, the ~molunt S ~s that I eP~l~ i to sal~te the matrDc in the area wherP rPflP~ ce will be ,leasu~ed (i.e., about ~10 ~L). After the s~ k is applied, li~lg of the ~ t iS in;ti~d :-t~ ir;~lly wh~n fluid ~ ales the m~h iy, and the a~-al ~t. ~c ~letech the resulting ~ilge in rPnp~ Ire of the testing s~ ace.~he l 1 .a.~F in refle~la~ ,~ over a pre~l?l~ ~ ~ .; . ~e l tiime, as a result of fc~rm~ti~n of 10 reaction ~.od~i~l, is then rPl~te l to the gluc~se co~ aLon in the sAmple Refl~iux refers in this s~;r;ra~ Q and in the s~el~ied claims both to the visible ~vav~ igth range and to i~ra~ed and ultraviolet r~ic3i~ti~
Asuitable ilwt.~ilent, such as a di~-lse refl~a.~e pholQ...elel withi 8~ J~ te sofl~. a~e, can be made to All~m-tir~lly read r~nP.t~Q~e at one or 15 more timie L~ ls, c~ t,? the refle~la.~ r h~ng~, and, using CalilJldiliiCi~l factors, o~ l the g]l~ ose col--~-.l-~ J~i in the blood sample. Details of such an insl~ ing the me~ gy used by the instrumient to CC~l~vc~
n~~ ~ m~c- ~ ~c~ into blood gl . ~rose c~,n~cr 1 . ~ l ;on.c, are provided in '346 and '468. In ~ ~ular, eQmm erc ially available One Touch~) meters are 20 s~-_Lle for use in co~ :- .al;~l with the reagent strip of th,e present ~IvenLo l to ~leasl~re ~ c~se C~1ICC1~ I;')~C in whole blood S~ ~~1eS. These meters read r~fl?~ ~ of the strip lesL,Ig sllrfA~ .~? at about 635 nm and about 700 nm.
The matrix of the ~~ccl,t invc,Lo ~ is ~ ,~ly a membrane that efrc~ivcly sc~aralcs the red blood cells _nd l~~loglobin from a whole blood 25 s~mrle to leave the gl.~ a~ g plAsmA- The sep~ R~ll takes place as the sg~ k moves through the mc~ .alle from the sAmple surface to the tesli~
- - -- 2 2 0 ~ ~ 7 0 rfarP, A mPmhrane to a~o~ )li~ that s~y~ , may have pores that trap ~e red blood ceDs, generally pore sizes in the range from about 0.1 ~um to about 5 ~m P~ele.aL.ly, the ~,e.nl)ra~Le is ~wol~:c, wi~ a range of pore sizes; more yle~dbly~ a broad range of pore sizes. Wl~ the matrix c~.l~,~es 5 an ~ isD~pic meLI~ane, the sample site is p.ef~dL.ly the large-pore side.
For e ~ r'~, a gratient of pore sizes from about 0.1 ~m to about 150 ~lm may extend through the me~ ule. C~n the large-pore side, pore size is ~ .ably in the range from about 30 ~m to about 40 ~ On the side of the me~ r~
where the pores are sm~ll~t (i.e., the b2aLll~; a ~ f. c~), the void volul-le is10 relatively small, and the m~ of the membrane is generally quite dense, within a layer that can typically ~.,sLlule up to 20% of the ~ "al~'s ~ickness. Within this layer, pore size is l"ef..dbiy in the range from about 0.1to about 0.8 ~m, with a ~ 1 pore size ~,~f~ly about 0.3 ~m.
When the whole blood sample is ay~lied to the 5~mrl~ side, the s- , 'e 5 e~ itw..7~ gly sm-ller pores as it penclrales the ml ~.h~
I ~- Ql ~IAlly~ soads such as red blood cells reac h a ~;1;~,- . in ~e membrane,generally near the sample s~ ra.~P~ where they can ~nel~ale no rullller~ The m~ .h,a, le not o~ly kaps red blood cells near the s-9-mp~? s~lrfAr~o~ but also ...;..;..~;,~c lysing of the cells, so that any portion of the ssmrl~ that is visible 20 from the testing slura~e does not absorb light to any ~e~i9~!e extent at about 700 nm. The balP~l~P of the s- -~e, still ro- ~1~;. .;. 1~, the dissd~d gll)c~5e, e~dles through to the t~ , side. As it passes ~rough the memhrane~
glll~ose in the sample reacts with the reagent, ~lsin~ a light-aL,sc~ lg dye to be formed near the lesL~g side, L~ sul~al~lLally arre.~lg refl ce from 25 the testing sllrfAc~. The a~ isohol,:c nature of the merïbrane and/or use of a LPS~9 S~y;i~dLng CQ ~I~-t (~i.c~vcse~l below) 1J~; .nil.4 relaLvely rapid flow rates through the membrane, even while s~y~aL;on of the solids is taking place.
