Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
DIA~NOSTIC TEST STRIPS
BACKGROUND OF THE INVENTION
The present invention generally relates to diagno tic
agents for testing biological liquids by providing rap;d
detection of given components therein, for example, fol the
detec~ion of blood glucose, ketones and ~he like.
Known diagnostic test strips generally comprise an
absorbent carrier which is impregnated with the reagents for ~-
carrying out a given coloured test reaction when wetted with
the li~uid to be ~ested.
The conventional carrier material in most test strips
currently used consists of filter paper which provides
distinct advantages, but also has certain drawbacks and
limita~ions such as insuf~icient physical and chemical
stability of the paper carrier when impregnated with certain
test reagents having high concentrations to provide a satis-
factory coloured test r0action.
It has been proposed to make filter papers more stable
by laminating them with a synthetic resin ilm, or to use
Z synthetic resin fibers to either reinforce or completely
replace cellulose fibers. However, it has been found that
cellulose fibers swell during impregnation and thus partly
take up the reagents wi~hin the fibers whereas impregnation
allows only a relati~ely small amount of the reagents to be
~5 deposited on the surface of syn-thetic -Eibers.
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In addition ~o ~hese limitations with regard to the
absorbent carrier material, the conventional production of
test strips generally requires multiple impregnations which
are qu.ite difficult to achieve on a large scale in a highly
reproducible manner and also considerably increase the
production costs.
SUMMARY_OF THE INVENTION
A main object of the present in~ention is to ob~iate
the abovementioned drawbacks as far as possible by providing
a simplified method of producing diagnostic test strips on a
large scale in a highly reproducible and enconomical manner.
The present invention thus essentiaIly provides a
method of producing diagnostic test strips for detecting
~iven c.omponents present in biological liquids such as
urine, said strips comprising a solid support medium carrying
at least two reagents for effecting a given colour test
reaction on wetting contact thereof with a liquid analysate
to be tested, said method comprising the steps of:
~a~ providing at least two reagent inks each COII-
slsking of a mixture of mutually compatible componentsincluding at least one of the said reagents for carrying out
a desired test reaction; a liquid solvent; and a binder
comprising a polymer;
(b) providing said suppor~ medium in the form of a
sheet ha~ing a surface suitable for printing with said
reagent inks thereon, said sheet being substantially in-
soluble in water and chemically inert to said reagent inks
at least at said surface thereof;
. . . .
(c) successively applying the said reagent to sai.d
sheet by printing on the said surface thereof a multitude of
dots of each said reagent ink so as to thereby form at least
two separate patterns of printed dots of said reagent inks,
the reagent ink dots of each said pattern being dried after
printing and being arranged in closely spaced relationship
with one another and with the dots of each different pat-
tern, so that the printed dots of each reagent ink are
separately arranged between the dots of each different
reagent ink, in close proximity thereto, but without contact
betweell the dots of different inks, so that the reagents in
the respective dry dots are thereby kept separate from one
another, while allowing said reagents to diffuse along .sai.d : ::
surface and to thereby mutually interact thereon in -the
presence of said liquicl analysate; and
(d) cutting up said sheet having said separate print-
ing patterns printed on the surface thereof into a plurality
of test strips of desired shape and size.
The use of printing to produce diagnostic test strips
according to the present invention offers various practical
: advantages, and in particular the following:
- The possibil.ity of readi:Ly separating different
components of the reagent system which are ordinarily
reactive, by including them in different reagent inks which
are then used for printing separate dot patterns on the
printing surface of the test strip. .:
- The possibility of providing a readily reproduc-
ible, more rapid and relatively simple printing technique
for applying exactly predetermined amounts of the reagents
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to the printing substra~e 7 whereby -the production of diag-
nostic test strips on a large scale may be greatly simpli-
fied and rendered more economical.
- The possibility of eliminating ~he need for s(~pa-
rate colour comparison charts, by also printing the re~pec-
tive t~st colours for comparison on given portions of the
same t-st strip.
Various considerations which are of practical interest
for providing such advantages in accordance with the princi-
ples underlying the present invention will now be discussed.
Reagent Ink Composition6
It may be readily seen that the respective ink compo-
sitions will primarily depend on the particular colour
reaction to be effected by means of the test strips, i.e. on
the particular reagent system necessary to provide the
desired test reaction in each case.
The constituents of each reagent ink should further be
selected so as to be chemically and physically compatible
with each other and with the printing substrate to which
they are applied.
In order to ensure satisfactory printing, the physical
properties of the reagent inks should moreover be adapted to
the type of print~ng substrate as well as to the printing
technique and printing means which are used to produce the
test strips.
The term reagent ink as here used implies an intimate
mixture of at least one main reagent necessary for the
colour test reaction, with auxiliary components and a
suitable liquid vehicle or carrîer medium, so as to provide
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an ink having suitable rheological properties adapted for
printiilg by ensuring proper ink transfer from the printing
means to the printing substrate used in each case.
The main reagents which are respectively lncluded in
the in'is used for printing according to the invention will
evidently depend in each case on the particular type of test
reaction for which the test strips are to be produced.
However, the reagent system which is used to provide a
given colour reaction on the test strips produced accordin~
to the present invention may generally comprise conventional
reagents which are known from the prior art relating to
diagnostic test reactions, known reagents being included in
the inks used in the examples described further below to
illustrate the inven~ion.
On the other hand, as already mentioned above, all
components of each reagent ink must he mutually compatible
and should provide suitable rheological properties to allow
proper printing. The choice of a suitable solvent and of
auxillary ink components other than the main reagent will
thus depend on various considerations discussed below.
I nk So Zven t
The function of the solvent in the reagent ink is to
provide a liquid medium which is necessary to retain the
main reagent and the auxiliary components of the ink in
solution or suspension~ until the ink is used for printing
on the substrate. After printing, the solvent has ~ulfilled
its role and should be removed by drying in order to provide
printed dots fixed on the substrate surface.
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When enzymes or other bioactive substances are present
in the reagent ink composition, the solvent will preferably
be watcr or an aqueous mixture of the water-ethanol type,
and should exclude more exotic solvents which cannot be used
in the presence of bioactive substances. A number of other
solvenrs, such as anhydrous benzene, dimethylsulfoxide, or
higher alcohols may also be of interest as a solvent, e.g.
glycol. Thus, any appropriate solvent may be used which is
compatible with the other ink components in each case.
However, certain inorganic salts, which may be included in
the reagent inks as buffers or enzyme activators, have
limitecl solubility in organic solvents and this must be
taken into account when selecting the ink components.
In1c B~der
Ir, order to impart to the inks the necessary rheolo-
gical properties for ensuring satisfactory printing, the ink
compositions generally include binding agents which are
likewise included in the reagent inks used in the present
invention.
Modern ink binding agents generally consist oE po]ymer
materials which dissolve or are suspended in the ink solvent
in a sufficient amount to provide satisfactory rheological
properties adapted to the printing method in which the inks
are to be used.
2S The binders used in the reagent inks for the production
of test strips for biological liquids~ in accordance with
this invention, must be compatible with the sol~ent and
other ink components and should preferably be hydrophilic in
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order to be able to freely absorh biological test liquids,
whereby to allow the desired test reactions to occur.
NaturaL hydrophilic binders which are suitable for ~he
reagen~ inks used in the invention are gelatin and gum
arabic, both of which possess a high swelling power and are
thus able to take up a considerable amount of water.
Moreover, during subsequent wetting of the printed test
strip when it is used for the diagnostic colour ~est, the
binder serves to prevent the primary reagents from going
into the surrounding analysate solution.
The binder should be able to rapidly absorb water at
room temperature in order to allow the reagents to diffuse
along the printed surface whereby to effect the desired
colour test reaction.
Various natural or synthetic binders may be contem-
plated for the reagent ink composition, such as the foll.owing,
for example: .:
cellulose derivatives
gelatin :
~ collagen
polyvinyl alcohol
poly~-vinylpyrrolidones) ;
In the present invention, preferred binders for the
reagent inks are the cellulosic binders which are used in ~ :-
the examples given further on. ~: :
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B~ffeY.;
The reagent inks may generally contain a buffer in
order ~o keep the pll of the printed reagents in a given
small ange to allow the desired colour reaction to ~ake
place in a suitable pH environment on the test strip.
The examples given below show various suitable buffers.
A major requirement for selecting the buffer in the
reagen1 inks used to efect a given test reaction is that
~he bu~fer should be chemically compatible with the whole
reactivn system, and especial]y with the polymeric binder
included in the reagent ink compositions.
In principle, the follo-wing four buffer types which are
predominantly used to control the pH of biochemical test
reactions between 5 and 7 may be contemplated:
~i) Citric acid/sodium citrate
(ii) Tris hydroxymethlamino-ethane
(iii) Phosphate
~iv) Phthalate
Screening tests effected to determine the compatihility
of various buffers with a number of polymers have shown that
the following buffer systems may be envi~aged for theiI
buffering properties at the pH value (4-7) which is neces-
sary for occult blood tests, and also for their relatively
low cost:
1) Na-H-maleate - NaOH (pH 5-6
2) Succinic acid - NaOH ~pH 5-6)
3) K-H-phthalate - NaOH ~pH 5-6)
4) ~ ~' dimethylglutaric acid - NaOH ~pH 5-6)
5) Na-citrate - citrlc acid bu--fer ~pH 5-6)
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Moreover, sodium citrate/citric acid buffer (pH 5^6)
may al.;o be used in a glucose test reagent ink.
A phosphate buffer (pH 8-10) may be used in a ketone
test reagent ink.
Table 1 below gives the results of a series o~ com-
patibility tests wherein the abovementioned buffer systems
were respectively mixed with a number of polymers and the
solubility of the polymer was observed both at normal room
temperature and at 80C.
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As may be seen from Table 1 above, the maleate, succinic,
phthal~te and glutaric acid bufers are compatible with most
of the polymers tested whereas the citrate buffer is not.
Surfacf~ Active Agents
Tl,e reagent inks may advantageously include surfactants
as wetling agents.
Thus, for example, sodium dodecyl sulfate (SDS), ~um
arabic and gelatin are surface active agents which may be
included as an emulsifier or emulsion stabilizer in a ~irst
reagent ink containing cumene hydroperoxide as a main
reagen1 for detecting occult blood in urine, with test
strips such as are produced according to the examples
described further below.
Similarly, ethyloxylated alkylphenol t such as ls known
by the Trademark "Renex 698" ~Atlas Chemical Industries J
Inc.) may be advantageously included as a surfactant in a
second reagent ink containing o-tolidine as the second main
reagent for detecting occult blood in urine.
Moreover, any other suitable surfactant may evidently
be included in the reagent inks, such as polyoxy-
ethylenesorbitan monolaurate known by the Trademark "Tween
20" ~Atlas Chemical Industries, Inc.) or polye~hylene ~lycol
known by the Irademark "Carbowax1' ~ICI America, Inc.).
It is understood that the use of these terms: binder,
surface active agent, emulsifier, stabilizer will largely
depend on the primary function which one attributes to the
respective ink components and ~hat these functions may
evidently overlap or have a relative importance o varying
lmportance either in a given ink or in different reagent
inks.
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Tllus, for example, gum arabic and gelatin are natural
polymers which can carry a large amount of solvation water
whereb~ to act as an emulsion stabilizer, while a~ the same
time increasing the viscosity of the reagent ink and tllus
simultaneously serving as an ink binder.
The various reagent ink components must evidently be
selected so as to be mutually compatible in each case and
relati~ely simple compatibility tests such as those pro-
viding the results in Table 1 above may be carried out for
~his purpose.
Thus, for example, it has been established that an
occult blood test reagent ink may include cumene, water,
cumene hydroperoxide (C~IP), sodium-dodecyl sulfate ~SDS),
gum arabic and gelatin which are all mutually compatible
with 0.5 M Tris Buffer and also with the following water
soluble binders:
Na - carboxymethyl cellulose ~NaCMC)
Hydroxyethyl-cellulose ~HEC); and
Methylethyl-cellulose (Trademark: "EDIFAS A", ICI)
20 PY~ ting Support Medium
The reagent ink dots may be printed according to the
invention on any suitable sheet which does not chemically
react with the different reagent inks used for printing.