The matrix is a hy~o~l~ilic ~Of~ IS memhrarle to which reagents may be covalently or non-covalently bound. The matrix allows for the flow of an 5 a(lueo ls ~ throughit. Italsoallowsfor binriinf~ of y~oleulc~",posilio"~
to the matcvc willloul a~iably adversely a~f~ting the biological activity of the yrot~ e.g. enzymatic a.livilr of an e~ e. To the extent that ~,ole~,s are to be covalently bound, the matrix will have active sites for covalent l o,,~lu.g or may be a.Lv.~led by means ~.~1l to the art. The ~;c....l~s;t;on ofthe matdx is reflective, and it has slluici~nt tl~ ess to y~ ul the form~ti~ of a light absorbing dye in the void ~/olu,ne or on the surface to substAnti~lly affect the n~ .- ~ from the m~ x- The matdx maybe of a ~--);f~.--.
~il;~ or a a~a~ , on a s~ s! ~gle ~ro.~i~.g the ll~cecs~- y s~u lu~e and physical p .Les, such as h~.lrot)l.il ity.
Polyslllf ~nes and poly~mi-3Ds (nylons) are e. _ rl~r of sllit~Akle matrK
m~tPriAlq Other polymers having c~ -A~ le ~,c,~lLes may also be used.
The polymers maybe m~ifi~ l to il.lr~l,lce other fun~tio~,al glO.l~S which provide for .l~ ,ed sl,u.l~es, so that the s~l~fA~ of the matrK may be nP1ltrAI, ~osilive, or l~gaLv~
A ~ ~ed ll,etllod of ~rel-A. ;. .~ the ~o~ ls mAtPriAl that forms the matrix is to cast the polymer without a su~,til~g core. Such a matrK is, for .ple, the al,iso~opic polysulfone ~,e l~l~ule available from ~ , Inc., T;..-o-.i.-..~, MD. The terms "matnxn and u"~ ne" are used angeably herein. Each term is understood to not be ~ it~l to a single 25 layer and may in~ ?, for P~AmrlD, an absorbent layer. A matrix of less than about 500 ~m thickness is usually employed, with about 115 to 155 ~m being 2 2 0 ~ 5 ~ ~
~d. A thickness of about 130 to 140 ~m is most ~.ef~ed, parti~ll~rly when the matrix is nylon or a~soh~ic polysulfone. ~he matnx generally does not ~1 ~f~rm on wetLng, thua ~e1~ its o.~7n~1 confo~ ti~ and size, and has 5~rr~ t wet al~ to allow for routine mal~ra,cl~e.
The m~ r~ has ~.~~ into it~ pores a testing reagent that is çap~ of rea~ g with gl~J~se to ~O~l~ a light-al~sc,.l ~~ reaction product.
The m ~ ~hr~LLe may be keat#~d with rea~ t by di~plLIg it into a ...;~ of the cQml~o~ ~,LlL~ sa~ t;~themembrane. Excessreagentmaybe r~nu.ei by mechanical means such as, for e~ c, an air knife, doctor blade, 10 or glass rod. The mPmbrane is then dried. Reagent tends to cu~L.~ltrale near the small-pore (t~sLLLL~,) side of the ~P.~ nP Other methods that are suitable for a~ LL~g reagent to the memhr~np will occur readily to a ~ having oldiLIar~r skill in the art.
The leaLiLLg reagent ro-~ r~s a co-~ ~nt for c~ ~LLng gll~ ose to 15 lL~.Log~Lperoxideandac..-..~ tfor~lcl~;-LglL~o~nperoxide.The rca~$~ntmayol~LoLLallyfuLLlLerco~ ~ a ~.a~_l;"~ whichcauses solids, such as red bloo ,d cells, to bPC~ e eLIh..~ed in the m~h ix, eLl~;LLvely removing the solids from the whole blood. ~ r~al c~ U~L euLa may also be included as described below.