The printing sheet selected to produce the printed test
strips ~ill essentially depend on the reagent inks which are
used in each case. This sheet should meet the following
requlrements as far as possible:
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(i) Substantial insolubility in water, and chem cal
inertn~ss at the printing sur~ace to the respectlve reagent
inks used;
(li) Ability to receive and fix the printed dots with
good a(Lherence o-f the reagent inks to the printed substrate
surface;
(iii) We~tability by the analysate liquid;
(iv) Ability to diffusely reflect all wave lengths of
the visible light spectrum, or full transparency thereto
1~ when mounted on an underlying white material;
(v) Resistance to curling and heat.
A large number of synthetic resins may be used to
provide a suitable printing support med:ium. Various thermo-
plasti~ resins which may be used to provide a suitable
printing substrate for the test strips are given by way of
example in Table 2 below:
TABLE 2: PRINTING SUPPORT MATERIALS
pol~ethylene (low, medium or high density)
polypropylene
polyvinyl chloride (rigid)
polyvinylidene chloride ~rigid)
polystyrene (e.g. high impact or A.B.S. resins)
styrene - acrylonitrile copolymer
acrylic resins ~e.g. high impact a.r.)
chlorinated polyether
polychlorotrifluoroethylene
fluorinated ethylene - propylene copolymer
polytetrafluoroethylene
Nylon ~66 or 6)
acetal resins
polycarbonate resins
polymethane resins
cellulose resins
cellulose acetate butyrate
cellulose propionate
ethyl cellulose
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.
The printed sheet should provide a substantially white
background in order to re-Elect as much visible light o~ all
wave lengths as possible and thereby ensure proper visual
~or ph~tometric) detection o-f the colour change which occurs
when the test strip is subsequently employed to e-ffect the
desire~l test reaction.
T]le printing substrate is preferably provided with a
mat surface finish which diffusely re-flec~s scattered light
in all directions and provides much better detection than is
the case with a high gloss finish which re-flects light like
a mirror.
In order to provide a high contrast, the substrate
surface material may itsel:E be made white in colour, either
by incorporating a white pigment or else by providing a
white surface coating. On the other hand, the printin~
substrate may also be made transparent and colourless while
being supported on an underlying white sheet, e.g. of paper.
White sheets made entirely of plastics ~or "synthetic
papers") are commercially available and currently used in
the graphic arts, particularly ~or photographic printing.
One such "synthetic paper" known by the trademark name o~
"Polyart" is manufactured by Bakelite-Xylonite Ltd. U.K. and
consists of modified polyethylene cast into a thin film. It
has the feel and handling properties of a good quality art
paper but its properties are otherwise those of a tough
continuous plastic film. Another synthetic paper known by
the trademark "Q' per" and manufactured by Nippon Art ~aper
Mfg. Co., Ltd., Japan7 COIlsists of a continuous polystyrene
film.
.
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Another material whlch may be used to provide a light-
re:flecting printing medium in the present invention is a
plasti--paper composite material comprising a paper base
coated with a thin transparent layer of plastics material.
The op~ical properties of the paper stock are thus retained
in thi; composite material, whereas i~s surface is polymeric.
This tvpe of material is produced by the firm Felix Schoeller~
Osnabrllck, West Germany and is commercially available ln
various grades with different surface finishes: silk grain,
glossy and mat.
In order to promote adhesion of the printed dots, the
printing medium may be provided with a more or less rough or
porous surace, or both.
The use o a more or less porous printing medium l)ro-
vides two advantages which cannot be obtained with non-
absorbent plastics materials. A first advantage is improved
adherence between the reagent ink and the porous substrate,
which has a much greater surface area than a non-porous
material and thus presents a much larger area for adhesion
and also for subsequently effecting the colour test re-
action.
A second advantage of a porous substrate is related to
subseq~lent mixing of the reagent inks in the presence of ~he
analysate being tested. A thin porous membrane will allow
the reagents to mix within the substrate itself. Moreover,
as in the case of a non-absorbent substrate, mixing will
also take place in the liq~id phase between the reagent ink
dots printed on the surface of the substrate.
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It may thus be seen from the foregoing that the use of
microporous plastics provides an absorbent substrate surface
having the advantages of firstly presentin~ no ink adhesion
problems and of secondly absorbing the printed reagents in a
chemically inert matrix.
With reference to the resins listed ;n Table 2 above,
it may be mentioned that polyethylene and polypropylene sub-
strates may be pretreated to improve adhes;on.
F~l~ the surface treatment of plastics film, there are
severa] conventional techniques to ;mprove adhcsion by
creatirlg reacti~e chemical groups on the surface of the
polymer: oxidat;on of the polymer can be e~fected by
treatment w;th a sulphur;c acid/d;chromate solution or with
similar solutions. The polymer is then washed before
printing. The action of W light particularly in the
presence of ozone may also be contemplated to make certain ~-
polymer substrates more ink receptive. Electrical pre-
treatment either by high-voltage corona discharge or by a
glow discharge at reduced pressure can also be used to
mod;y the polymer surface. An electron beam can l;kewise
be used ~or this purpose.
In addition to "Polyart" sheets, other syn~hetic lesin
sheets such as a fibrous polyester sheet known by the l`rade-
mark "SILBOND" (Faserbrodukte GmbH, Wes~ Germany), a fibrous
polyamide sh~et known by the Trademark "SYNTOSIL" (SIHI,
Papeteries Zurichoises sur Sihlg Zurich, Switzerland~, and a
spunbonded polyethylene sheet kno~n by the Trademark "TYVEK"
~E.I. DuPont de Nemours and Co.) were successfully used as a
printing support medium to provide printed test strips
according to the present invention~
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Another material which may he used to provide a light-
reflecting printing medium is compounded glass fibre which
is commercially available in thin sheets of density 70 g/m2
from Schleicher and Schuell~ West Germany. Yet, another
material which may be used to provide a light-reflecting
printing medium is absorbent paper stock, which was success-
fully used as a print support to receive discrete dots of
two reagent inks.
Pri~t~ ~g PYOC?e8S
In order to ensure a sufficient colour intensity to
provide satisfactory visual or photometric detection by
means of the test reaction occurring at the surEace of the
test strip, the thickness oE the reagent ink film deposited
in the form of printed dots should e~idently be as great as
possib]e.
Il may be mentioned that each reagent ink should he
sufficiently viscous for it to be able to form a thick dot-
shaped printed layer on a given support medium, the thiclc-
ness of the deposited ink evidently also being dependent on
the printing process. This means that a high ink viscosity
cannot by itself ens~lre the deposition of thick ink Ei~ms by
printing.
Thus, ofEset printing with a viscous ink allows layers
to be printed which are only a few microns thick. A similar
limitation applies to letterpress printing wherein a paste-
like ink is used but provides only thin printed layers.
Consequently, o~ffset, letterpress, besides flexography and
non-impact printing, all present certain inherent limi- -
tations with regard to the thickness of the printed in]c
layer ~e.g. about 2-5~)~
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In rotogravure printing, an ink is generally used which
is of low viscosity and contains a high proportion of an
organic solvent (e.g. about 50%) that evaporates after
printi]lg so as to ]eave a relatively thicker dried ink
layer, of about 12~ thickness, for example.
In contrast, the technique to screen-printing may be
considered particularly suitable for the purposes of the
invention, inasmuch as it allows highly viscous inks to be
printe(, with a thickness several times greater than with the
above-eited processes, namely with a thickness of the dried
printe(l ink layer which may range between 15 and 16~ in
variou~ conventional screen-printing processes.
It has been determined that conventional, commercially
availal-le reagent strips, which are impregnated to a thick-
ness o~ about 300~ can provide an occult blood test with
colour changes which can be readily detected visually by
light reflection from the reagents present in the upper 70~ -
thick ~ayer of the imbibed test strip.
It may thus be seen ~rom the foregoing that the reagent
ink dots will pre-Eerably be prin~ed by screen-printing or a
related process using ~iscous inks, the dimensions of the
printing screen and the rheological properties of the
reagent inks used being in each case mutually adapted so as
to provide printed dots of minimum size and maximum thickness.
The printed dots can have a diameter as small as 50~,
but reagent dots of a larger size lying in the range between
about 30~ and 4S0~ have been successfully obtained by
screen-printing in the manner described further below.
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lhe different reagent inks are deposited on the inert
printing substrate in distinct, consecutive printing steps,
i.e. a first array of printed dots of one reagent ink is
deposited and dried before depositing a second array of
printed dots of a second reagent ink, etc. ;
Tile dots of each array are preferably arranged between
the dots of another array, the dots of different arrays
being mutu~lly spaced at a short distance, so that the main
reagents in the respective inks are separately fixed to the
printing substrate of the test strip, while providing only a
short diffusion path for the reagents during subsequent:
wettin" of the test strip with the analysate solution -to be
tested
The printed dots are thus packed as closely as possible
in ord~r to provide a maximum concentration of the dif~erent
reagents which are fixed by printing per unit area of the
test s1:rip surface, whereby to provide a rapid ~est re(,ction
thereon with a resulting colour change of sufficient inten-
sity tc allow satisfactory visual detection.
The relativ0 arrangement of the mutually spaced plinted
dots o~ different reagent inks, so as to provide a closely
packed distribution thereof, may be explained in terms of
arranging two types of dots say A and B, of radius R + E
which exactly touch each other, R being the diameter oE the
printed dots and E the distance separating adjacent dots.
A very densely packed arrangement of dots A and B
consisting of two different reagent inks can be printed in a
particularly simple manner by using a highly simplified
screen-printing technique using a metal sheet which is
'
perforlted with tiny holes spaced apart in parallel rows,
with the holes of each row being staggered with respect to
the holes of adjacent rows.
A basic triangular printing pattern is thus formed in
the saLd metal she0t by means of the perforations therein,
whereb~ the inlaging steps which are normally required -for
producing a desired hole pattern in a printing screen may be
comple~ely eliminated.
~Thus, screen-printing with two dif-ferent reagent inks,
which will be designated by the letters A and B, may be
simply effected by means of the said perforated metal ~heet
in the following manner:
- The perforated metal sheet is used as a printing
screen stretched across a metal frame which is Eixed to a
screen printing machine.
l'he printing sheet, e.g. a sheet of Polyart synthetic
paper, is placed on the printing table in a set position
underlying said perforated sheet forming the printing -
screen.
A small array of register dots is first printed in one
corner of the printing sheet by placing a small amount of a
coloured (e.g. red) marking ink on a small edge portion of
the pe~forated printing screen and passing a squeegee to
spread this ink over a limited surface area at one corner of
the screen.
A second small array of register dots can also be
printed at the opposite corner of the printing sheet in
order to more readily ensure accurate positioning of the
screen on this sheet.
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The first reagent ink is then applied to the edge of
the screen furthest away -from the printing operator in a
quantity sufficient to print the whole sheet of the prlnting
support medium.
A rubber squeegee with a hardness on the Shore scale
lying between 80 and 90, and having a blade with a square
profile, is now drawn slowly across the surFace of the
printillg screen which is pressed down into contact with the
printing sheet while the ink is forced through the holes of
lQ the sc-reen. The ink is thus brought into contact with the
printing sheet and adheres sufficiently to it, so that when
the printing screen returns to its initial position after
the squeegee has passed by, the ink remains on the printing
sheet in the shape o an array of dots of diameter equal to
or slightly larger than the diameter of the holes in the
screen used. The overall pattern of the ink dots thus
printed is then identical with the arrangement of the holes
in the printing screen.
A first array of printed dots A is thus screen-printed
Gn the sheet wlth the first reagent ink. -
The frame bearing the printing screen is next removed
from the machine, the screen washed in running waterl rinsed
with acetone and drled, the frame is placed once more on the
machine in as near to the original position as possible, and ;
each array of coloured r~gister dots is then aligned with
the corresponding perforations of the printing screen~ by
effecting any displacement of the printing table holding the
printing sheet, which may be necessary to cause the register
dots to exactly underlie the corresponding perforations,
whereby all prlnted dots A of the first array are brought in
to register with the perforations of the printing screen.
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The printing sheet is next displaced parallel to the
edges of the frame by shifting the printing table over pre-
determined d.istances X and Y in such a manner that the
per.for.ltions of the printing screen are caused to overlie
unprin~:ed zones which are substantially centrally located
between adjacent dots A already printed and which may each
lie centrally either within a triangle of three adjacent
printe(' dots A or within a rhombus of four adjacent dots A
of the first array.
The physical displacements X and Y of the printing
table are accurately determined by means of microguages
associated with this table.