I~e~ ico---~-o-LeQLsforc~l.,~LLE;~ aeto1I~U,~.LpProYiliP
in~lt~ -rOaP oYi~i~cP~ an eLL~R that is usually ~tai~d from Aspergillus niger or Pe~irillillm ~l~rose ~Yi~4P reacts with gl~se and oArgeL~ to ~c~iuce gl-~rono~ onP and lI~o~l per~Yide. Opti,LI~L~ g~ USP oY~ 4e co. u~ ~ d~ls on the cc -..~ io-~ of the indir~tor s~ral~L; ho~
~ oae oy~ ce in the range from about 500-10,000 U./mL L ge~erally sl~it~
more ~r~ l ly from about 700-2000 U./mL. Generally, higher c~nceL~ lhons LFS~9 of ~ ose oY~ ce cause the re~i~ to ~.ooeed more rapidly and lower a;lIc~haliO~s, less rapidly. O~ c~ alio.. can be ~l~t~ ed by ~uLIe ~ latiorL
- The llr~c,g~ peroxide so ~ ed reacts wi~ the cc"l,po~ for S ~rt~t; ~ peroxite,whichro ~ Saper~ ethatreleclively catalyzes a reactionl~et~ the llr~Gg~ peroxide and an ~dica~r. The peroYi~l~ce uses hydrog~l pcro~d~ as an oxidant which is rap~h~e of re~
h~L.,g_~ atoms from various s~l,shales. A s~ Ahle peroxi~lAce may c~nlain ,.o~o~..t)llr,i." a red hemin ~ained from plants. Peroxi~l~cec o~a,~led from _-lim~lc~ for P~ lc from the thyroid glands of animals, are also suitable.
Horseradich per~Yi~ ~ee ff~PO) is eS~-;~lly ~f~ed as a c~ n~ of the r~ v -.~for~e~;u~h~ o,~ peroxide. Thehy~oge~l pel'OYi~D, f~ ly catalyzed by a peroy~ ce~ reacts either di~lly or i~ itLClly to form an ir~dira~or dye that redu.~ 635 nm ,en~a~ Ice at the testing sllrhre Testing s ~ race reflecku~e is measLIted at two waveleng~s - about 635 nm and about 700 nm.
R~flPC~ P mPacLll~~~lb are made in a timed sequence. The sequence is ;at~l by the refle~ e ~ I at 635 nm that results from the arrival of a ~. l;ol~ of ~e sAmrl~ at the Leslin~ s~ ~. ra-~ We denote this initiA*~ of timing as "rPfl~1~ wil~LL ~g". The ~n S~l~nc~ at 700 nm is ~~P~c~ed 15 seconds later. By that time, the blood will have s~lLualed the reagent pad, and the . a~;~ of the ghlrose cc."lai,~,~; blood s~m~l~ with the reagent~c..,~il~,E~, ,~,e will have ~~ll~i a reduction in r~fl~~ e at 700 nm that is SL~ hntially equivalent to the ~ o~ e~ by blood color being visible 25 at the testing ~!'- r''AP. Thus, although any s~mI~le that is visible from the testing sLurace does not absorb light to any ayyleciable extent at 700 nm, ~e LF~9 meter ~l~t~t-C the lQ''l~ rl in 700 nm rpn~l;on that it ~C~tPs with a~ oe by the blood color, and that causes it to then make refl?ct~-lce ements at about 635 nm. The gl.~ se CO~ tion in the s~m, 'e is r~ Pt~ from the 635 nm refle.l~~, using the 700 nm LF n~ ~ to S r~ be a co,le~1io~ factor. Note that since blood absorbs at 635 nm, so too should the blood;cimyl~ting 700 nm a~ r. Ideally, the blood~im~ ti~g m~tPri~l cllo~lld have the same ratio of a~ .r~ at 700 nm to aL.s~,L,anc~ at 635 nm as does whole blood, but for l,~vil~ we refer to the blood~imlll~ti~
mAtp~ S ~l ~su ba~rD at 700 nm only. Details of the ral~ll~tio~, iru luding the 10 c~ LG.~ for the "blood" r~n~u~p at 700 nm, ay~eal in the aforPm~ti~
'346 The re~ P~l lesLIg-s--- r~ n~l ..~? at 700 nm that cimlllatPc the blood color can be ~rr~1~ in four Al~ at;ve ways. First, the meml~r~e may C~
a ro~ -.,- ~l that absorbs 700 nm radiaLo.~ and the l~xL-~ s~rfAce may be S ~1~S~ 11Y opaque until it ~ -.DC more ~ya~ t to 700 nm light when wet The cc,~ ~n~t that ~t~sorbs at 700 nm may be a ~IO ~WO~ for ~
that is not visible from the dry t~sl;ng a ~ -'P- The C~I~G~lt could also be a su~.l onto which the ~ ~e is cast, a coating on the sAmpl~ suLracP of the m~mhrane~ or the lL~e.