The second reagent ink is inally applied to the
printing screen in the manner described above and used to
lS print ~ second array of printed dots B on said zones of the
printing surface which lie centrally between the already
printed dots B of *he first array.
Printing was,carried out successfully in this manner
with two reagent inks having the compositions which are
given with reference to the E,xamples described furtller
below.
For this purpose perforated nickel sheets manufactured
by the firm Zeefplatenfabrick N.V. in Eerbeek/Holland were
used as screens for printing in the manner described above.
Six types of commercially available Veco sheets which
are designated by the references 25R, 30R, 60P, 80P and 125P
were used as printing screens which respectively have the
dimensions shown in Table 3 below.
- 23 -
TABLE 3: PRINTING SCREENS
. ___ ._ _ _
Veco ;heet Thickness Hole Si~e Hole Spacing
(mm) (mm~ ~mm)
25R 0.31 0.30 1
30R 0.25 0.25 0.83
40R 0.31 0.19 0.63
6(~P 0.09 0.17 0.~2
8~P 0.07 0.13 0.31
5P 0.05 0.08 0.20
.'
Several series of printing tests with these sheets
provided good results with the inks shown i.n Table 5 Eurther
below, the printed .ink dot s:izes being somewhat larger (5-
20%) than the hole size oE the Veco sheets used in each
case, while the dot size evidently decreased as the hole :~
size decTeased.
T~Lble 4 below shows the average sizes of the dots
printe~l with four different Veco screens having the corre- ~.
sponding dimenslons shown in Table 3 above J the inks used
for printing having in this case the same :Eormulations as
the in~.s designated RI.A4 and RI.B4 in Table 5 further
below.
TABLE 4: AVERAGE DIAMETER OF PRINTF,D DOTS
_ _ .
Veco Sheet Hole Diameter ~ ~e lo~ I =
1st Reagent 2nd Reagent
25. Ink RI.A4 RI.B4
___ __~_
25~ ~ 0.30 0.314 0.317
60P 0.17 0.187 ~.180
8~P 0.13 0.1~7 0.30
: 125P _ D.083 0O078
_ ~_ .
- 24 -
The printed dots A and B of the two reagent inks do not
touch each other and the proportion of printed area covered
by the dots to the total printing surface oE the sheet
varied between l.l and 50%, and subsequently provided
clearly visible colour test reaction for detecting the
presence of blood in urine.
It may also be noted that the dimensions of the print-
ing screens should preferably be especially adapted to the
reageni inks used so as to provide maximum coverage of the
printing surface. Thus, for example, a Veco sheet of the
type 125P has a hole size of 0.08 mm with an interaxial
spacing of 0.20 mm and thus provides much more closely
packed printed dot arrays than a Veco sheet oE the type 25R
having a hole size oE 0.30 mm and interaxial spacing of l
lS mm.
The increased density of the dots printed with screens
of the 60P, 80P and 125P types (I'ables 3 and 4) thus pro-
vides a more homogeneous and intense colour change during
the test reaction.
Thus, the results of printing reagent ink dots, as
herein described, consistently provided a visually detect-
able colour test reaction, although the packing density and
film thickness of the printed reagent ink dots may certain1y
be considerably increased by printing through more closely
spaced perforations and by using reagent inks with a sub-
stantially reduced solvent content to provide a coTrespond-
ingly increased viscosity.
The invention may further be illustrated by means of
the examples given hereina-fter.
- Z5 -
The compositions of the different reagen~ inks used in
the following Examples 1 to 7 are summarized in Table 5
below, wherein abbreviations and Trademarks represent the
following substances:
Reagsnts:
cumene hydroperoxide = CHP
ortho-tolidine = (C6H3 ~CH3) NH2)2 = o-tolidine
Binders:
hydroxyethyl-cellulose: "NATROSOL" (type 250 LR, llercules)
polyvinylpyrrolidone : "PVP" ~type K90, BASF)
sodium-carboxymethyl-cellulose: NaCMC ~type 7HF, Hercules)
methylethyl-cellulose : MEC "EDIFAS A" (ICI)
hydroxypropyl-cellulose: ~LUCEL~ (type LF~ Hercules)
dextran (Pharmacia, Uppsala, Sweden)
FiZZe~:
silica powder
Surfactants:
sodium-dodecyl sulfate : SDS
ethyloxylated-alkylphenol : ~RENEX 698
Buffer:
sodium-hydrogen maleate bufEer, pH 5~8 MAL~AI~F~
- 26 -
.
TABLE 5: OCCULT BLOOD TEST REA~ENT INKS
INK SOLVENT REAGENT ~INDER, SURFACTANT BUFFER
wt% FILLER
EXAMPLE _
RI.Alwater CHP NaCMC SDS MALEATE
79% ~3.14g~ (0.5g) ~0.5g) ~30 ml)
PVP
(14 g)
RI.Blethanolo-tolidine PVP Renex 698
82% (0.4g) (20 g) ~0.5 g)
E MPLE 2
RI.A2water CHP NaCMC SDS MALEATE
74.5% (3.14g) (0.6g) ~0.5g) ~30 ml)
PVP ` .
~18 g)
RI.B2ethanolo-tolidine PVP Renex 698
83% (0.6g) (27 g) (0.6 g)
LXAMPLE 3
RI.A3water CHP NaCMC SDS MALEATE
76% ~3.14g) (0.6g) ~0.5g) (30 ml)
PVP
(16 g)
RI.B3ethanolo-tolidine PVP Renex 698
83% (0.6g) (27 g) ~0.6 g)
Z5 F.XAMPL~S 4-7
RI.A4water CHP "NATROSOL" SDS MAL~ATB
68% ~6.3g) (8 g) (l g) (35 ml)
"AEROSIL"
~5 g)
GELATIN
~0.5g)
RI.~4ethanol o-tolidine "KLUCEL" Renex 698
~0.8g) ~10 g) ~1 g)
Examp ~ ~ ~
Diagnostic test strips for the detection of blood in
urine, or so-called occult blood test strips are produced as
follows:
(;L) Preparation of Reagent Inks
Tllo reagent inks RI.Al and RI.Bl (see Table 5) are pre-
pared ~Is a fluid carrier medium for the respective reagents
cumene hydroperoxide (CHP) and o-tolidine which provide an
oxidat.lon colour test reaction in the presence of blood.
lhey a~e obtained by admixing the aqueous buffer with an
aqueous solution which contains the dissolved binder and
emulsiiier, (surface active agen~) together wi.th the respec-
tive reagent~ The resulting mixture is energetically
stirrecl so as to provide ink in the :Eorm of a viscous homo-
geneouc, stable emulsion or colloidal suspension having the
corresponding composition respectively glven for RI.Al and ~ :
RI.Bl .in Table 5 above.
The resulting reagent ink compositions have a rela-
tively high viscosity which is particularly adapted ~o the
screen-printing technique by which these inks are to be
applied to the test strip support medium.
The inks given in Table 5 above respectively have a
~iscosity of AI = 1~000 to 20,000 CP and BI = 1,000 to
20,000 CP. :
(b) Support Medium
A sheet of white synthe^tic "paper" which is known by
the Trademark "Polyart" (90 g/m2), has a mat surface finish
and a thickness of ~ 80~, is used as printlng support medium
for producing test strips.
- 28 -
:
This type of Polyart paper consists of a modified poly-
ethylerle cast into thin film. It is commercially avai~able
for use in the graphic arts industry.
(o) Printing with Reagent Inks
The two reagent inks RI.Al and RI.Bl are consecutively
applie(l by means of a special screen-printing technique onto
the surface of the abovementioned white Polyart sheet used
as the printing support.
Each reagent ink is printed in the form of tiny dis
crete dots which are mutually spaced apart at a short
diskance according to a triangular printing patternO
A perforated nickel sheet of the type Veco 25R ~see
Table 4 above) was first used to screen-print a first
triangular array o~ reagent ink dots A having a diame~er
lS between 300 and 370~ and an interaxial spacing of 1 mm,
using the reagent ink RI.Al (see Table 5 above) in the
manner already described hereinbefore under the heading
"Printing Process".
The same sheet Veco 25R was used to screen-prillt, as
already described, a second triangular array oE reagent ink
dots B each central~y located with a rhombus formed by four
adjacent dots A already printed. These dots B have a
diameter lying between 300 and 35Q~ and the same interaxial
spacing of 1 mm as the dots A and the holes of the per-
forated sheet used as a printing screen.
The proportion of the printed surface covered by both
dots A and B amounted in this case to 17.7% of the total
surface o the printing support sheet.
~ .
- 29 -
.' ' ' '''.
;3~ ~7
(d) Cutting up into Test Strips
The printed sheet of Polyart is cut up in~o test strips
having a width of 4 mm.
A blue colour change may be distinctly observed when
the test strips thus obtained are dipped in urine containing
haemog:lobin in an amount equal to or greater than 0.00].4
mg/100 ml.
E~amp ~e 2
Occult blood test strips are produced ;n substantially
the salne manner as described in Example 1, except that the
reagent inks RI.A2 and RI.B2 (see Table 5 above) are here
used tn print through a perforated Veco sheet of the 30R
type (~;ee Table 3 above).
The interaxial spacing of the screen holes and hence of
the printed dots is in this case 0.83 mm, while the printed
reagent ink dots have respectively a diameter of 315 to 335
and 320 to 360~, the proportion of the printed area covered
by all dots A and B being about 16.5% o- the total printing
surface.
The blue colour change which is observed when thc
printed test strips thus produced are utilized to detect
blood in urine is substantially -the same as with the test
strips produced according to Example 1.
E~amp~e 3
Occult blood test strips are produced in substantially
the same manner as described in Example 1 except that the
reagent inks RI.A3 and RI.B3 (see Table 5 above) are here
used to print through a perforared Veco sheet of the 40R
type (see Table 3 above).
- 30 -
The int,eraxial spacing of the screen holes and hence of
the printed dots is in this case 0.63 mm, while the printed
reagent ink dots A and B respective].y have a diameter of 235
to 255~ and 255 to 260~, the proportion of the printed arca
covered by all dots A and B being about 15% of the total
printing surface.
The blue colour change which is observed when the
printed test strips thus produced are utilized to detect
blood i.n urine is substantially the same as with the test
strips produced according to Examples 1 and 2.
Examp Z~ 4
B~ood test stripC are produced in substantially the
same mOnner as described in Example 1, except that the
reagent inks RI.A4 and RI.B4 (see Table 5 above) are used to
print with a perforated Veco sheet of type 60P ~see Table 3
above) on a sheet of absorbent white paper stock.
The interaxial spacing o-E the screen holes and hence of
the printed dots of each array is 0.42 mm in ~his case~
while the printed reagent ink dots A and B respectively have
diameters of about 0.187 mm ancL 0.180 mm, the proportion of
the printed area covered by all dots A and B being abollt 34~ ~ '
of the total printing surface.
The printed dots of inks RI.A4 and RI.B4 did not spread
out on the absorbent paper stock but remained as small
25`,:'~ dlscret.e dots on the surface of the paper. This non-flowing
' property of the inks is due to t,heir high viscosities and
paste-like rheology which neverth~eless allows them to be
:correctly printed by the process described above.
, - 31 - .
A blue colour change is observed l~hen the prin~,ed test
strips thus produced are utilized to detect haemoglobin in
soluti~n, in the same way as with the test strips produced
accord~ng to Examples 1, 2 and 3, but with the added advan- -
tage Ol' pro~iding a more homogeneous and deeper colour
response in the test strips produced in the present example.
Exam p Z ~ 5
Oc:cult blood test strips are produced in substantially
the same manner as described in ~xample 1 with the same inks
and Veco sheet (60P) as described in Example 4, except that
the second reagent ink RI.B4 is printed in two successive
impressions as two sets of discrete dots.
The ink RI.A4 is Eirstly printed on absorbent papeT
stock in the previously mentioned triangular dot array.,
When t}`ese printed dots are dry, the ink RI.B4 is printed
with the same Veco screen ~60P) within triangles of dots
~ormed by the ink ~I.A4, while there are adjacent triangles
of dots formed by this RI.A4 ink which do not contain a dot
of the RI.B4 ink. Therefore, a second lmpression of the
RI.B4 in'k is carried out to print dots in these vacant
triangles. ; ,;
The proportion of the total printed area covered by all
dots A and B is then about 50% of the total printing surface.