~eco l~i, the memhrane may in~ude a water SO1~1JI~ dye thathas light a~so~d.ue at 700 nm that is slll~sl~ lly in~eased wh_n the dye goes into sol~l;on For PYAmple~ the dye could initiallybe in the forrn of finely divided ~vale. soluble crystals, a~ylied to the ...~ ule as ~1;4~ solids that appear white and provide no sl~hsl~Lal absorbance at 700 nm. The aqueous s~mple 25 dissolves the dye, at which point it l~-c -.~ colored and Ahsorhs at 700 nm. An ~.~.. .pl~ of such a dye is ~;c yp~ phthal~;ral~e.
LFS~9 --Third, the ;..l ~ ;~bet~veen gl.~cose and the reagent in the me,~
can res~t in a ~l~ro~.v~l~re that pl ~sc;.bs light at both 635 nm and 700 nm, ;. A~ ose ac,,.~x,.~aL~ and, at the same time, sim~ ng the ~res~e of blood.
S Fin~lly, the blood-rca~-l ;- .t.~ ~1 can yield two cl~o~lophores, one of which ~hso~bs at 635 nm and the other of which absorbs at 700 nm. F~ulllel, since a¢lly ~f o~ 700 nm refle~ ~ re~ltl~i~n is needed to simtll~te the p,es~-ce of blood color, ~Lf~a~ly only a small ~-OUnl of the ~luo,~.u~llore that ~bsorbs at 700 nm is ~ l. In the first two cases, in which 700 nm Pl-s."ba~ ce (i.e., le~-r~1 refle~ e) results from ~ .el me~ne ~- "l~'~' .l, the 700 nm abso~L,&b~e does not r~ e a ~uv~Llv~llvle.
In the third and fourth cases, the rP~~ ~ in 700 nm rPflP~ e is Pff~*~l by a ~o~v~l v~e. The third case re~ es that the ~ ~se reagent ;~1 g~dt~ a ~hro~lv~lv.e whose ~l-~-l~a- ,~e at 700nm simtll~tP~c lS whole blood and whose ~ .Z~-~P at 635 nm r~ i*~ ly meAcllres the ~ gl~ osecO~ .'haliv~lintheblood. t~ ally,themagritt~i?ofthere~ n in rPfl~ - ~ce at 635 nm, adj. sled as ~ rlo-ce~l in '346, at a sui~hle tim-e after l;zl;o,~of the timing s~~ ~, is a u.easu~e of the ~ r~se c~l~-haLon in the whole blood s~ , le Dye couples that are suitable as in~ tQrs indude z~ ne (AAP) and ~uo~.otrc,l ic acid; AAP and ~anilino 1-alenesulf~nate (ANS); AAP and N~thyl-N~2 l~yd~Ar-~sulfo~rû~.yl) m-tohli~lin~P (TOOS); 3-methyl-2~. ~ l;na~ ~ hy ir~7~P l-~ oride (MBI~ and ANS; and MBTH w~ -ed with its fc~rmalA~~yde azine.
The last case involves ~al ale ~hromo~ es, one to in~lirate ~ Qse 25 w~ alion by dev~ ir~ ~so l,al,~e at 635 nm that is a m~Cllre of g~ ose w ~c~ I ;o~ ~ in the blood ~amrle and the other to cimlllate blood (by matrhing - -2 ~ O ~ 5 7 0 whole blood's ~t~;.L,~ at 700 nm). A suitable dye y~ or to indicate ose co~ tio.n iS MBTH combined with3 ~ .P!l~y~ n~ic aad (DMAB).