A blue colour change lS observed when the printed test
~ strips thus produced are utilized to detec~ haemoglobln in
solution in the same way as the strips described in Example
4, but with the added advantage of having a more homogeneous
and deeper colour response than in the case of P~xamples 1
to 4.
- 32 -
,
.
ExampZ(~ 6
Occult blood test strips are produced in substant:ially
the sa~ne manner as described in Example 4, except that the
pri.nting support medium used in the present case is a thin
glass Fiber-sheet special filter paper type 10,70 g/m2, from
Schleicher and Schull GmbH, West Germany.
This printing surface is receptive to the ink and the
ink dots adhere well thereon. The test strips printed
this ~aterial present a hydrophilic surface to the haemo-
globin solutions and respond with a blue colour change tohaemoglobin concentrations equal to or greater than 0.0154 mg/ml.
Exc~mpZe 7
Blood test strips are produced in substantially the
same manner as described in ~.xamp:Le 5, except that the ~.
printing support medium used in the present case is a micro~
porous plastic sheet which is based on polyvinyl chloride
and is produced by the Amerace Corporation, Microporous
Division.
The test strips produced on this support medium were
~ used for test reactions with hclemoglobin in solukion and
provided a very satis.factory colour change, as in the case
of F.xample 5.
.
The following Examples 8 and 9 moreover illustrate the
production of diagnostic test strips for the detection of
glucose in urine. .
The compositions of the glucose test reagent inks used
in Examples 8 and 9 are given in Table 6 below wherein those
abbreviations and Trademarks which have not already been
explained with reference to the foregoing examples represent
the following substances:
- 33 -
- . . . . . . . ................ . ~ . .
': ~
~eagen s:
glllcose oxidase = GOD
pe~oxidase = POD
polassium iodide = KI
brilliant blue FCF dye = FD ancl C Blue No. l
Binde~s:
carboxymethyl-cellulose = CMC (type 7LF, Hercules)
po]yvinylpyrrolidone = PVP
= 'PLASDONE" (type K29-32),
GAI Corp.
Surfact an~s:
po]yexyethylenesorbitanne monolaurate - "Tween 20" (ICI :
Americas, Inc.)
Bllff'er .
0.8 M citrate = 350 ml H~O ~ 257.3 g sodium citrate
dihydrate ~ 25 g anhydrous citric acid
TABLE 6: GLUCOSE TEST REAGENT INKS
..... _ _ _ , _
INK¦ SOLVENT REAGENTBINDER SURFACTANT BU~Fr:R
_ .. . --- ~ ~ . _
Exa~ 8:
_ _
water GOD (0.06 g) CMC "Tween 20" Citrate
RI.A8 85% POD ~0.01 K) (6 g) ~0.3 g) ~50 ml)
RI~B8 ethanol o-tolidine "Klucel" "Renex 698"
72~ ~0.8 g) ~10 g) ~1 g)
Example 9: .
water GOD ~0.3 g) CMC "Tween 20'l Citrate : :
RI.A9 73% POD (0.04 g) ~2 g) ~0.06 g) ~10 ml) :
RI.B9water KI ~0.08 g) PVP ~0.2g) "Tween 20" Citrate :
77% blue dye CMC (Z.oR) (0.08 g) ~15 ml) :
,..
' ' '
., .
- 34 -
- - :
'7
E~cam p ~ ~ 8:
Diagnostic test strips for the detection of glucose in
urine are produced as follows:
(.1) Preparation of Reagent Inks
Two reagent inks RI.A8 and RI.B8 (see Table 6 above)
are prepared as a fluid carrier rnedium for the reagents
glucos~ oxidase (GOD) and peroxidase ~POD) on one hand and
for ortho-tolidine on the other, which provide an oxidation
colour test reaction in the presence of glucose.
The first reagent ink RI.A8 is obtained by admixing the
aqueous CITRATE buffer (0.8 M) with the two reagents (G~D
and POI) in powder form) and with the surEactant "Tween 20",
and dissolving the binder CMC - 7IF therein. The resulting
mixture is energetically stirred so as to provide the first
reagent ink RI.A8 in the form of a viscous, homogeneous,
stable solution with the composition given in Table 6.
Ihe second reagent ink RI.B8 is the same as the second
ink RI.B4 given in Table 5 above with re-ference to the
forego-ng Examples 4 to 7.
These reagent inks RI.A8 and R].B8 both have a rela-
tively high viscosity which is particularly adapted to use
of a s~reen-printing technique for applying these inks to
the test strip support medium.
(b} Support Medium ~ -
A sheet of absorbent white paper is used as the print-
ing support medium for producing the glucose test strips.
(c) Printing with Rea~ent Inks
.
Glucose test strips are produced by printing in substan-
tially the same manner as described in Example 1, except
- 35 -
~ 7
that t}le reagent inks RI.A8 and RI.B8 are used in the
present case to print through a perforated Veco sheet of the
125P type (see Table 3 above).
The proportion of the printed surface covered by all
the dots A and B amounts in this case to more than 30% of
the total surface of the printing support sheet.
~d) Cuttin~ up into Test Strips
The resulting printed paper sheet is finally cut Ip
~nto g ! ucose test strips of 4 mm width.
A strong blue colour change may be distinctly observed
when the test strips thus obtained are dipped in urine con-
taining glucose in an amount equal to or greater than
0.1 g/lO0 ml.
E~amp ~e 9:
Diagnostic test strips for the detection o glucose in
urine are produced in essentially the same manner as de-
scribed in Example 8~ except that the reagent inks RI.~9 and
RI.B9 are used~ which have the compositions given in Table 6
above.
Tllese reagent in~s RI.A9 and RI.B9 are used to pr;nt
througl~ a perforated Veco sheet of the 60P type (see fore-
going Table 3) on an absorbent paper sheet, as in Example 8
abo~e, and the resulting printed sheet is final]y cut up
into test strips of 4 mm width.
The unreacted printed glucose test strips thus obtained
are blue in colour due to the presence of a small amount of
an oxidizable blue dye (FD and C blue No. 1), in addition to
the wa~er soluble iodide salt ~KI), in the second reagent
ink RI.B9.
- 36 -
.
A colour change may be dis-tinctly observed when the
test strlps thus obtained are dipped in urine containillg , '~
,glucose ln an amount equal to or greater than 0.1 g/100 ml.
The observed colour changes depend on the glucose concentra-
tion ac follows:
G~ucose Colour Developed
(g/100 ml) in 1 minute
o blue
0.1 light green
0.5 brown-green
1 brown
:
The following example illustrates the production oE
dlagnostic test strips for the detection of ketone bodies
(acetone, acetoacetic acid, betahydroxybutryric acid) in
lS~ ' body fluids, especially acetoacetic acid in urine. ''
The compositions of the ketone test reagent inks used
ln the ollowing Example 10 are given in Table 7 below,
wherein, the abbreviations and Trademarks used for the binder
are th~ same as indicated above with reference to the -fore-
going examples.
"GAFAC RE-610" (see Table 7 below) is a TrademaTk for a ~'
surfactant manufactured by GAF Corp. , '
"PVP/VA" is a polyvinylpyrrolidone/vinyl acetate
copolymer (50% in ethanol).
', '
- 37 - ;
.: f ., .
TABLE 7: KETONE TEST REAGENT INKS
INK SOLVENT REAGENT BINDER SURFACTANT BUFFER
Example 1_:
RI.Al0 water aminoacetic CMC-76F -Na PO 12~1 O
(36 ml) acid ~9 g) (3 g) (1~ g)
Na2HPO~
anhydrous
~4.3 g)
RI.B10 EtOH Na-nitroferri- PVP/VA "GAFAC RE-
~54 ml) cyanide (2.9g) co-polymer 610"
(23 ml) (0.3 g}
"KLUCFiL JFt' dioctyl-
(10 g) sodium- -
sulfoccinate
~ . ,
15 Examp~f 10:
Diagnostic test strips for ~he detection of ketone ~ :
bodies in body -fluids are produced in essentially the same
manner as described in Examples 8 and 9, except that the
reagent inks RI.A10 and RI.B10 here used respectively com-
pr:ise the aqueous phosphate compounds,.the sodium nitro-
ferric~anide and the ethanol-soluble binders (PVP/VA,
"KLUCE~, JF" ) in alcoholic phase which are given in Table 7
above.
T]lese reagent inks RI.A10 and RI.B10 are used to pr1nt
througll a perforated Veco sheet of the 60P type (see fore-
going Table 3) on an absorbent paper sheet, as in Examples 8
and 9 above, and the resulting printed sheet is finally cut
up into test strips of a desired width.
A violet colour change may be distinct1y observed when
the printed ketone test strips thus obtained are dipped in
liquids containing acetoacetic acid.
- 38 -
-
The colour varies from very light purple in the pres-
ence of 10-20 mg per 100 ml of acetoacetic acid to a very
dark purple indicating over 100 mg per 100 ml.
Il has been experimentally established, as appears from
the foregoing examples, that the total printed area covered
by all dots of the patterns printed with different reagent
inks, to produce printed test strips in accordance with the
present invention, should cover 30% and preferably 45~ of
the total area of the printing surEace enclosing the different
patterns, in order to provide the best colour changes and to
thereby ensure the most satisfactory colour test react;ons
by means of the printed tesk strips in all cases.
Such coverage of at least 30% of the surface area oE
the printing support medium may be readily accomplished by
suitabLy selecting perforated screens used for printing~ -
namely screens having perforations whereof ~he size and
spacing is as small as possible, while allowing satisfac-
tory, successive printing of different discrete tiny dots
which Lie between each other and are very closely spacecl
~0 togeth~r, without being in contact with each other.
Tilus, for example, the Veco screens of the types GOP,
80P antl 125P, having the dimensions shown in Iable 3 ahove
antl ust~d in the foregoing Examples 4 to 10, are partlc~llarly
suitable for printing patterns of dlf-ferent dots covering
about 30-50~ o-f the corresponding surface area of the
printing support sheet.
It has likewise been experimentally established that
the total number of dots printed per unit area of the
printing support sheet should further be equal to or g1eater
.
- 3~ -
,
147
than 1~00 dots per square centimeter, in order to provide
the best colour changes and to thereby ensure the most
satisfactory colour test reactions by means of the printed
test strips in all cases.
An overall density of discrete printed dots greater
than 1300 dots per square centimeter may also he readily
accomplished by suitably selecting perforated screens used
for printing9 such as for example, the said Veco screens of
the types 60P, 80P and 125P used in the foregoing Examples 4
to 7.
In order to also ensure satisfactory colour test
reacti(lns in all cases, it has moreover been exper:imentally
found hat the test strips procluced by printing in accord-
ance with the present invention should be provided with
printed dots having a thickness lying between 5 and 60
microns. It has further been found that, for similar
reasons, the viscosity of the reagent inks used for printing
test strips in accordance with the present invention should
preferably lie in the range between 5000 and 300,000 centi-
poise in order to ensure satisfactory printing.
The reagent inks describecL above (Table 5) with refer-
ence to the foregoing examples are able to provide a s~lffi-
cient :ink viscosity and dot thickness, with a sufficient
surface coverage and overall dot density, for ensuring most
satisf.lctory colour test reactions by means of the printed
strips in all cases.
It may be seen from the foregoing that the production
of printed diagnostic test strips in accordance with the
present inventlon may be likewise applied so as to provide -~
similar advantages in a broad variety of colour ~est re-
actions using more or less conventional reagen~s and other
- 40 -
~ '7
ink components, whereof the chemically compatibility with
each other and with more or less conventional printing
support media may be experimentally establ:ished beforehand
without great difficulty.
I~ is thus understood that the reagent ink composl-
tions~ the printing support medium and the printing me~ns
used may in each case be mutually adapted on the basis oE
prior flrt experience in the relevant fields of diagnostic
agents and or printing methods.
Tlle present invention is applicable to the presently
known reactant compositions used in the preparation of
diagnostic test devices. Typical test reactant compositions
are set Eorth in U.S. Patents 3,438,737; 3,095,277; 3,212,855;
3,1~4,`i34; 3,050,373; 2,981,606; 3,123,443; 3,252,762;
3,290,117; 3,0~2,463; 3,012,976; 3,122,420; 3,453,180;
3,585,001; 3~585,004; and 3~447,905. It will, however, be
understood that the invention is especially applicable to
diagnostic formulations in which it is important or desirable
to keep reactants separated before use.