The blood~imtll-o-tit~ dye canbe ~ a ~ in a va~;ely of ways. First, it 5 canbe b~ l~ by a redox 1~~ ~;~n, pmilor to ~atwhich ;g~.~ales the aL,s~;,L an~e at 635 nm that intlicatPs the ~ iO., ~y~"~yt~ of such dyes are MBTH ~..~ ~1 with primoqttin~P ~ l ale (PDP), AAP
c~"1~:.~1withPDP,and com~ al;.~. LC ll.e~eof.~,thebloo~d-~,cimtll~t dye can be g. f~r ~l~l by a pH ~ .~ The high pH of blood means that the rcag~t pH increases from about 4.2 to about 7, or more, when blood ~ .uh ~s the m~t i-c. Dyes that develop blood~imtll~ti~ color in r~ e to that pH
~hange include ali7at in red S (an ~- .io~ anthr; q ~ e dye) and phenol red (phenal~ fo~ al~in). Third, the dye canbe g~.a~ by a ~7~1;0n with a n~l-r ~lly o ~ blood ~ ent (other than g~ se)- For ~ le, metallo~.ro~ ic dyes can de ~ . Iop color by co ~ , with metals ~s_~t in the blood. 1~ ~oI~ alein complexone will E,~lale blood~imul~ting color by complexing with cAl~itlm in the blood. RO~lti~ a~ can yield the ~ ~ dye or dye co ~ :n~;~ to ~imtll~t~ the Absc.ba~c~ of whole blood at 700 nm.
,~ltl n~I~h the ~- ~;CG~ "1~"~e that is the ~ ed m~triy filters out red blood cells and holds them away from the t~tu-~, side, ~tiol.ally the testing r~ag~_~t may also c~ . a sey~ , c.,-~ p~ (see, for PYamrl~, the a~ ino~ U.S. Pat. No. 5,~06,6'~-~, to Kiser et aL) The se ~
ro-..~n~.t should be Ca~ IP of produ~ng a relatively clear colorless fluid 2~ from fluid co- ~ red blood cells, e.g., whole blood, by s~uest~.i.~ red blood cells in the matrL~c and, ~lef~ly, also seq~ ~g any small amounts LFS~L9 of free hemoglobirL Sr~ cc -~~J~ s for use in the itbl~lt ~l~r~,lion inrll~de but are not l;---ile-l to ~ yl~l2 glycol, poly (metllylvi~
ether/m~leir) al.hy~;de, poly~,ro~lene glycol, polysl~ r~ e sulfonic acid, ~lya~rlic acid, polyv-i~lyl alcohol, and polyv~lyl sulfonic acid at a pH of 5 about 4.0~Ø Such s~a- ~ P- .I~ are ~ l in thP matnx in amounts that will vary ,l~ upon their charge and molecular weight, the other co~l~or~e~ Ic ;---~ in the m~t iY, the matnx pH and pore size, and the resi~ l-.ni~ e of the matrix after &~-g. Such par~mPPrs are readily d~te.~ able by one S~ 1P~1 in the art. For ~A.~ le, when poly~,opyl~e glycol is employed as the 5~pa~1;~ CO~ O~ (e.g., PPG 410 from BASF, Wya~dotte, MI~, it is l.~ably ~.~s_ll at about 2-30% weight to volume (w/v), and more ~.- fe; ~l -ly 8-10% w/v. Other ~ g CQ- -.l~ - ~ can also be employed in a ~r~ l;~ of about 2-30% w/v. The polyll ~;c lillg col--l~ may be ~I~ ~ or im~ ~ in the matrix or cast 15 in the membrane .1--. I~ m~ ra~ 2.
Some water soluble salts can also effect blood s~r~ ;~ Among salts slli~hl~ for s~aLi..E; blood ro--.l~~ ls are ~ s, f~ t~s, and slllf~t~s, as well as ~.lain acids, such as amino acids, citric acid, phytic acid, and malic acid. (See, e.g., U.S. Pat 3,552,928, issued Jan~ ~ 5, 1971, to M.C. Fetter.) ~ I;.gco~ ,-,~~ areyr~ hlyinrll~ inthetestingreagent,1~
~ey i~l.,ease d e ~_liv~ness of the me--lh~ e in e~ ~at no ay~al~le amount of red blood gets through They thus ensure that samrle that is visible from the testing surface does not absorb light to any a~re ~ hle extent at 700 nm. , Other com~l~lts may be imhe~ into the matrix to enhance the cclcratis~ and reaA~hility of the reagent strips and to p~ese..~e the ~iro~ it~
and illle~;l;ty of the m~triy For e~mrle, the testing reagent may indude salts and/or b~,~ to aid in the seyard~on of the dye in the m~triY Such 1,~
rnay c~llail~ for PY~mple~ citrate, ~es~ll in soltlti~n at from about 0.01M to about 1.0 M, and ~.efe dl,ly at about 0.1M O~er 1,~ may also be S employed.
Co~.lyo~ds that make the matrix l-r~ llilic or c~.uyo~nds that can act as stabilizers, such as hydrolyzed ~ olehls, may also be employed. Such compounds include but are not li...i~P l to for PYAmrle l,o~ ,e serum albumin, tides and the low molec~ r weight ~.u~e~l available as Crotein* SPA
10 (CRODA, Inc. New York, N. Y.). Such co.,l~u,lds are used at cu.~ll.ations of for example about 1 mg/mL to about 100 mg/mL. In the case of Crotein, about 30 mg/mL is ~r~.~
Other sPhili7prs and ~ ives may also be irlrl~ e 1 in the coA~ for the m~triY. For e~ le ethylene diamine tetraacetic acid (EDTA), die~ylene 15 triamine per t~~~etic acid (DTPA) and related com~ mds may be employed, for e~ lc, at c~ dli~. s of about 0.01 mg/mL to about 10 mg/mL.
V~ri~ti-~ns of the detail ~ .l~ herein may be made ~illlout d~ lg from the scope and spirit of the ~ esellt .ll~/el li~rL
* Trade-mark
Claims (13)
1. A reagent test strip for use in an apparatus for determining a concentration of glucose in a sample of whole blood, the apparatus comprising optical means for detecting intensity of light at wavelengths of about 635 nm and about 700 nm reflected from at least a portion of a matrix disposed near one end of the strip, which matrix comprises a) a sample receiving surface for receiving the whole blood sample and passing a portion of it toward a testing surface opposite thereto, b) a structure that selectively retards the passage of red blood cells through the matrix and minimizes the lysing of the cells in the matrix, whereby any portion of the sample that is visible from the testing surface does not absorb light to any appreciable extent at about 700 nm, and c) a reagent for indicating the glucose concentration by creating at the testing surface a change in reflectance at about 700 nm that is substantially equivalent to that produced by the absorbance of hemoglobin in blood and a change in reflectance at about 635 nm that is indicative of the glucose concentration.
2. The strip of claim 1 in which the matrix comprises a membrane that has pores that trap the red blood cells of the whole blood sample.
3. The strip of claim 1 in which the matrix membrane an anisotropic membrane.
4. The strip of claim 3 in which the membrane has pores that are larger near the sample receiving surface and smaller near the testing surface.
5. The strip of claim 1 in which the matrix comprises a polysulfone membrane.
6. The strip of claim 1 in which the reagent comprises a dye precursor that forms a chromophore indicative of the glucose concentration, the chromophore absorbing light appreciably at both 635 nm and 700 nm.
7. the strip of claim 6 in which the dye precursor is selected from dye couples in the group consisting of 4-aminoantipyrene and chromotropic acid; 4-aminoantipyrene and 8-anilino-1-naphthalene-sulfonate, and combinations thereof.
8. The strip of claim 6 in which the dye precursor is selected from the group consisting of 3-methyl-2-benzothiazolinone hydrazone hydrochloride and 8-anilino-1-naphthalenesulfonate, 3-methyl-2-benzothiazolinone hydrazone hydrochloride combined with its formaldehyde azine, and combinations thereof.
9. The strip of claim 1 in which the reagent comprises a first dye precursor that forms a chromophore whose absorbance at 635 nm is indicative of the glucose concentration and a second dye precursor that forms a chromophore whose absorbance at 700 nm simulates the absorbance of whole blood.
10. The strip of claim 9 in which the first dye precursor comprises 3-methyl-2-benzothiazolinone hydrazone hydrochloride combined with 3-dimethyl-aminobenzoic acid.
11. The strip of claim 9 in which the second dye precursor is selected from dye couples in the group consisting of 3-methyl-2-benzothiazolinone hydrazone hydrochloride and primaquine diphosphate, 4-aminoantipyrene and primaquine diphosphate, and combinations thereof.
12. The strip of claim 9 in which the second dye precursor is selected from the group consisting of alizarin red S, phenol red, and combinations thereof.
13. The strip of claim 9 in which the second dye precursor is phenolphthalein complexone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62753096A | 1996-04-04 | 1996-04-04 | |
| US08/627,530 | 1996-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2201570A1 true CA2201570A1 (en) | 1997-10-04 |
Family
ID=24515038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002201570A Abandoned CA2201570A1 (en) | 1996-04-04 | 1997-04-02 | Reagent test strip for determination of blood glucose |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5972294A (en) |
| EP (1) | EP0799896B1 (en) |
| JP (1) | JPH1031023A (en) |
| KR (1) | KR100490185B1 (en) |
| CN (1) | CN1184480C (en) |
| AT (1) | ATE205541T1 (en) |
| CA (1) | CA2201570A1 (en) |
| DE (1) | DE69706594T2 (en) |
| DK (1) | DK0799896T3 (en) |
| ES (1) | ES2163099T3 (en) |
| IL (1) | IL120587A (en) |
| MX (1) | MX9702502A (en) |
| NO (1) | NO317633B1 (en) |
| PT (1) | PT799896E (en) |
| SG (1) | SG73447A1 (en) |
Families Citing this family (117)
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| Publication number | Priority date | Publication date | Assignee | Title |
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-
1997
- 1997-04-01 IL IL12058797A patent/IL120587A/en not_active IP Right Cessation
- 1997-04-02 CA CA002201570A patent/CA2201570A1/en not_active Abandoned
- 1997-04-03 NO NO19971515A patent/NO317633B1/en not_active IP Right Cessation
- 1997-04-03 PT PT97302307T patent/PT799896E/en unknown
- 1997-04-03 EP EP97302307A patent/EP0799896B1/en not_active Expired - Lifetime
- 1997-04-03 DK DK97302307T patent/DK0799896T3/en active
- 1997-04-03 ES ES97302307T patent/ES2163099T3/en not_active Expired - Lifetime
- 1997-04-03 JP JP9099566A patent/JPH1031023A/en active Pending
- 1997-04-03 AT AT97302307T patent/ATE205541T1/en active
- 1997-04-03 DE DE69706594T patent/DE69706594T2/en not_active Expired - Lifetime
- 1997-04-04 CN CNB971112320A patent/CN1184480C/en not_active Expired - Lifetime
- 1997-04-04 SG SG1997001042A patent/SG73447A1/en unknown
- 1997-04-04 KR KR1019970012449A patent/KR100490185B1/en not_active IP Right Cessation
- 1997-04-04 MX MX9702502A patent/MX9702502A/en unknown
-
1998
- 1998-03-16 US US09/039,577 patent/US5972294A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE69706594D1 (en) | 2001-10-18 |
| DK0799896T3 (en) | 2001-11-19 |
| ATE205541T1 (en) | 2001-09-15 |
| CN1184480C (en) | 2005-01-12 |
| SG73447A1 (en) | 2000-06-20 |
| IL120587A (en) | 2000-10-31 |
| IL120587A0 (en) | 1997-08-14 |
| EP0799896A3 (en) | 1998-12-23 |
| JPH1031023A (en) | 1998-02-03 |
| NO971515L (en) | 1997-10-06 |
| CN1169533A (en) | 1998-01-07 |
| MX9702502A (en) | 1998-04-30 |
| DE69706594T2 (en) | 2002-07-11 |
| KR970071005A (en) | 1997-11-07 |
| KR100490185B1 (en) | 2005-08-31 |
| US5972294A (en) | 1999-10-26 |
| ES2163099T3 (en) | 2002-01-16 |
| NO971515D0 (en) | 1997-04-03 |
| EP0799896B1 (en) | 2001-09-12 |
| EP0799896A2 (en) | 1997-10-08 |
| PT799896E (en) | 2001-12-28 |
| NO317633B1 (en) | 2004-11-29 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |