CA1040170A - Biological fluid dispenser and separator - Google Patents
Biological fluid dispenser and separatorInfo
- Publication number
- CA1040170A CA1040170A CA293,159A CA293159A CA1040170A CA 1040170 A CA1040170 A CA 1040170A CA 293159 A CA293159 A CA 293159A CA 1040170 A CA1040170 A CA 1040170A
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- Canada
- Prior art keywords
- serum
- chamber
- platform
- valve
- container
- Prior art date
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Abstract
BIOLOGICAL FLUID DISPENSER AND SEPARATOR
Abstract of the Disclosure A blood serum separator-dispenser capable of collecting, separating and/or dispensing a biological fluid such as serum from an essentially closed container. A
valve can be provided to separate the container into two compartments, one for serum separation and the other for serum dispensing.
Abstract of the Disclosure A blood serum separator-dispenser capable of collecting, separating and/or dispensing a biological fluid such as serum from an essentially closed container. A
valve can be provided to separate the container into two compartments, one for serum separation and the other for serum dispensing.
Description
~ACKGROUND OF THE INV~NTION
1) Field o~ the 'I'nv'ent'ion This invention relates to a container which provides for the collection o~ a sample of a biological ~luid, the centri-fugation of the fluid in the ca~e of seruml and accurate dispens-ing of micro amounts of the fluid for testing, all without requiring the pouring of the fluid into a variety of separate containers.
1) Field o~ the 'I'nv'ent'ion This invention relates to a container which provides for the collection o~ a sample of a biological ~luid, the centri-fugation of the fluid in the ca~e of seruml and accurate dispens-ing of micro amounts of the fluid for testing, all without requiring the pouring of the fluid into a variety of separate containers.
2) State of the Prior Art The most common conventional method of providing biological fluid such as blood serum for clinical analysis utilizes a plurality of containers en route to the actual test.
That is, the blood sample is conventionally collected in an evacuated container, and separation of the serum from the whole cells may be achieved by centrifuging the sample within that container, or within another container to which the sample has been transferred. Thereafter, the serum is commonly poured off into~,~et,~another container,-Eor the desired clinic~l;testing. All such transfer operations ar~ time consuming, requiring either hand processing or complicated, expensive automatic handling.
Furthermore, whenever there is a transfer of a liquid sample to a separate, open container, the sample is aerated and CO2 loss or gain can occur. There is also the danger of improper trans~er, either by the use of the wrong container, by the improper patient labeling of the new container, or by both. Still further, con-tamination of the serum by foreign materials or infection of the operator can oocur. Reuse of the same dispensing device for sequential samples requires careful sterilization to avoid con tamination. Thus, a system which kèeps the blood sample confined to essentially one container from its collection to the actual dispensing for analysis is a distinct, sought-after improvement.
~,~ At the centrifuging stage, a variety of means have been provided for more or less plugging the serum-cell interface that is formed during centrifuging, whereby remixing of the cells and serum ls prevented. U. S. patent Nos. 3,647,070;
That is, the blood sample is conventionally collected in an evacuated container, and separation of the serum from the whole cells may be achieved by centrifuging the sample within that container, or within another container to which the sample has been transferred. Thereafter, the serum is commonly poured off into~,~et,~another container,-Eor the desired clinic~l;testing. All such transfer operations ar~ time consuming, requiring either hand processing or complicated, expensive automatic handling.
Furthermore, whenever there is a transfer of a liquid sample to a separate, open container, the sample is aerated and CO2 loss or gain can occur. There is also the danger of improper trans~er, either by the use of the wrong container, by the improper patient labeling of the new container, or by both. Still further, con-tamination of the serum by foreign materials or infection of the operator can oocur. Reuse of the same dispensing device for sequential samples requires careful sterilization to avoid con tamination. Thus, a system which kèeps the blood sample confined to essentially one container from its collection to the actual dispensing for analysis is a distinct, sought-after improvement.
~,~ At the centrifuging stage, a variety of means have been provided for more or less plugging the serum-cell interface that is formed during centrifuging, whereby remixing of the cells and serum ls prevented. U. S. patent Nos. 3,647,070;
3,779~383; 3~780,935; 3,800,947; 398499072 and 3,850,174 are repre3entatlve of device3 o~ thls nature. In U~ S. patent Nos. 3,647,070; 3,779,383, 3,800,947 and 3,849,o72, for example, ; there are dlsclosed mechanlcal valve devices which prevent flow across the interface. 5uch devices however are quite compli-cated, re~ultlng in increased cost of manufacture, and requiring in some instances more than one tubular container. Furthermore, they are susceptible to mechanical failure and do not automatic-. 10 ally seek out the serum-cell inter~ace. InsteadJ a mechanical constriction of some klnd must be provided which will not permlt variation ln blood volumes. Devlces such as are shown in U. S. .
patent No, 3,779,383 are not provided with valve means at the erum end to permit ready removal o~ the serum. Instead, the . ~ plug mu~t be. removed and the serum either poured off, as by tllting the contalner, or it must be asplrated or otherwise drawn off.
I 0~ the many device~ available to provlde blood serum i ror ana}y~is, the one whlch has become the norm ls the evacuated container. This is ~lmply a partially evacuated glass tube open ' : . - , . . .
'-.
,, . ' ' .
. .
..
.
~, ' ' at one end except for a septum placed there. One improvement over such an evacuated container which is particularly use~ul comprises a glass tube open only at one end, a septum fixed to that end when the tube is evacuated, and a movable plug contained within the tube The plug is pre~erably a silica gel, with or without a plastic cup-like mandrel positioned with its open end pointed to the septum. By reason of the vacuum, collected blood is.easily drawn into the container. The container is then spun about a centri~uge axis adjacent to the septum end, and the gel by reasQn of its selected specific gravity works up to the serum-cell inter~ace where it plugs the container against remixing o~
the serum and cells. An example o~ such.a container but without ~he mandrel is shown in ~.S Patent No. 3,852~194.
Although such a device is useful in separating the serum from the cells, it has not avoided the transfer difficulties noted above. Furthermore, by pouring out the serum through-the theretofore septum-plug~ed end, it is possible to contaminate the serum with blood cells which collected at the septum-container . interface prior to centrifuging, a condition known as "blood-i 20 .ring contamination." Still further, coagulation is required to i assure maximum serum separation, and this requires about a 10 I minute "hold" even when coagulants are used.
j Other patents relating to blood serum separation in ¦ general are U.S. Patent Nos. 3,645,253; 3,687,296; 3,706,305;
¦ 33706,606; and 3,771,965. Some o~ these, while not relying on a plug-to pro~ide a barrier between se~Lm and cells, use a filter 1 The disclosure of Patent 3,77~,965 specifically protects the out-! let of the evacuated container ~rom blood ring contamination.
j In commonly owned UOS. Patent No. 3,977,568 o~ David ¦ 30 Smith entitled "Biological Fluid Dispenser ~or Dispensing Micro : . Amounts," issued August 31, 1976, there is disclosed the dispensing . of a fluid such as serum f.rom a blood separatQr by the connection ~, . ' -~ ' ' ' 1'-' . `. . . .
L7~
. .
thereto of a separate: dlspensine headg the dispensing head relying, for exampleg upon pls.t-on action to dispense the serum, A conventional blood separator such as the glass tube . type described above3 is shown.
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OBJECTS OF I~E IN ENI'ION
It is an ob;ect of the invention to provide apparatus for separating blood serum ~rom blood which is capable of transmitting the separated serum to a metering device with a mlnimum of handling.
A related ob~ect of the invention is to provide such apparatus which eliminates the need for the addition of other devices during the processing of the serum, to complete that processing.
Another related o~ect o~ the invention is to provide such apparatus whereln a single container is used to handle the blood ~or all its processing prior to actual testing, namely for the collection of a blood sample from a patient, the centrifuging o~ the sample to segregate the blood serum, and the dispensing of the serum in accurate mlcro amounts.
Another ob~ect o~ the invention is to provide such apparatus in as compact a form a possible`so as to be readily ~tored and dispensed.
Another ob~ect of tho lnvention is to provide a serum ~eparator which minimizes the delay prior to centrifuging which I is necessary for coagulation.
¦ Yet another obJect o~ the invention ls to provide an apparatus for separating blood serum from blood cells by centri~ugation, havlng an lmproved seal which prevents remixing l . . .
of the two components.
Stlll another ob~ect i~ to provide such apparatus - which by reason of its simpllclty can be disposed of after use thereo~ w1th one blood sample, to avoid the need for careful sterllization.
Yet another ob~ect of the invention- i9 to provlde such apparatus which will prevent blood ring contaminatlon of the serum.
Other ob~ ect~ and ad~antages will become apparent upon reference to the ~ollowlng Summary and Description of Preferred Embodiments, when considèred in llght of the attached drawlng~.
- -4b-SUMMARY OF THE INVENTION
:
The inven~ion concerns a blood handling device which simpli~ies the processing of whole blood taken from a patient w~ereby serum is extracted therefro~ and dispensed for testing. In accordance with the teachings of the inven-t,ion, there is provided dispensing apparatus for use with a blood serum separation device comprising a separation compartment open at at least one end o~ the compartment; the apparatus comprising a generally cylindrical dispensing chamber having a platform at one side thereof suitable for the formation of drops~ and a central axis, the platform having an aperture in fluid cornmunication with the chamber, the maximum dimension o~ the aperture being sufficiently small as to prevent flow of the serum under gravity; a passageway capable of fluidly connecting the separation compartment to the chamber; and a rotatable value mounted within the chamber ~or rotation about the axis of the chamber, the value including means for temporarily blocking flow of serum through the passageway into the charnber.
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BRIEF DESCRIPTION F THE DRAWINGS
F~g. 1 is a sectional view o~ an evacuated serum separator constructed in accordance with the prior art;
Figs. 2A and 2B are sectional views of a serum separator constructed in accordance with the invention, the ~irst of which illustrates the device prior to blood collect~on~
and the second of which illustrates the device a~ter centrifuging;
Fig. 2C is a plan view of the mandrel shown in phantom, Fig. 2B;
Fig. 3 is a perspective view of a unitized container of the invention within which the separator o~ Fig. 2 can be incorporated, Fig. 4 ls an elevational view in section of the container of Fig. 3~ illustrating its orientation for centrlfuging;
Fig. 5 is an enlarged ~ectional view of a portion of Fig-. 4, namely o~ cavlty 96;
Figs. 6 and 7 are views similar to Fig. 5 but of alternate embodiments;
Fig. 8 is a ~ragmentary vlew similar to ~lg. 4, but ~ lllustrating the use of the container to dispense the serum a~ter centrifugal separation;
Fig. ~ is a fragmentary sectional vlew similar to . ~ . . . .
Flg. 8, but illustrating the pour-o~ override mechanism;
Flg. 10 ls a partially broken away plan view of an alternative embodiment o~ the oontalner;
Fig. 11 ls a sectionaI view, partially broken away, enerally taken along the llne XI-XI of Fig. 10, Fig. 12 is a sectional vlew similar to Flg. 11, but 3 without the valve;
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Fig. 13 is an end elevational view of the contalner of Fig. 10,.
Fig. 14 is a perspective view of the valve shown in Flg. 11;
: Fig. 15 is an elevatlonal view of an alternate embodiment of the valve Of Fig. 14;
Fig. 16 is a plan view o~ the valve of Fig. 15;
Figs. 17-19 are fragmentary sectional views of a valve similar to that shown in Fig. 15, but illustrating other : 10 embodiments;
igS. 20-23 are gectïonal views similar to Flg. 11, but illustrating still other ëmbodiment ~ and Fig. 24;is a ~ect~onal view of the improved Sep~um of Fig. 231 ~ ' , ' , ' .
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~4~7~) DESCRIPTIOM OF T~I~ PR~FERRED EMBOD~NTS
.The invention is intended ~or use in the dispensing of blood sera directly from blood separators onto suitable substrates, for clinical analysis. Typical o~ such substrates are those shown, for example~ in U.S. Patent No. 3,992,158 ~ issued to E. Prz~bylowicz et al on November 16g 1976. However, - the apparatus of this invention is neither limited to use with just such substrates, nor to just the dispensing o~ drops of ' blood sera. Other f.luids capable o~ being dispensed can also be handled by this apparatus.
As used in this application, terms such as "up" and "down" refer to the orientation of the disclosed parts during their actual use, in reference to the direction of the force of gravity.
There is illustrated in Fig. 1 a blood serum separator ~ 20 which lS typical o~ those prior art devices described above featuring a gel plug. In such devices, a tubular container 22, made for example from glass to permit the formation and maintenance of a vacuum, has a closed end 24, an open end 26, ~t 20 a septum 28 ~itted into the open end, a gel 30 positioned adjacent to the closed end, and a mandrel 32 embedded in the gel, the mandrel being a cup-shaped member with its open end 34 extending toward's the septum. Closed end 35 of the mandrel is adjacent to ciosed end 24 of the container. Typicall'y, the ~:i gel 30 is a silica gel which can be a blend of hydrophobic silicon ! dioxide and a silicone~ If-the gel is used by itself without a mandrel, as is taught for example in the aforesaid U.S. Patent No. 3,852,194, the silicone can be dimethylpolysiloxane, blended to give a thixotropic gel having a specific gravity between ~ 3 about 1.035 and 1.06, and preferably about 1.04-1.05, and a .': viscosity between about 400 and about 500 poise at.a shear ~ rate o- about 500 sec. 1, and typlcally 451 poi~e at 506 ~ec. 1 .
.
' 1L7~
Such a device operates to separate blood serum from cells in the following manner. After blood is drawn into the separator 20 by a cannula, not shown, a centrifugal force F is applied from the septum 28 towards the closed e~d 24. The force causes the heavier blood cells to separate from the serum and the gel to flow past the mandrel. In reaction, the lighter weight gel moves past the mandrel, assisted by optional ribs 36 thereon, towards septum 28.
Because the gel has a speci~ic gravity between that o~ the cells and serum, while the plastics commonly used with the mandrel have a specific gravity (1.186) greater than both, the gel moves to seal the serum-c~ll interface but the mandrel remains substantially where it was initially, leaving the gel seal without any structural reln~orcement. A better plugging or sealing to prevent remixing of cells and serum would be achieved if the mandrel remained with the gel.
As is common in the art, the mandrel may be provided with glass beads, not shown, to aid in the clotting of the cells. Thi9 requires, however, that the sample sit in the container ~or about 10 minutes prior to centri~u~ation.
A representative separator o~ the above type is manufactured by Corning Glass Works under the trademark "Corvac".
Turning now to Flgs. 2A, 2B and 2C, in accordance with one aspect of the invention, there is provided a blood serum separation device 40 having advantages over the device shown in Fig. 1. Such a devlce 40 comprises a generally tubular wall 42 such as can be achieved by opposed walls arranged about an axis 44 to de~ine a blood separation compartment open at both ends 46 and 48g a closure means 50 such a~ a septum secured to end 46 which serves a~ a blood inlet,mean secured to the other end 48 for temporarlly blocking serum flow out of the - compartment, and a movable plug comprlsing gel 30 subs~an ,~ ~ _9._ , L7~
tially identical to that described ~or Fig. 1, disposed adjacent to the blocking means. Thus, the compartment can be any suitable shape, including cylindrical. As shown, the blocking means comprises a ~rangible me~er 52 such as a thin sheet of metal the edges 54 of which are wrapped around end 4~ of walls 42. The serum can be dispensed mere]y by punching through the sheet, as described below. As is conventional, septum 50 can be formed from a self~sealing elastomeric material capable of penetra-tion by the ¢annula used to fill the compartment.
Such a construction of device 40 permits the centrifugal force F to be applied towards the se~t~m~ end, by spinning the device about a point of ~otation "X" positioned adjacent end 48.
The portion adjacent to end 46 becomes the cell-collecting portion o~ the compartment, and the portion adjacent end 48 becomes the serum-collecting portion. Member 52 permits subse-quent withdrawal of the serum S out end 48 in a manner described below, rather than end 46. The gel 30 th~s is initially positi-oned in the serum-collecting portion, where it assists member 52 in closing that end off to fluid flow prior to centrifuging, thus permitting partial evacuation of the container. Furthermore, the plug formed by gel 30 serves as means for preventing any "blood ring" ifrQm forming at the junction of the blocking means 52 with the end 48, thus preventing "blood ring contamination".
~ Yet another advantage of device 40 is that the gel ; moves with the line of force F, rather than against it, so as to permit the gel to be used without a mandrel. However, optionally the mandrel 32 o~ Fig. 1, shown in phantom in Fig. 2B, and in solid lines in Fig. 2C and Fig. 4, can be used. In that event, the mandrel is initially oriented with its cpen end 34 towards the temporary blocking means rather than the septum, and the closed end 35 towards the septum. Although the mandrel 32 can be identical in structure with that shown in Fig. 1, its behavior during centrifuging is quite different due to the - !~
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initlal posltion o~ the gel and the mandrel. That is, not - only is the mandrel 32 imbedded in the gel initially (Fig.
patent No, 3,779,383 are not provided with valve means at the erum end to permit ready removal o~ the serum. Instead, the . ~ plug mu~t be. removed and the serum either poured off, as by tllting the contalner, or it must be asplrated or otherwise drawn off.
I 0~ the many device~ available to provlde blood serum i ror ana}y~is, the one whlch has become the norm ls the evacuated container. This is ~lmply a partially evacuated glass tube open ' : . - , . . .
'-.
,, . ' ' .
. .
..
.
~, ' ' at one end except for a septum placed there. One improvement over such an evacuated container which is particularly use~ul comprises a glass tube open only at one end, a septum fixed to that end when the tube is evacuated, and a movable plug contained within the tube The plug is pre~erably a silica gel, with or without a plastic cup-like mandrel positioned with its open end pointed to the septum. By reason of the vacuum, collected blood is.easily drawn into the container. The container is then spun about a centri~uge axis adjacent to the septum end, and the gel by reasQn of its selected specific gravity works up to the serum-cell inter~ace where it plugs the container against remixing o~
the serum and cells. An example o~ such.a container but without ~he mandrel is shown in ~.S Patent No. 3,852~194.
Although such a device is useful in separating the serum from the cells, it has not avoided the transfer difficulties noted above. Furthermore, by pouring out the serum through-the theretofore septum-plug~ed end, it is possible to contaminate the serum with blood cells which collected at the septum-container . interface prior to centrifuging, a condition known as "blood-i 20 .ring contamination." Still further, coagulation is required to i assure maximum serum separation, and this requires about a 10 I minute "hold" even when coagulants are used.
j Other patents relating to blood serum separation in ¦ general are U.S. Patent Nos. 3,645,253; 3,687,296; 3,706,305;
¦ 33706,606; and 3,771,965. Some o~ these, while not relying on a plug-to pro~ide a barrier between se~Lm and cells, use a filter 1 The disclosure of Patent 3,77~,965 specifically protects the out-! let of the evacuated container ~rom blood ring contamination.
j In commonly owned UOS. Patent No. 3,977,568 o~ David ¦ 30 Smith entitled "Biological Fluid Dispenser ~or Dispensing Micro : . Amounts," issued August 31, 1976, there is disclosed the dispensing . of a fluid such as serum f.rom a blood separatQr by the connection ~, . ' -~ ' ' ' 1'-' . `. . . .
L7~
. .
thereto of a separate: dlspensine headg the dispensing head relying, for exampleg upon pls.t-on action to dispense the serum, A conventional blood separator such as the glass tube . type described above3 is shown.
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.
`~ ~
OBJECTS OF I~E IN ENI'ION
It is an ob;ect of the invention to provide apparatus for separating blood serum ~rom blood which is capable of transmitting the separated serum to a metering device with a mlnimum of handling.
A related ob~ect of the invention is to provide such apparatus which eliminates the need for the addition of other devices during the processing of the serum, to complete that processing.
Another related o~ect o~ the invention is to provide such apparatus whereln a single container is used to handle the blood ~or all its processing prior to actual testing, namely for the collection of a blood sample from a patient, the centrifuging o~ the sample to segregate the blood serum, and the dispensing of the serum in accurate mlcro amounts.
Another ob~ect o~ the invention is to provide such apparatus in as compact a form a possible`so as to be readily ~tored and dispensed.
Another ob~ect of tho lnvention is to provide a serum ~eparator which minimizes the delay prior to centrifuging which I is necessary for coagulation.
¦ Yet another obJect o~ the invention ls to provide an apparatus for separating blood serum from blood cells by centri~ugation, havlng an lmproved seal which prevents remixing l . . .
of the two components.
Stlll another ob~ect i~ to provide such apparatus - which by reason of its simpllclty can be disposed of after use thereo~ w1th one blood sample, to avoid the need for careful sterllization.
Yet another ob~ect of the invention- i9 to provlde such apparatus which will prevent blood ring contaminatlon of the serum.
Other ob~ ect~ and ad~antages will become apparent upon reference to the ~ollowlng Summary and Description of Preferred Embodiments, when considèred in llght of the attached drawlng~.
- -4b-SUMMARY OF THE INVENTION
:
The inven~ion concerns a blood handling device which simpli~ies the processing of whole blood taken from a patient w~ereby serum is extracted therefro~ and dispensed for testing. In accordance with the teachings of the inven-t,ion, there is provided dispensing apparatus for use with a blood serum separation device comprising a separation compartment open at at least one end o~ the compartment; the apparatus comprising a generally cylindrical dispensing chamber having a platform at one side thereof suitable for the formation of drops~ and a central axis, the platform having an aperture in fluid cornmunication with the chamber, the maximum dimension o~ the aperture being sufficiently small as to prevent flow of the serum under gravity; a passageway capable of fluidly connecting the separation compartment to the chamber; and a rotatable value mounted within the chamber ~or rotation about the axis of the chamber, the value including means for temporarily blocking flow of serum through the passageway into the charnber.
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.
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tV
BRIEF DESCRIPTION F THE DRAWINGS
F~g. 1 is a sectional view o~ an evacuated serum separator constructed in accordance with the prior art;
Figs. 2A and 2B are sectional views of a serum separator constructed in accordance with the invention, the ~irst of which illustrates the device prior to blood collect~on~
and the second of which illustrates the device a~ter centrifuging;
Fig. 2C is a plan view of the mandrel shown in phantom, Fig. 2B;
Fig. 3 is a perspective view of a unitized container of the invention within which the separator o~ Fig. 2 can be incorporated, Fig. 4 ls an elevational view in section of the container of Fig. 3~ illustrating its orientation for centrlfuging;
Fig. 5 is an enlarged ~ectional view of a portion of Fig-. 4, namely o~ cavlty 96;
Figs. 6 and 7 are views similar to Fig. 5 but of alternate embodiments;
Fig. 8 is a ~ragmentary vlew similar to ~lg. 4, but ~ lllustrating the use of the container to dispense the serum a~ter centrifugal separation;
Fig. ~ is a fragmentary sectional vlew similar to . ~ . . . .
Flg. 8, but illustrating the pour-o~ override mechanism;
Flg. 10 ls a partially broken away plan view of an alternative embodiment o~ the oontalner;
Fig. 11 ls a sectionaI view, partially broken away, enerally taken along the llne XI-XI of Fig. 10, Fig. 12 is a sectional vlew similar to Flg. 11, but 3 without the valve;
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-- .
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Fig. 13 is an end elevational view of the contalner of Fig. 10,.
Fig. 14 is a perspective view of the valve shown in Flg. 11;
: Fig. 15 is an elevatlonal view of an alternate embodiment of the valve Of Fig. 14;
Fig. 16 is a plan view o~ the valve of Fig. 15;
Figs. 17-19 are fragmentary sectional views of a valve similar to that shown in Fig. 15, but illustrating other : 10 embodiments;
igS. 20-23 are gectïonal views similar to Flg. 11, but illustrating still other ëmbodiment ~ and Fig. 24;is a ~ect~onal view of the improved Sep~um of Fig. 231 ~ ' , ' , ' .
' ~ , ' ' ' ' " ' '.'' :' ' ' , ' ' ' ' , . , -:~" ' .
~" '" , . ' '`. , , ' ' ' ~` ' ' ' , ~' . , ' ~~;
: - -7 ~: -.
~4~7~) DESCRIPTIOM OF T~I~ PR~FERRED EMBOD~NTS
.The invention is intended ~or use in the dispensing of blood sera directly from blood separators onto suitable substrates, for clinical analysis. Typical o~ such substrates are those shown, for example~ in U.S. Patent No. 3,992,158 ~ issued to E. Prz~bylowicz et al on November 16g 1976. However, - the apparatus of this invention is neither limited to use with just such substrates, nor to just the dispensing o~ drops of ' blood sera. Other f.luids capable o~ being dispensed can also be handled by this apparatus.
As used in this application, terms such as "up" and "down" refer to the orientation of the disclosed parts during their actual use, in reference to the direction of the force of gravity.
There is illustrated in Fig. 1 a blood serum separator ~ 20 which lS typical o~ those prior art devices described above featuring a gel plug. In such devices, a tubular container 22, made for example from glass to permit the formation and maintenance of a vacuum, has a closed end 24, an open end 26, ~t 20 a septum 28 ~itted into the open end, a gel 30 positioned adjacent to the closed end, and a mandrel 32 embedded in the gel, the mandrel being a cup-shaped member with its open end 34 extending toward's the septum. Closed end 35 of the mandrel is adjacent to ciosed end 24 of the container. Typicall'y, the ~:i gel 30 is a silica gel which can be a blend of hydrophobic silicon ! dioxide and a silicone~ If-the gel is used by itself without a mandrel, as is taught for example in the aforesaid U.S. Patent No. 3,852,194, the silicone can be dimethylpolysiloxane, blended to give a thixotropic gel having a specific gravity between ~ 3 about 1.035 and 1.06, and preferably about 1.04-1.05, and a .': viscosity between about 400 and about 500 poise at.a shear ~ rate o- about 500 sec. 1, and typlcally 451 poi~e at 506 ~ec. 1 .
.
' 1L7~
Such a device operates to separate blood serum from cells in the following manner. After blood is drawn into the separator 20 by a cannula, not shown, a centrifugal force F is applied from the septum 28 towards the closed e~d 24. The force causes the heavier blood cells to separate from the serum and the gel to flow past the mandrel. In reaction, the lighter weight gel moves past the mandrel, assisted by optional ribs 36 thereon, towards septum 28.
Because the gel has a speci~ic gravity between that o~ the cells and serum, while the plastics commonly used with the mandrel have a specific gravity (1.186) greater than both, the gel moves to seal the serum-c~ll interface but the mandrel remains substantially where it was initially, leaving the gel seal without any structural reln~orcement. A better plugging or sealing to prevent remixing of cells and serum would be achieved if the mandrel remained with the gel.
As is common in the art, the mandrel may be provided with glass beads, not shown, to aid in the clotting of the cells. Thi9 requires, however, that the sample sit in the container ~or about 10 minutes prior to centri~u~ation.
A representative separator o~ the above type is manufactured by Corning Glass Works under the trademark "Corvac".
Turning now to Flgs. 2A, 2B and 2C, in accordance with one aspect of the invention, there is provided a blood serum separation device 40 having advantages over the device shown in Fig. 1. Such a devlce 40 comprises a generally tubular wall 42 such as can be achieved by opposed walls arranged about an axis 44 to de~ine a blood separation compartment open at both ends 46 and 48g a closure means 50 such a~ a septum secured to end 46 which serves a~ a blood inlet,mean secured to the other end 48 for temporarlly blocking serum flow out of the - compartment, and a movable plug comprlsing gel 30 subs~an ,~ ~ _9._ , L7~
tially identical to that described ~or Fig. 1, disposed adjacent to the blocking means. Thus, the compartment can be any suitable shape, including cylindrical. As shown, the blocking means comprises a ~rangible me~er 52 such as a thin sheet of metal the edges 54 of which are wrapped around end 4~ of walls 42. The serum can be dispensed mere]y by punching through the sheet, as described below. As is conventional, septum 50 can be formed from a self~sealing elastomeric material capable of penetra-tion by the ¢annula used to fill the compartment.
Such a construction of device 40 permits the centrifugal force F to be applied towards the se~t~m~ end, by spinning the device about a point of ~otation "X" positioned adjacent end 48.
The portion adjacent to end 46 becomes the cell-collecting portion o~ the compartment, and the portion adjacent end 48 becomes the serum-collecting portion. Member 52 permits subse-quent withdrawal of the serum S out end 48 in a manner described below, rather than end 46. The gel 30 th~s is initially positi-oned in the serum-collecting portion, where it assists member 52 in closing that end off to fluid flow prior to centrifuging, thus permitting partial evacuation of the container. Furthermore, the plug formed by gel 30 serves as means for preventing any "blood ring" ifrQm forming at the junction of the blocking means 52 with the end 48, thus preventing "blood ring contamination".
~ Yet another advantage of device 40 is that the gel ; moves with the line of force F, rather than against it, so as to permit the gel to be used without a mandrel. However, optionally the mandrel 32 o~ Fig. 1, shown in phantom in Fig. 2B, and in solid lines in Fig. 2C and Fig. 4, can be used. In that event, the mandrel is initially oriented with its cpen end 34 towards the temporary blocking means rather than the septum, and the closed end 35 towards the septum. Although the mandrel 32 can be identical in structure with that shown in Fig. 1, its behavior during centrifuging is quite different due to the - !~
~4~7~
initlal posltion o~ the gel and the mandrel. That is, not - only is the mandrel 32 imbedded in the gel initially (Fig.
4)~ in the serum collecting portion, it stays imbedded in the gel as together they move wi~h the gradually forming serum-cell interface. Such a combination gives the gel a structural reinforcement which insures that the final posi-tioning of the plug, Fig. 2B, wlll in fact effectively coincide with and seal the inter~ace against remixing of the cells C and the serum S. It is believed that the mandrel 32 does not move into the ce11-collecting portion-adjacent end 46 - because together the gel and mandrel provide a specific gravity less than that of the cells C. Also, it appears that the spacing o~ the mandrel from the walls 42, and the ribs 36, are adequate to assist in the countercurrent ~low of the serum S past the mandrel and gel during centrifuging, and that such flow occurs as soon as the centrifugal force F lnltiates separatlon of the serum ~rom the blood cells.
Still another alternate embodiment within the scope o~ this invention is the use o~ plastic beads as a gel extender in lieu o~ the mandrel. The b~ads move with the gel during cen-tri~uging.
It is not clear what the actual mechanism is ~or the g~ erum movement, but lt ls believed that, as soon as a cen-trifuglng ~orce F iB applled, the serum when separated moves - again~t the gel towards end 48, due to lts lighter specific gravlty. If a mandrel ls used, the gel has nowhere else to go, except Into the mandrel 32, the open end 34 of the mandrel being direct~d towards the gel. After the separation ls complete, the ~low o~ the serum pas~ the plug terminates and contlnued spinning causes the ma~s of the gel to ~pread back intv contact with the wall Or container 40, completlng the sealing arrangement.
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The structural relnforeement given to the gel by the mandrel is o~ particular utility when forces occur which tend to disturb the gel. One example o~ such f'orces occurs when the centriruged sample is frozen prior to removal of the serum.
Without structural rein~orcement3 there is a tendency of the expansion of the frozen blood cells to distort the gel 3eal.
By its simplicity, the device 40 is quite suitable to disposal af~er a single use, thus avoiding the need for sterilization between samples.
To further impro~e the opening of member 52, and to process and control the dispenslng of the serum S in a unit container, so as to dispense 1~ only in micro-liter drops, the processing container 60 is provided as shown in Figs. 3-7. The container comprises a box-llke frame defined by walls 72, 73 and 74, conflning therein, Fig. 4, a separator-holding cavity 64 at one end 66, a mounting aperture 68 at the opposlte end 70 of the frame for a plunger 110 described hereafter, and a ! dispensing chamber 82 located adJacent to cavity 64 between the two ends 66 and 70. Chamb~r 82 is in air co~munication with , . .
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opposite exterior surfaces of the walls 73 by reason o~ opposed~
generally aligned, apertures 84 and 86. Aperture 84 permits pressuriza~io~ o~ chamber 82, as will become apparent, while aperture 86 permits the L ormation o~ a drop o~ serum in response to the pressurization o~ the chamber 82.
More specifically, ca~ity 64 comprises two pairs of opposed walls 72 and 73, end wall 74, and intermediate wall 75.
Walls 75 and 74 have passageways 76 and 78 in which the separation device 40 can be inserted with.serum-collectlng end 48 pro~ect.ing into chamber 82. To give gravity assist to the flow of serum out of device 40 when ~rangible mem~er 52 is punched through, passageway 76 is centered in its wall 72 while Eiassageway 7 is located slightly above the center line 80 of cavity 64, giving a pour-out angle of a which may be as large as 10 degrees.
The dispensing chamber 82 is defined by wall 75, an opposed wall 88 in which aperture 68 is formed for plunger 110, and extensions of walls 72 and 73 which form the exterior surfaces of the frame 62. This chamber preferably incorporates those features disclosed and claimed in the commonly-owned application of 20 R~ Columbue, Canadian Ser. No. 2l~3,828 filed on January 20~ 1976, ¦ entitled "Gas Pressure-Activated Drop Dispenser~" and comprises the following: an end closure wall 92 with opposed faces 93 and 94~
Fig 5, a cavity 96 in face 9~, the opposed side walls 75 and 88.
extending from face 93 of wall 92, and a specially.constructed drop-l forming platform 102 isolated'from the rest of face 94 of wall 92, :j aperture.86 being generally centered in the platform.
.i Because'the preferred use of the invention is to ' dispense a plurality of drops, one at a time, for analysis, it is essentiai that the chamber 82 have a capacity suf~icient ' I 30' to accommodate all the drops of serum to be tested without ~ 'refilling Speci~ically, due to the number of tests normally '¦ ~run on a single sample, the compartment preferably has a capacity which is equal to at least about 100 1, and preferably . - .
. , ' ' . . .
3.~ 7~ `' up to about 1000 ~ 1. The lower amount of this range would be used by patients having a lim~ted blood supply, such as in~ants.
As also is disclosed in said Columbus application, the platform 102 is generally a flat surface and can be in a wall surface which is part of wall 92 but is isolated from the rest of the container by a notch or groove 104. Details such as these and others are illustrated best in Fig. 5. Alternatively, another embodiment, Fig. 6, features the formation of platform 102 as a separate wall surface joined to the wall 92 by sloped walls 108 to form a tip. In either embodiment, there preferably is a vertical separation of the platform from the face 94 by a distance "h", and in Figs.-4 and 5, groove 104 preferably has a minimum width "w". Both of these preferably is such as to prevent a drop o~ blood sera from spreading ~rom the platform to the remaining chamber portions prior to drop transfer.
Such drop spreading would interfere with accurate drop transfer. It has been ~ound that a suitable value for the height "h" is about 0.127 cm, while width "w" should be at least about 0.05 cm, and pre~erably about 0.127 cm. Furthermore, the surface Or the walls immediately ad~acent to platform 102, that is the inner walls of groove 104, Fig. 5, or the walls 108, Fig. 6~ preferably slope away ~rom a line 106 along whlch the force of gravity acts when the drop ls formed, by an angle ~ which i9 between about 0 and about 15 degrees. Negative angles are also usable. Any slope greater than this will encourage the drop formed on the platform to spread up the walls into I groove 104, or up the walls 108, Fig. 6, thus interfering ¦ with the proper d~op slze and drop removal. The surface of the platform 102 termlnates ln relatively sharp edges 109, which are defined by the platform sur~ace's lntersection with the walls o~ groove 104, or with walls 108. The surface : connection proYided by the walls of cavity 96 to aperture 86 I - may be ste~ped down, aa in Flg~. 4 and 5, or smooth ~s shown i in Flg. 7. ~14~
~L~4`~'7~
To insure that blood serum of the types commonly received ~rom patients are properly dispensed as a drop from plat~orm 102~ in accurate micro-amounts, it has been determined further that the chamher ~2 nre~erablv has ~,he addltional ~ollowing properties:
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1) Aperture 86 pre~erably has a maxlmum dimension at the exterior sur~ace o~ plat~orm 102, measured transversely to Pluld ~low therethrough, which is less than that which will permit flow of blood serum under t~e influence of gravlty and - which is large enough to retard closure of the aperture by proteln agglomeration. To perform this function with blood sera having a sur~ace tension of between a~out 35 dynes/cm and about 75 dynes/cm, it has been found that the maximum d~mension should be between about 0.025 and about 0.046 cm. This dimen-5ional range appears to be operative even when the relativeviscosity is as low as about 1.2 centipoises and is as high or higher than about 2 centipoises.
The upper value can be increa ed if the head of fluid is cor-respondingly decreased a would be the case if the container diameter was increased. A typlcal head of fluid for such a maxlmum aperture dlmenslon is 2.29 cm. A particularly useful embodlment is one in whlch the aperture is generally circular ln shape, with the circle dlameter being 0.038 cm.
2) It ls al~o preferred that the lntersectlon of the aperture wlth the platform surface be essentially a sharp edge, i.e., having a radlus o~ curvature no greater than about 0.02 cm.
Further, the platform should be ~ree of protrusions such as por~ions of flashing~ whlch would proJect either away from the platform or in-.
to the fluld passageway. Wlthout such precision in the formation ofthe aperture, caplllary effect~ would be created tending to cause premature fluid ~low.
3) The transitlon zone between platform 102 and the connecting ~urface such a~ wall 108 de~lnes an edge 109 which preferably ls sufficiently sharp a~ to prevent the tendency of the serum drop to climb up the wall 108 or gro~ve 104 under the lnfluence of surface tension. For the range of flulds anticlpated, it ls preferred that the maxlmum radius o~ curvature to achieve uch an ef~ect, does not exceed about 0.02 cm.
~94~
The effect of ~he precedlng features is to confine thedrop dispensed from the contalner 30 to the sur~ace of the platform 102. It will be appreciated that the entire sur~ace of the platform is contac~ed by the drop, and because the drop naturally assumes a quasi-spherical form, ~he contacted surface area of the pla~form will range from about 0. 0026 sq . cm. for a 1 ~1 drop, to about 0~018 sq. cm. for a 30 ~1 drop. Thi~ represents a range in platf~rm diameter, between edges 109, which i3 between about 0.05 cm and about 0.15 cm. Alternatively, the surface area supportlng, and in contac~ wlth, the drop can be increased for a given drop volume and platform diameter by either 1) forming a downwardly pro~ecting rim around edge 109, 2) making the platform surface concave, or 3) roughenin~ the surface of platform 102.
Without such roughening, it has been found that a pre~erred sur~ace smoothness is between about 1 to 30 RMS.
To asslst in drop detachment and to minimize protein agglomeration in aperture`86, the platform 102 of the embodiment of Fig. 5 preferably has a cross-sectional thickness, measured along a plane extendlng perpendlcular through the plat~orm, which is no greater than about 0.025 cm. A particularly useful ; thickness is about 0.0127 cm. The effect of such a construction is to minlmize the neck o~ fluld connecting the drop to the main volume in compartment 82. This in turn permlts rapid detachment wlth llttle secondary flow out of the container. Alternati~ely, Pig. 7, aperture 97 can be such as to blend into aperture 86 by a smooth wall which obvlates the need for a separate wall thlckness - in the platform. In such a case, it is preferable that the dimension ~or the aperture 97 of compartment 82 be considerably greater than that of aperture 86, to avoid pre~enting to the serum a long constriction capable o~ protein agglomeration. ~his can be achieved by an angle Y, Fig. 7, of conversion from aperture 97 to 86 which is no less than about 5.
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7~3 All of the above ~eatures can be obtained by forming the cha~ber walls out of copolymers such as acrylonitrile-butadiene-styrene (AB~), and polymers such as acetal, poly-propylene, polystyrene, high density polyet~ylene, and poly-esters.
Considering now plunger 110, Fig. 4, it comprises a projectile-like body having opposite ends 112 and 114, each end . being hollowed out to form a cavity 116 and 118, respectively, separated by a frangible portion 120. ~nd 112 is further shàped to provide a sharp point 121. Fins 122 and 124 are provided on the sides of the plunger, dimensioned to give to the plunger a sliding fit within aperture 68 along an axis extending generally perpendicularly to sheet 52. When so mounted, portion 120 is generally parallel to fral~ible sheet 52, to permit by-passing of chamber 82, described be.low.
Cavity 116 is provided with at least one passageway 130, and-.the fins 122 and 124 should be keyed to aperture 68 so as to always orient passageway 130 downwardly. The end 70 Or the container 60 should overhang the plunger 110, with protective lips 132, so as to protect the plunger against accidental actuatlon.
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In operation, Fig~ 8, the plunger 110 is displaced inwardly by lmpinging end 114 with an implement 134 having sufficient force to cause frangible member 52 to break and open un~er the impact. Alternatively, the plunger can be ; actuated by hand. The serum S then pours out of the separation device 40 into cavity 116, through passageway 130 and into the chamber 82 where the constriction at aperture 86 impedes further flow. Cells C are retained in device 40 by plug 30. Pressuri-zation of chamber 82 is achieved by placing in sealed position over aperture 82 a source of air pressure 140. Sealing is achieved by means such as a rib 142. Sufficient increase in pressure is provided by source 140 within chamber 82 as to form a single drop of serum on the plat~orm. A suitable substrate 150 can then be raised lnto position to remove the drop for clinical analysis. Preferably, after each drop, chamber 82 is vented to the atmosphere, such as ~y lifting source 140 from aperture 84, to permit the use o~ a uniform pressurization for subsequent drop dispensing.
As reported in the aforesaid Columbus application, it has been found that a chamber 82 constructed as described above, when the contents are approprlately pressurized, repeatedly will give uniform volumetric drops of blological flu1d, such as blood sera, even when the relative viscosity, surface tension and total protein content varies drastically as is characteristic of blood ~era drawn from diseased as well as healthy patients. Table 1 sets forth typical results ln the dlspenslng of a varlety o~ biological fluids. "~" represents the arithmetic mean, while "COV" is the coefficient of variation as is commonly used in statistical analysls. The variation of only about 2% from the mean insures that repeated drops have about the same volume. Thls accuracy is achieved not only for blood serum, but also for other biologlcal flulds such as Rlnger solutions and water. Such control of volume is essentlal to insure that the same potential for the tested component éxists in each drop.
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In the preceding table, the blood sera was obtained from whole blood samples taken on a random basis from various human patients. The Ringer Solution was isometric 0.9% NaC1 in water. The "calibrated reference serum" was "Versatol", provided by General Diagnostics, a division of Warner-Lambert Co. The assay for "Versatol" ~erum is given in Table Z.
~able 2 "Versatol" Serum Constituent Amount Bilirubin 0.5 mg~100 ml : Calcium 10.2 mg/100 ml Chloride 103 mEq/L
Cholesterol, total 170 mg/100 ml Creatinine 1.7 mg/100 ml Glucosel 81.0 mg/100 ml Iron 143 mcg/lOO ml Magnesium 2.2 mg/100 ml Phosphorus, inorganic 4.0 mg/100 ml . Potassium 5.0 mEq/L
Proteln Bound Iodine 7.2 mcg~100 ml Sodium 140 mEq/L
TIBC : 397 mcg/100 ml Total Nitrogen . 1192 ml/100 ml Total-Protein2 . 7.1 gm/100 ml Urea Nitrogen 12.2 mg/100 ml Uric Acid 3.3 mg/l00 ml - lActual glucose recovere~ by methods such as glucose oxidase or Nelson-Somogyi.
2Calculated as [(Total Nltrogen)-(Non-protein nitrogen)] x 6.25.
.
. -20-The ion-free-calibrated reference serum was "Chemvarion", produced by Clinton La~oratories~ Table 3 sets for.th the assay for this test fluid.
Table 3 "Chemvari.on"
Range Found . Mean Constltuent (per 100 ml? ~er 100 ml) ... . _ _ , - NPN N.A. 36 mg Total Nitrogen N.A. 960 mg Total Protein (TN-NPN) x 6.25 5.77 gms Protein-bound Iodine 2.5-2.8 mcg 2.65 mcg Cholesterol 135-149 mg 142 mg Iron, Total 79-106 mcg 92 mcg Magnesium N.A. nil Copper . -34-43 mcg 33 mcg The following determinations were made by adding back pure standard concentrates in recovery experiments Sodium -- nil 2C Potassium -- nll Calclum . -- nil Chloride -- nil Urea Nitrogen -- nil Uric Acid -- nil - Phosphorous 0.1-0.3 mg 0.2 mg*
Glucose -- nil Creatinine -- - nil Lithium - . -- nil *Probably protein--bound and liberated durlng deter~inat1on.
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7() To permit pour out of serum without going through dispensing chamber 82, a pour-out tube 160 can be ~orced through : frangible portion 120, as by hand, Fig. 9. Such a tube has a passageway 162 extending its length, and a sharp, pointed end 164. As the tube is ~orced through portion 120 and sheet 52, it carries plùnger 110 sufficlently far lnto end 48 of separation device 40 so as to cover paSsageway 130. The serum S exits then through passageway 162.
Container 60 preferably is used for the entire sequence of blood collection, centri~uging, and dispensing. Thus, the ; blood stays with the same container for its entire processing.
The centrifuging requires that it be spun about a point "X", Fig. 4, delivering a ~orce F along axis 44.
To permit patient identification of the container 60 ~or this entire processing, a label 170 can be provided on, or . recessed into, any exterior surface. To perm~t ready stacking ; of the container, and/or machlne handling, opposite walls 73 are rormed one with a groove 172. and the other with a rib .174, both . extending the ~ull length o~ the container. .As is àpparent, the size and shape of the groove and rib should be such as to permit then to ma.te with a rib or ~roove, respectively, o~ a second container. .
It will be appreclated that container 60 can be used to dispense single-pha3e b~ological fluids fro~ container 40, merely by removing the ~el 30 and the.mandrel 32, if used, ~rom the compartment de~ined by walls 42 prior to collectlon . o~ the fluid..
. Valved Container Turnlng now to the remalning Figures, there ls illustrated an alternate embodiment for the blood separation deuice and serum dispenser wherein all the parts can be : 1ntegrated into a single, unltized body~ and the temporary , ~ _22-L7~
blocking means is replaced by a valve. As used in this application~ the term "valvel' means a member by which the flow of fluid through a passageway may be blocked, permitted, or otherwise regulated by a movable part tha~ shuts, opens, or partially obstructs, respectively, the fluid flow. Such a member is in contrast-to the frangible member of the previous embodiment, inasmuch as a valve can be reclosed after it is opened.
Parts similar to those previously described bear the same reference number to which the distinguishing suffix "a" has been added.
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Thus, as best seen in Figs 10-12, a unitized processing container 60a is provi~ed, comprising a body hav~ng two opposite ends 66a and 70a, and exterior opposed walls 72a and 73a. Extending into the container 60a from end 66a is a blood separation compartmen 1l2a, open at both ends and having a generally tubular shape with an axis 44a, Fig. 12. The outer end 46a of compartment 42a can be enlarged to accommodate a septum 52a permanently secured thereto.
Compartment 42a terminates in inner end 48a at a locator surface 175a, Fig. 12, which coincides with the walls of a second compart-ment or dispensing chamber 82a to define a passageway 176 betweenthe two compartmentsO Chamber 82a has a longitudinal axis 106a extending generally perpendicular to axis 44a. As in the previous embodiment, a movable plug 30a is positioned in the serum-collecting end 48a of compartment 42a, and may optionally include a rnandrel 32a Fig. 20. Preferably, the plug 30a comprises a gel, the nature of which is the same as in the prevlously discussed embodiment, Fig.
4, as is the mandrel if used. As is seen in Flg. 12, the centrifugal ~orce F is agaln applied against the plug 30a towards the end 46a accommodating the closure means 50a.
.
` Chamber 82a extends from an opening 180 in wall 73a, past passageway 176 to a second locator surface defined by an I end wall 92a. ~enerally centered in the end wall is a cavity 96a derining a third compar~ment in fluid communication, Fig. 12, : - Wit]l the other two compartments. Wall 92a is further provided with a platform 102a which ls here shown as ~oined to wall 92a by sloping walls 108a as in Fig. 6. The wall 92a and its plat-~orm 102a pre~erably are recessed with respect to a ridge 177 surrounding the platformj to protect the surface of the platform ~¦ ~rom contamlnatlon. Alternatively, the platform may be ¦ 3o constructed as shown in either Figs. 5 or 7. Regardless of the form of the cavity 96a, the chamber 82a and particularly ~j the plat~orm lO?a~ aper~ure 86a, and angle ~, Fig. 12, ~ 1. ' . . .
~ 7 ~
have the same properties and values as enumerated in detail in the previous embodiment, except that the platform 102a can be recessed with respect to the ridge 177.
The exterior 3urfaces of the container 60a can have the same additional features as shown in the embodlment of Fig. 4. That is~ a patien~ identification marker 170a can be placed on an exterior sur~ace, and groove 172a and rib 174a can be ~ormed along the full length of opposed walls 73a. Any suitable mating shape can be used for the groove and rib. In addition, a notch 190 extends circumferentially around ~he container 60a, concentric with axis 44a, Fig. 12, the notch being located generally in alignment with the gel 30a, and extending toward compartment 42a. The functlon of the notch is to permit the contalner 60a to be broken by snapping off the chamber 82a. In the manner, serum obtained in compartment 42a can be poured off, or otherwise aspirated away, without requiring drop-by-drop dispensing through chamber 82a.
A concave surface 195~ Fig. 10, can be provided in end wall 70a for the purpose of ready identification and for machine I centering or handling of the contalner, if deslred.
I 20 To control the flow of ~erum from compartment 42a into oompartments 82a and 86a, blocking means in the form of a valve 200 is seated within chamber 82a) having a portion removably I blocking passageway 176. More specifically, to obtain selective j flow of serum from compartment 42a, the valve comprises, Fig. 14, -a body 204 having a face plate 206, a valve stem 208 extending from body 204, and a supporting leg 210 also extending from the valve body at a position generally opposite to stem 208. The stem and leg are spaced apart by an opening 211 which is at least as large as passageway 176, Fig. 10.
¦ 30 Th~ body's exterior surface is designed to mate ~,. within chamber 82a. Thus a preferred shape of chamber 82a and ;~l body 204 is generally cylindrical. The va~ve ls further mounted ¦ for rotation within chamber 82a about axis 106a, Fig. 12, a ,~ . . .
'7~
circumferentially-extending rib 212 in body 204 being provided to rotate within a mating groove 214 in chamber 82a (Fig.
12). To permit pressurized alr to be delivered lnto valve 200 and thus into chamber 82a, an aperture 84a extends through plate 206. A suitable interface, such as a rib, can be provided as a seal in a manner similar to the embodiment of Fig. 8. To provide a rotary drive for valve 200, at least one, and preferably two, cavities 220 are formed in I plate 206 to mate with a driving member, the cavities being 10 offset ~rom axis 106a.
As means ~or sealing o~ the passageway 176, the stem 208 is provided with a closure member 230 pro~ecting radially outwardly away from the valve, of a shape and si~e as to fit into and close the passageway. To permit opening of the valve merely by rotating body 204g the member 230 is preferably ~lexible enough as to be compressed by such rotation~ whereby it will clear the wall o~ chamber 82a just outside of passageway 176. Typical materials having such properties include foamed or solid elastomers, such as silicone rubber, which may be adhered as by suitable adhesives directly onto the stem.
To.bias the closure member against passageway 176a it is preferred that the stem 208 and leg 210 be formed so ¦ as to pro~ect outwardly a di~tance which is slightly larger ~than the diameter o~ chamber 82a, whereby the stem and leg - are pressed together.when the valve 200 is forced into the chamber. Alternatively, leg 210 may extend generally perpen-dicularly to ~ace plate 206, as seen in Fi~..15.
By the above means, a sufficient seai is provlded 30 . for passageway 176 as to permit compartment 42a to be at . least partially evacuated, i~ desired, and maintained in ¦ this condition prior to use. - Blood may easily be drawn into ~ such evacuated. compartment when a cannula is inserted into ; septum 50a~
r 2 5 ~ .
Figs. 15 and 16 illustrate an alternate embodiment of the valve,. whereln the closure member protruding from stem 208 has been eliminated. Parts similar to those previously circumferentially-extending described bear the same reference numeral to which the distinguishing suffix "a" has been added. Thus, valve 200a has a body 204a, a face plate 206a, a stem.208a and a supporting leg 210a, as before. However, ~ in place Or the closure member, the stem itse~f is molded so as to pro~ect even further away from the body 204, and is rurther provided adjacent to -~he ~uncture of the stem with the body, with wings 240 which flare outwardly from the body. The flexibility of the wings 240 and of the stem are sufficient to permit the valve 200a to be compressed and forced into chamber 82a, where the compressive forces act to ` uniformly'load.and seal the stem against passageway 230.
Flgs. 17-19 illustrate still other embodiments o~
the invention wherein yet other means are provided for selectlvely sealing passageway 176. Parts similar to those previously described bear the same reference numeral, to which 1 20 the distinguishing suffixes "b", "c" and "d" are applied. Thus, '~ in Fig. 17, valve 200b ls constructed as in Fig. 14, except that closure member'230b comprlses a flexible grommet inserted .into an aperture 250 rormed in stem 208b. The grommet's size is such as to block passageway 176 when it 1s aligned, by rotation o~ the valve, wlth the passageway. In Fig. 18, valve .l 200c comprises a ball 2.56 held in aperture 250c by a clip 258, 1. . .
. one end 260.of which is;secured over the end of stem 208c.
. Either the ball or the clip, or both, is sufficlently resilient ¦ as to permit the ball'to be ~orced out of passageway 176 when the valve is rotated to its open position. In Fig. 19, the valve 200d is constructed as in the embodiment of Fig. 14, there being however? no protFudlng closure member on stem 208d.
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Instcad, a coating 270 of an adhesive capable of being activated by ultraviolet exposure, is coated over the exterior surface of the stem, so that passageway 176 can be sealed after the stem is positioned there~cross. Typical of the adhesives which can be used as acrylic-modified urethane resins having unreac~ed isc-cyanate groups comprising at least about 2.0% by weight of the r-esin. The adhesive disclosed in British Pa~e~t No. 1,147,732 is also believed to be suitable.
In addition to the readily apparent advantages of valve 200, yet other advant~ges are that it provides a maximum or enhanced flow of serum through passageway ~76 into chamber 82a.
That is, the opening 211 between the stem 208 and leg 210, in all the valve embodiments, is as large as the passageway 176 ~Fig. 10), and therefore as large as the diameter of compartment `42a. Also, t~e valve can be reclosed after the serum passes into chamber 82a, so as to present a smaller volume of air which has to be pressurized as by a device such as source 140 of the previous embodiment.
The above construction permits the container 60a to be used as an evacuated container, the same uniti3ed body ~unctioning first as the bloo~ collector, then the separator, and lastly the , dispenser, all wlthout requiring transfer to a separate container.
I In addltion, lt is contemplated that the blood can be I
collected wlthout flrst provlding a partial vacuum in compartment 42a, and further that an air vent or aperture 300 can be formed in wall 73a, Flg. 20, to avoid air-bU1ldup as blood is forced lnto compartment 42a. To prevent leakage of serùm out of the hole, while still permitting air flow, the vent 300 can either be fllled with air permeable material, not shown, such as a 11quid-impermeable membrane, , ' ' ' ' .
~ . .
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~1~4~'70 or a cellular material the pores of which will readily plug when serum flows into it. Such poresg whlch provide the e~fective air passageways, should be sufficiently small as to resist blood flow therethrough under the radially outward pressure commonly encountered during centrifuging. Such pressures have been found to be, for example, about 1.245 x 105 dynes per s~uare centimeter. Alternatively, the vent may be cut on a diagonal axis which ~s non-rectilinear to the compartment axls, as sh~wn in phantom, rather than a radius, to further discourage blood leakage during centrifugation. Still further, the plug 30a can prevent leakage by strategically locating the inner end 302 of the vent which opens into compartment 42a. That is, the blood drawn into the container will normally have a serum content occupying a space having a length between about 35 and about 60% of the free length of compartm-ent 42a, thus insuring that the plug 30a will move to this position. Still ~urther, exterior covers, such as tape, can be positioned arter the sample i5 drawn, to prevent leaka~e.
The contalner 60a as descrlbed above can be made ~ 20 O~ synthetlc rl~id polymer9, or "plastics". I~ compartment :! 42a is to hold a vacuum, a relatlvely non-porous synthetic , .
:! polymer is preferred~ such a ~Saran~7 vinyl chloride-vinylidene ~¦ chloride copolymer manufactured by Dow Chemical Company.
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It will be appreciated that, by reason of t~e above construction, the container 6Ga can have a minimal s~ze, and can be formed of materia]s such as various plas-tics which ~ill permit it to be disposed of, after a single use. A typical len~th of the container would be, from end 66a to end 70a, only about 5.85 cm. This can be shortened if`, for example, a retest container is to be supplled, because in that case the serum will already be separated and plug 30a can be eliminated. Such a container could also be used to dispense biological flulds other than serum. ~ven if a non-plastic surface ~or the walls of compartment 42a is required ~or any reason, a cylindrical liner, such as a glass sleeve, can be readily incorporated.
A further advantage found with the devices described above is that the delay required for coagulation can be reduced below that necessary in using devices such as those shown in Fig. 1.
Yet another advantage of the container 60a is that it will readily fit within conventional centrifuges and/or syringes ' .
without requirlng the redeslgn of this related equipment.
It will be appreclated that the valve and dispensing ., . . .
I chamber along with it~ plat~orm, can be combined to form a detached 1 . .
device which can be readily inserted into or-mounted over a serum container after the serum is ~eparated fro~ the blood cells, or compined with a contalner prov~ded with serum in any fashlon.
'l These embodiments are illustrated in Figs. 21 and 22. Parts I simiIar to those previously described bear the same reference ¦ numeral to whlch the distlnguishing suf~ixes "e" and "f" have ! been added. Thus, Fig. 21, the processing container 60e com-i prises a serum separation tube 40e open at both ends, a septum 50e closin~ one o~ the ends at the blood inlet and cell col-lecting portion ad~acent end 46e. At ~he serum-collecting portlon adJacen~ end- 42e~ a`dispensing apparatus has been , .
?
inserted, either before or a~ter serum centrifuging, to permit dIspenslng of the serum. The details of the dispensing chamber 82e, the valve 200e and the pla~form 86e are the same as des-cribed for the preceding embodiments. The whole assembly fits into end 42e by means of a neck portion 310 having an end 312 which telescopes well into the end 42e, and an end 314 adjacent valve 200e. The serum passageway 1j6e traverses neck portion 310 from end 312 to end 314~ which is blocked by closure member 230e. To seal the neck portion and the entire dispensing 10apparatus within tube 40e, ribs 320 project fr~m the neck portion into contact with the tube.
-Alternatively, Fig. 22, the chamber 82f containing the valve 200f and the neck portion 310f can be mounted over the exterior of the tube 40~ so that end 42f of the container fits withln the neck ad~acent end 314f . The only change necessary is of course to mount the sealing ribs 320b on the inside Or the neck portion 310f, rather than the outsid~.
These embodiments can be preassembled be~ore use, in which case the rlbs must ~it tight enough to the tube to 2Q permit air evacuatlon of the tube. The phase separat~on gel (not shown) is then inserted ad~acent the closure member 230e or f ,of the valve. In such a case use of container follows substan-tially the same procedure as described for previous embodiments.
peration of the valve and dl~pensing chamber also would be exactly as descrlbed above.
i Other suitable modificatlons of the preYlous embodlments include any suitable means to augment the serum separation or the flow of ~erum from the separation compart~
ment to the dispenslng chamber when the valve is open. For example, increased surface area in the walls of the separation compartment will lncrease the speed of clotting prior to serum separation. Also, the septum end of the contalner can be tilted up at the dlspens~n~ station to augment serum flow.
,' ` .
o Turnlng now to Fig. 23, there is illustrated an integral embodiment in whlch the rotatabl~ valve is positioned to rotate about an a~is parallel to or coincident wi~h the axis of the serum separation tube. Parts similar to those previously described bear the same re~erence numeral to which the dis- -tlnguishing suffix llgll has been added.
A unitized contalner 60g is provide~ with a serum separatlon compar~ment 42g havlng an axis 44g,~ the compartment end 48g being lnclusive, in this case, of the interior of the dispensing chamber 82g. An improved septum 350, described here-inafter, is positloned at body end 66g, while the rotatable valve 200g fits withi~ chamber 82g. ~he valve is identical to that described previou~ly, except for the modifications necessary to ~ permit it to rotate about an axi~ parallel to axis 44g. Thus, j the rlb 212g mates wlth a groove 214g ln end 70g of th;e unit, rather than ln the top portlon. Pressurizing aperture 84g is formed in the wall 73g of container 60g, rather than in the plate 206g o~ valve 200g. Mean~ 360 are then provided on leg 210g to seal off aperture 84~ untll the valve 1~ rotated, and such means can be a clo ure member ldentlcal to closure member 230g mounted on valve ~tem 208g, as described ln the pre~iou~ embod~ments.
Closure member 230g serves in thls embodlment to temporarlly block or ~eal of~ the dispen~ing platform 102g, and wall 92g from whl~h the platform depends may be reces~ed to accommodate member 230g. To assist in prouiding a vacuum seal, the stem 208g and the leg 210g each have a rib 364 ` protruding away from the valve body, and a matlng groove 366 is formed in th~ walls oP ~ompartment 4?g to receive the rlbs.
.
In operatlon, the partitlonlng gel 30~ i5 located in~ide the chamber 82g and between the value stem and valve leg, adJacent to valve plate 206~, prior to cent~ifuglng, 80 that chamber 82g i8 used to accommodate part of the sample as collected and at lea~t a portlon o~ the ~erum a~ter centrlfuglng.
. ~ .
The gel 30g 1~ agaln posltloned in the ~erum-collec~ing portion ad~acent compartment end 48g. Aa be~ore, the ,centrifugal force ., ~1 ' ' . ' ~ _ . .
is applied along axis 44g ~rom the chamber 82g toward end 66g~
causing the gel to move out o~ chamber 82g into compartment 42g where it separates the serum from the blood cells~ This provides the advantage Or shortening the overall length of the~container 60g. Dispensing of separated serum is achieved by rotating the valve ZOOg and pressurizlng the interior of ch~amber 82g 'hrough aperture 84g, as described for the preceding embodiments.
' Septum 350, Fiæ. 23, which can be used in any of I the embodlments of the invention, is provided with means to improve its sealing performance, particularly during centri-fuging. That is 3 as with conventional septums it has a neck portion 352 and a head por~ion 354. However, the J'unction of the'neck and head portions features- an annular undercut or groove 356 extending ~he en~lre circumference of the septum.
This groove permlts the formation of a more flexible lip 358 in neck portion 352~ and thererore extra sealing power against the inner wall of comparkment 42g, insuring that the seal will be malntained when the vacuum is drawn on the body 60g, and when the centri~uge force ls directed against the septum in a directlon tending to force the septum out.
It will be appreclated that the embodiment o~
Flg. 23 can also be used as a detached dispensing chamber adapted for lnsertion into or over a serum-containing compartment or tube in the manner ~hown'in'Fi~s. 21 or 22~ before or after centrifuging.
' The inventlon ha~ been defined in detail with reference to certain pre~erred embodlments thereof, but it wlll be understood that variations 'and modirications can' - be effected within the spirit and scope of the invention.
, .._
Still another alternate embodiment within the scope o~ this invention is the use o~ plastic beads as a gel extender in lieu o~ the mandrel. The b~ads move with the gel during cen-tri~uging.
It is not clear what the actual mechanism is ~or the g~ erum movement, but lt ls believed that, as soon as a cen-trifuglng ~orce F iB applled, the serum when separated moves - again~t the gel towards end 48, due to lts lighter specific gravlty. If a mandrel ls used, the gel has nowhere else to go, except Into the mandrel 32, the open end 34 of the mandrel being direct~d towards the gel. After the separation ls complete, the ~low o~ the serum pas~ the plug terminates and contlnued spinning causes the ma~s of the gel to ~pread back intv contact with the wall Or container 40, completlng the sealing arrangement.
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The structural relnforeement given to the gel by the mandrel is o~ particular utility when forces occur which tend to disturb the gel. One example o~ such f'orces occurs when the centriruged sample is frozen prior to removal of the serum.
Without structural rein~orcement3 there is a tendency of the expansion of the frozen blood cells to distort the gel 3eal.
By its simplicity, the device 40 is quite suitable to disposal af~er a single use, thus avoiding the need for sterilization between samples.
To further impro~e the opening of member 52, and to process and control the dispenslng of the serum S in a unit container, so as to dispense 1~ only in micro-liter drops, the processing container 60 is provided as shown in Figs. 3-7. The container comprises a box-llke frame defined by walls 72, 73 and 74, conflning therein, Fig. 4, a separator-holding cavity 64 at one end 66, a mounting aperture 68 at the opposlte end 70 of the frame for a plunger 110 described hereafter, and a ! dispensing chamber 82 located adJacent to cavity 64 between the two ends 66 and 70. Chamb~r 82 is in air co~munication with , . .
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opposite exterior surfaces of the walls 73 by reason o~ opposed~
generally aligned, apertures 84 and 86. Aperture 84 permits pressuriza~io~ o~ chamber 82, as will become apparent, while aperture 86 permits the L ormation o~ a drop o~ serum in response to the pressurization o~ the chamber 82.
More specifically, ca~ity 64 comprises two pairs of opposed walls 72 and 73, end wall 74, and intermediate wall 75.
Walls 75 and 74 have passageways 76 and 78 in which the separation device 40 can be inserted with.serum-collectlng end 48 pro~ect.ing into chamber 82. To give gravity assist to the flow of serum out of device 40 when ~rangible mem~er 52 is punched through, passageway 76 is centered in its wall 72 while Eiassageway 7 is located slightly above the center line 80 of cavity 64, giving a pour-out angle of a which may be as large as 10 degrees.
The dispensing chamber 82 is defined by wall 75, an opposed wall 88 in which aperture 68 is formed for plunger 110, and extensions of walls 72 and 73 which form the exterior surfaces of the frame 62. This chamber preferably incorporates those features disclosed and claimed in the commonly-owned application of 20 R~ Columbue, Canadian Ser. No. 2l~3,828 filed on January 20~ 1976, ¦ entitled "Gas Pressure-Activated Drop Dispenser~" and comprises the following: an end closure wall 92 with opposed faces 93 and 94~
Fig 5, a cavity 96 in face 9~, the opposed side walls 75 and 88.
extending from face 93 of wall 92, and a specially.constructed drop-l forming platform 102 isolated'from the rest of face 94 of wall 92, :j aperture.86 being generally centered in the platform.
.i Because'the preferred use of the invention is to ' dispense a plurality of drops, one at a time, for analysis, it is essentiai that the chamber 82 have a capacity suf~icient ' I 30' to accommodate all the drops of serum to be tested without ~ 'refilling Speci~ically, due to the number of tests normally '¦ ~run on a single sample, the compartment preferably has a capacity which is equal to at least about 100 1, and preferably . - .
. , ' ' . . .
3.~ 7~ `' up to about 1000 ~ 1. The lower amount of this range would be used by patients having a lim~ted blood supply, such as in~ants.
As also is disclosed in said Columbus application, the platform 102 is generally a flat surface and can be in a wall surface which is part of wall 92 but is isolated from the rest of the container by a notch or groove 104. Details such as these and others are illustrated best in Fig. 5. Alternatively, another embodiment, Fig. 6, features the formation of platform 102 as a separate wall surface joined to the wall 92 by sloped walls 108 to form a tip. In either embodiment, there preferably is a vertical separation of the platform from the face 94 by a distance "h", and in Figs.-4 and 5, groove 104 preferably has a minimum width "w". Both of these preferably is such as to prevent a drop o~ blood sera from spreading ~rom the platform to the remaining chamber portions prior to drop transfer.
Such drop spreading would interfere with accurate drop transfer. It has been ~ound that a suitable value for the height "h" is about 0.127 cm, while width "w" should be at least about 0.05 cm, and pre~erably about 0.127 cm. Furthermore, the surface Or the walls immediately ad~acent to platform 102, that is the inner walls of groove 104, Fig. 5, or the walls 108, Fig. 6~ preferably slope away ~rom a line 106 along whlch the force of gravity acts when the drop ls formed, by an angle ~ which i9 between about 0 and about 15 degrees. Negative angles are also usable. Any slope greater than this will encourage the drop formed on the platform to spread up the walls into I groove 104, or up the walls 108, Fig. 6, thus interfering ¦ with the proper d~op slze and drop removal. The surface of the platform 102 termlnates ln relatively sharp edges 109, which are defined by the platform sur~ace's lntersection with the walls o~ groove 104, or with walls 108. The surface : connection proYided by the walls of cavity 96 to aperture 86 I - may be ste~ped down, aa in Flg~. 4 and 5, or smooth ~s shown i in Flg. 7. ~14~
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To insure that blood serum of the types commonly received ~rom patients are properly dispensed as a drop from plat~orm 102~ in accurate micro-amounts, it has been determined further that the chamher ~2 nre~erablv has ~,he addltional ~ollowing properties:
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1) Aperture 86 pre~erably has a maxlmum dimension at the exterior sur~ace o~ plat~orm 102, measured transversely to Pluld ~low therethrough, which is less than that which will permit flow of blood serum under t~e influence of gravlty and - which is large enough to retard closure of the aperture by proteln agglomeration. To perform this function with blood sera having a sur~ace tension of between a~out 35 dynes/cm and about 75 dynes/cm, it has been found that the maximum d~mension should be between about 0.025 and about 0.046 cm. This dimen-5ional range appears to be operative even when the relativeviscosity is as low as about 1.2 centipoises and is as high or higher than about 2 centipoises.
The upper value can be increa ed if the head of fluid is cor-respondingly decreased a would be the case if the container diameter was increased. A typlcal head of fluid for such a maxlmum aperture dlmenslon is 2.29 cm. A particularly useful embodlment is one in whlch the aperture is generally circular ln shape, with the circle dlameter being 0.038 cm.
2) It ls al~o preferred that the lntersectlon of the aperture wlth the platform surface be essentially a sharp edge, i.e., having a radlus o~ curvature no greater than about 0.02 cm.
Further, the platform should be ~ree of protrusions such as por~ions of flashing~ whlch would proJect either away from the platform or in-.
to the fluld passageway. Wlthout such precision in the formation ofthe aperture, caplllary effect~ would be created tending to cause premature fluid ~low.
3) The transitlon zone between platform 102 and the connecting ~urface such a~ wall 108 de~lnes an edge 109 which preferably ls sufficiently sharp a~ to prevent the tendency of the serum drop to climb up the wall 108 or gro~ve 104 under the lnfluence of surface tension. For the range of flulds anticlpated, it ls preferred that the maxlmum radius o~ curvature to achieve uch an ef~ect, does not exceed about 0.02 cm.
~94~
The effect of ~he precedlng features is to confine thedrop dispensed from the contalner 30 to the sur~ace of the platform 102. It will be appreciated that the entire sur~ace of the platform is contac~ed by the drop, and because the drop naturally assumes a quasi-spherical form, ~he contacted surface area of the pla~form will range from about 0. 0026 sq . cm. for a 1 ~1 drop, to about 0~018 sq. cm. for a 30 ~1 drop. Thi~ represents a range in platf~rm diameter, between edges 109, which i3 between about 0.05 cm and about 0.15 cm. Alternatively, the surface area supportlng, and in contac~ wlth, the drop can be increased for a given drop volume and platform diameter by either 1) forming a downwardly pro~ecting rim around edge 109, 2) making the platform surface concave, or 3) roughenin~ the surface of platform 102.
Without such roughening, it has been found that a pre~erred sur~ace smoothness is between about 1 to 30 RMS.
To asslst in drop detachment and to minimize protein agglomeration in aperture`86, the platform 102 of the embodiment of Fig. 5 preferably has a cross-sectional thickness, measured along a plane extendlng perpendlcular through the plat~orm, which is no greater than about 0.025 cm. A particularly useful ; thickness is about 0.0127 cm. The effect of such a construction is to minlmize the neck o~ fluld connecting the drop to the main volume in compartment 82. This in turn permlts rapid detachment wlth llttle secondary flow out of the container. Alternati~ely, Pig. 7, aperture 97 can be such as to blend into aperture 86 by a smooth wall which obvlates the need for a separate wall thlckness - in the platform. In such a case, it is preferable that the dimension ~or the aperture 97 of compartment 82 be considerably greater than that of aperture 86, to avoid pre~enting to the serum a long constriction capable o~ protein agglomeration. ~his can be achieved by an angle Y, Fig. 7, of conversion from aperture 97 to 86 which is no less than about 5.
,~
.
7~3 All of the above ~eatures can be obtained by forming the cha~ber walls out of copolymers such as acrylonitrile-butadiene-styrene (AB~), and polymers such as acetal, poly-propylene, polystyrene, high density polyet~ylene, and poly-esters.
Considering now plunger 110, Fig. 4, it comprises a projectile-like body having opposite ends 112 and 114, each end . being hollowed out to form a cavity 116 and 118, respectively, separated by a frangible portion 120. ~nd 112 is further shàped to provide a sharp point 121. Fins 122 and 124 are provided on the sides of the plunger, dimensioned to give to the plunger a sliding fit within aperture 68 along an axis extending generally perpendicularly to sheet 52. When so mounted, portion 120 is generally parallel to fral~ible sheet 52, to permit by-passing of chamber 82, described be.low.
Cavity 116 is provided with at least one passageway 130, and-.the fins 122 and 124 should be keyed to aperture 68 so as to always orient passageway 130 downwardly. The end 70 Or the container 60 should overhang the plunger 110, with protective lips 132, so as to protect the plunger against accidental actuatlon.
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In operation, Fig~ 8, the plunger 110 is displaced inwardly by lmpinging end 114 with an implement 134 having sufficient force to cause frangible member 52 to break and open un~er the impact. Alternatively, the plunger can be ; actuated by hand. The serum S then pours out of the separation device 40 into cavity 116, through passageway 130 and into the chamber 82 where the constriction at aperture 86 impedes further flow. Cells C are retained in device 40 by plug 30. Pressuri-zation of chamber 82 is achieved by placing in sealed position over aperture 82 a source of air pressure 140. Sealing is achieved by means such as a rib 142. Sufficient increase in pressure is provided by source 140 within chamber 82 as to form a single drop of serum on the plat~orm. A suitable substrate 150 can then be raised lnto position to remove the drop for clinical analysis. Preferably, after each drop, chamber 82 is vented to the atmosphere, such as ~y lifting source 140 from aperture 84, to permit the use o~ a uniform pressurization for subsequent drop dispensing.
As reported in the aforesaid Columbus application, it has been found that a chamber 82 constructed as described above, when the contents are approprlately pressurized, repeatedly will give uniform volumetric drops of blological flu1d, such as blood sera, even when the relative viscosity, surface tension and total protein content varies drastically as is characteristic of blood ~era drawn from diseased as well as healthy patients. Table 1 sets forth typical results ln the dlspenslng of a varlety o~ biological fluids. "~" represents the arithmetic mean, while "COV" is the coefficient of variation as is commonly used in statistical analysls. The variation of only about 2% from the mean insures that repeated drops have about the same volume. Thls accuracy is achieved not only for blood serum, but also for other biologlcal flulds such as Rlnger solutions and water. Such control of volume is essentlal to insure that the same potential for the tested component éxists in each drop.
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In the preceding table, the blood sera was obtained from whole blood samples taken on a random basis from various human patients. The Ringer Solution was isometric 0.9% NaC1 in water. The "calibrated reference serum" was "Versatol", provided by General Diagnostics, a division of Warner-Lambert Co. The assay for "Versatol" ~erum is given in Table Z.
~able 2 "Versatol" Serum Constituent Amount Bilirubin 0.5 mg~100 ml : Calcium 10.2 mg/100 ml Chloride 103 mEq/L
Cholesterol, total 170 mg/100 ml Creatinine 1.7 mg/100 ml Glucosel 81.0 mg/100 ml Iron 143 mcg/lOO ml Magnesium 2.2 mg/100 ml Phosphorus, inorganic 4.0 mg/100 ml . Potassium 5.0 mEq/L
Proteln Bound Iodine 7.2 mcg~100 ml Sodium 140 mEq/L
TIBC : 397 mcg/100 ml Total Nitrogen . 1192 ml/100 ml Total-Protein2 . 7.1 gm/100 ml Urea Nitrogen 12.2 mg/100 ml Uric Acid 3.3 mg/l00 ml - lActual glucose recovere~ by methods such as glucose oxidase or Nelson-Somogyi.
2Calculated as [(Total Nltrogen)-(Non-protein nitrogen)] x 6.25.
.
. -20-The ion-free-calibrated reference serum was "Chemvarion", produced by Clinton La~oratories~ Table 3 sets for.th the assay for this test fluid.
Table 3 "Chemvari.on"
Range Found . Mean Constltuent (per 100 ml? ~er 100 ml) ... . _ _ , - NPN N.A. 36 mg Total Nitrogen N.A. 960 mg Total Protein (TN-NPN) x 6.25 5.77 gms Protein-bound Iodine 2.5-2.8 mcg 2.65 mcg Cholesterol 135-149 mg 142 mg Iron, Total 79-106 mcg 92 mcg Magnesium N.A. nil Copper . -34-43 mcg 33 mcg The following determinations were made by adding back pure standard concentrates in recovery experiments Sodium -- nil 2C Potassium -- nll Calclum . -- nil Chloride -- nil Urea Nitrogen -- nil Uric Acid -- nil - Phosphorous 0.1-0.3 mg 0.2 mg*
Glucose -- nil Creatinine -- - nil Lithium - . -- nil *Probably protein--bound and liberated durlng deter~inat1on.
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7() To permit pour out of serum without going through dispensing chamber 82, a pour-out tube 160 can be ~orced through : frangible portion 120, as by hand, Fig. 9. Such a tube has a passageway 162 extending its length, and a sharp, pointed end 164. As the tube is ~orced through portion 120 and sheet 52, it carries plùnger 110 sufficlently far lnto end 48 of separation device 40 so as to cover paSsageway 130. The serum S exits then through passageway 162.
Container 60 preferably is used for the entire sequence of blood collection, centri~uging, and dispensing. Thus, the ; blood stays with the same container for its entire processing.
The centrifuging requires that it be spun about a point "X", Fig. 4, delivering a ~orce F along axis 44.
To permit patient identification of the container 60 ~or this entire processing, a label 170 can be provided on, or . recessed into, any exterior surface. To perm~t ready stacking ; of the container, and/or machlne handling, opposite walls 73 are rormed one with a groove 172. and the other with a rib .174, both . extending the ~ull length o~ the container. .As is àpparent, the size and shape of the groove and rib should be such as to permit then to ma.te with a rib or ~roove, respectively, o~ a second container. .
It will be appreclated that container 60 can be used to dispense single-pha3e b~ological fluids fro~ container 40, merely by removing the ~el 30 and the.mandrel 32, if used, ~rom the compartment de~ined by walls 42 prior to collectlon . o~ the fluid..
. Valved Container Turnlng now to the remalning Figures, there ls illustrated an alternate embodiment for the blood separation deuice and serum dispenser wherein all the parts can be : 1ntegrated into a single, unltized body~ and the temporary , ~ _22-L7~
blocking means is replaced by a valve. As used in this application~ the term "valvel' means a member by which the flow of fluid through a passageway may be blocked, permitted, or otherwise regulated by a movable part tha~ shuts, opens, or partially obstructs, respectively, the fluid flow. Such a member is in contrast-to the frangible member of the previous embodiment, inasmuch as a valve can be reclosed after it is opened.
Parts similar to those previously described bear the same reference number to which the distinguishing suffix "a" has been added.
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Thus, as best seen in Figs 10-12, a unitized processing container 60a is provi~ed, comprising a body hav~ng two opposite ends 66a and 70a, and exterior opposed walls 72a and 73a. Extending into the container 60a from end 66a is a blood separation compartmen 1l2a, open at both ends and having a generally tubular shape with an axis 44a, Fig. 12. The outer end 46a of compartment 42a can be enlarged to accommodate a septum 52a permanently secured thereto.
Compartment 42a terminates in inner end 48a at a locator surface 175a, Fig. 12, which coincides with the walls of a second compart-ment or dispensing chamber 82a to define a passageway 176 betweenthe two compartmentsO Chamber 82a has a longitudinal axis 106a extending generally perpendicular to axis 44a. As in the previous embodiment, a movable plug 30a is positioned in the serum-collecting end 48a of compartment 42a, and may optionally include a rnandrel 32a Fig. 20. Preferably, the plug 30a comprises a gel, the nature of which is the same as in the prevlously discussed embodiment, Fig.
4, as is the mandrel if used. As is seen in Flg. 12, the centrifugal ~orce F is agaln applied against the plug 30a towards the end 46a accommodating the closure means 50a.
.
` Chamber 82a extends from an opening 180 in wall 73a, past passageway 176 to a second locator surface defined by an I end wall 92a. ~enerally centered in the end wall is a cavity 96a derining a third compar~ment in fluid communication, Fig. 12, : - Wit]l the other two compartments. Wall 92a is further provided with a platform 102a which ls here shown as ~oined to wall 92a by sloping walls 108a as in Fig. 6. The wall 92a and its plat-~orm 102a pre~erably are recessed with respect to a ridge 177 surrounding the platformj to protect the surface of the platform ~¦ ~rom contamlnatlon. Alternatively, the platform may be ¦ 3o constructed as shown in either Figs. 5 or 7. Regardless of the form of the cavity 96a, the chamber 82a and particularly ~j the plat~orm lO?a~ aper~ure 86a, and angle ~, Fig. 12, ~ 1. ' . . .
~ 7 ~
have the same properties and values as enumerated in detail in the previous embodiment, except that the platform 102a can be recessed with respect to the ridge 177.
The exterior 3urfaces of the container 60a can have the same additional features as shown in the embodlment of Fig. 4. That is~ a patien~ identification marker 170a can be placed on an exterior sur~ace, and groove 172a and rib 174a can be ~ormed along the full length of opposed walls 73a. Any suitable mating shape can be used for the groove and rib. In addition, a notch 190 extends circumferentially around ~he container 60a, concentric with axis 44a, Fig. 12, the notch being located generally in alignment with the gel 30a, and extending toward compartment 42a. The functlon of the notch is to permit the contalner 60a to be broken by snapping off the chamber 82a. In the manner, serum obtained in compartment 42a can be poured off, or otherwise aspirated away, without requiring drop-by-drop dispensing through chamber 82a.
A concave surface 195~ Fig. 10, can be provided in end wall 70a for the purpose of ready identification and for machine I centering or handling of the contalner, if deslred.
I 20 To control the flow of ~erum from compartment 42a into oompartments 82a and 86a, blocking means in the form of a valve 200 is seated within chamber 82a) having a portion removably I blocking passageway 176. More specifically, to obtain selective j flow of serum from compartment 42a, the valve comprises, Fig. 14, -a body 204 having a face plate 206, a valve stem 208 extending from body 204, and a supporting leg 210 also extending from the valve body at a position generally opposite to stem 208. The stem and leg are spaced apart by an opening 211 which is at least as large as passageway 176, Fig. 10.
¦ 30 Th~ body's exterior surface is designed to mate ~,. within chamber 82a. Thus a preferred shape of chamber 82a and ;~l body 204 is generally cylindrical. The va~ve ls further mounted ¦ for rotation within chamber 82a about axis 106a, Fig. 12, a ,~ . . .
'7~
circumferentially-extending rib 212 in body 204 being provided to rotate within a mating groove 214 in chamber 82a (Fig.
12). To permit pressurized alr to be delivered lnto valve 200 and thus into chamber 82a, an aperture 84a extends through plate 206. A suitable interface, such as a rib, can be provided as a seal in a manner similar to the embodiment of Fig. 8. To provide a rotary drive for valve 200, at least one, and preferably two, cavities 220 are formed in I plate 206 to mate with a driving member, the cavities being 10 offset ~rom axis 106a.
As means ~or sealing o~ the passageway 176, the stem 208 is provided with a closure member 230 pro~ecting radially outwardly away from the valve, of a shape and si~e as to fit into and close the passageway. To permit opening of the valve merely by rotating body 204g the member 230 is preferably ~lexible enough as to be compressed by such rotation~ whereby it will clear the wall o~ chamber 82a just outside of passageway 176. Typical materials having such properties include foamed or solid elastomers, such as silicone rubber, which may be adhered as by suitable adhesives directly onto the stem.
To.bias the closure member against passageway 176a it is preferred that the stem 208 and leg 210 be formed so ¦ as to pro~ect outwardly a di~tance which is slightly larger ~than the diameter o~ chamber 82a, whereby the stem and leg - are pressed together.when the valve 200 is forced into the chamber. Alternatively, leg 210 may extend generally perpen-dicularly to ~ace plate 206, as seen in Fi~..15.
By the above means, a sufficient seai is provlded 30 . for passageway 176 as to permit compartment 42a to be at . least partially evacuated, i~ desired, and maintained in ¦ this condition prior to use. - Blood may easily be drawn into ~ such evacuated. compartment when a cannula is inserted into ; septum 50a~
r 2 5 ~ .
Figs. 15 and 16 illustrate an alternate embodiment of the valve,. whereln the closure member protruding from stem 208 has been eliminated. Parts similar to those previously circumferentially-extending described bear the same reference numeral to which the distinguishing suffix "a" has been added. Thus, valve 200a has a body 204a, a face plate 206a, a stem.208a and a supporting leg 210a, as before. However, ~ in place Or the closure member, the stem itse~f is molded so as to pro~ect even further away from the body 204, and is rurther provided adjacent to -~he ~uncture of the stem with the body, with wings 240 which flare outwardly from the body. The flexibility of the wings 240 and of the stem are sufficient to permit the valve 200a to be compressed and forced into chamber 82a, where the compressive forces act to ` uniformly'load.and seal the stem against passageway 230.
Flgs. 17-19 illustrate still other embodiments o~
the invention wherein yet other means are provided for selectlvely sealing passageway 176. Parts similar to those previously described bear the same reference numeral, to which 1 20 the distinguishing suffixes "b", "c" and "d" are applied. Thus, '~ in Fig. 17, valve 200b ls constructed as in Fig. 14, except that closure member'230b comprlses a flexible grommet inserted .into an aperture 250 rormed in stem 208b. The grommet's size is such as to block passageway 176 when it 1s aligned, by rotation o~ the valve, wlth the passageway. In Fig. 18, valve .l 200c comprises a ball 2.56 held in aperture 250c by a clip 258, 1. . .
. one end 260.of which is;secured over the end of stem 208c.
. Either the ball or the clip, or both, is sufficlently resilient ¦ as to permit the ball'to be ~orced out of passageway 176 when the valve is rotated to its open position. In Fig. 19, the valve 200d is constructed as in the embodiment of Fig. 14, there being however? no protFudlng closure member on stem 208d.
_26- - ~
L7~
Instcad, a coating 270 of an adhesive capable of being activated by ultraviolet exposure, is coated over the exterior surface of the stem, so that passageway 176 can be sealed after the stem is positioned there~cross. Typical of the adhesives which can be used as acrylic-modified urethane resins having unreac~ed isc-cyanate groups comprising at least about 2.0% by weight of the r-esin. The adhesive disclosed in British Pa~e~t No. 1,147,732 is also believed to be suitable.
In addition to the readily apparent advantages of valve 200, yet other advant~ges are that it provides a maximum or enhanced flow of serum through passageway ~76 into chamber 82a.
That is, the opening 211 between the stem 208 and leg 210, in all the valve embodiments, is as large as the passageway 176 ~Fig. 10), and therefore as large as the diameter of compartment `42a. Also, t~e valve can be reclosed after the serum passes into chamber 82a, so as to present a smaller volume of air which has to be pressurized as by a device such as source 140 of the previous embodiment.
The above construction permits the container 60a to be used as an evacuated container, the same uniti3ed body ~unctioning first as the bloo~ collector, then the separator, and lastly the , dispenser, all wlthout requiring transfer to a separate container.
I In addltion, lt is contemplated that the blood can be I
collected wlthout flrst provlding a partial vacuum in compartment 42a, and further that an air vent or aperture 300 can be formed in wall 73a, Flg. 20, to avoid air-bU1ldup as blood is forced lnto compartment 42a. To prevent leakage of serùm out of the hole, while still permitting air flow, the vent 300 can either be fllled with air permeable material, not shown, such as a 11quid-impermeable membrane, , ' ' ' ' .
~ . .
' .
~1~4~'70 or a cellular material the pores of which will readily plug when serum flows into it. Such poresg whlch provide the e~fective air passageways, should be sufficiently small as to resist blood flow therethrough under the radially outward pressure commonly encountered during centrifuging. Such pressures have been found to be, for example, about 1.245 x 105 dynes per s~uare centimeter. Alternatively, the vent may be cut on a diagonal axis which ~s non-rectilinear to the compartment axls, as sh~wn in phantom, rather than a radius, to further discourage blood leakage during centrifugation. Still further, the plug 30a can prevent leakage by strategically locating the inner end 302 of the vent which opens into compartment 42a. That is, the blood drawn into the container will normally have a serum content occupying a space having a length between about 35 and about 60% of the free length of compartm-ent 42a, thus insuring that the plug 30a will move to this position. Still ~urther, exterior covers, such as tape, can be positioned arter the sample i5 drawn, to prevent leaka~e.
The contalner 60a as descrlbed above can be made ~ 20 O~ synthetlc rl~id polymer9, or "plastics". I~ compartment :! 42a is to hold a vacuum, a relatlvely non-porous synthetic , .
:! polymer is preferred~ such a ~Saran~7 vinyl chloride-vinylidene ~¦ chloride copolymer manufactured by Dow Chemical Company.
!
1 : - : . : -.
! ~
.
.
~ . ' .
7~
It will be appreciated that, by reason of t~e above construction, the container 6Ga can have a minimal s~ze, and can be formed of materia]s such as various plas-tics which ~ill permit it to be disposed of, after a single use. A typical len~th of the container would be, from end 66a to end 70a, only about 5.85 cm. This can be shortened if`, for example, a retest container is to be supplled, because in that case the serum will already be separated and plug 30a can be eliminated. Such a container could also be used to dispense biological flulds other than serum. ~ven if a non-plastic surface ~or the walls of compartment 42a is required ~or any reason, a cylindrical liner, such as a glass sleeve, can be readily incorporated.
A further advantage found with the devices described above is that the delay required for coagulation can be reduced below that necessary in using devices such as those shown in Fig. 1.
Yet another advantage of the container 60a is that it will readily fit within conventional centrifuges and/or syringes ' .
without requirlng the redeslgn of this related equipment.
It will be appreclated that the valve and dispensing ., . . .
I chamber along with it~ plat~orm, can be combined to form a detached 1 . .
device which can be readily inserted into or-mounted over a serum container after the serum is ~eparated fro~ the blood cells, or compined with a contalner prov~ded with serum in any fashlon.
'l These embodiments are illustrated in Figs. 21 and 22. Parts I simiIar to those previously described bear the same reference ¦ numeral to whlch the distlnguishing suf~ixes "e" and "f" have ! been added. Thus, Fig. 21, the processing container 60e com-i prises a serum separation tube 40e open at both ends, a septum 50e closin~ one o~ the ends at the blood inlet and cell col-lecting portion ad~acent end 46e. At ~he serum-collecting portlon adJacen~ end- 42e~ a`dispensing apparatus has been , .
?
inserted, either before or a~ter serum centrifuging, to permit dIspenslng of the serum. The details of the dispensing chamber 82e, the valve 200e and the pla~form 86e are the same as des-cribed for the preceding embodiments. The whole assembly fits into end 42e by means of a neck portion 310 having an end 312 which telescopes well into the end 42e, and an end 314 adjacent valve 200e. The serum passageway 1j6e traverses neck portion 310 from end 312 to end 314~ which is blocked by closure member 230e. To seal the neck portion and the entire dispensing 10apparatus within tube 40e, ribs 320 project fr~m the neck portion into contact with the tube.
-Alternatively, Fig. 22, the chamber 82f containing the valve 200f and the neck portion 310f can be mounted over the exterior of the tube 40~ so that end 42f of the container fits withln the neck ad~acent end 314f . The only change necessary is of course to mount the sealing ribs 320b on the inside Or the neck portion 310f, rather than the outsid~.
These embodiments can be preassembled be~ore use, in which case the rlbs must ~it tight enough to the tube to 2Q permit air evacuatlon of the tube. The phase separat~on gel (not shown) is then inserted ad~acent the closure member 230e or f ,of the valve. In such a case use of container follows substan-tially the same procedure as described for previous embodiments.
peration of the valve and dl~pensing chamber also would be exactly as descrlbed above.
i Other suitable modificatlons of the preYlous embodlments include any suitable means to augment the serum separation or the flow of ~erum from the separation compart~
ment to the dispenslng chamber when the valve is open. For example, increased surface area in the walls of the separation compartment will lncrease the speed of clotting prior to serum separation. Also, the septum end of the contalner can be tilted up at the dlspens~n~ station to augment serum flow.
,' ` .
o Turnlng now to Fig. 23, there is illustrated an integral embodiment in whlch the rotatabl~ valve is positioned to rotate about an a~is parallel to or coincident wi~h the axis of the serum separation tube. Parts similar to those previously described bear the same re~erence numeral to which the dis- -tlnguishing suffix llgll has been added.
A unitized contalner 60g is provide~ with a serum separatlon compar~ment 42g havlng an axis 44g,~ the compartment end 48g being lnclusive, in this case, of the interior of the dispensing chamber 82g. An improved septum 350, described here-inafter, is positloned at body end 66g, while the rotatable valve 200g fits withi~ chamber 82g. ~he valve is identical to that described previou~ly, except for the modifications necessary to ~ permit it to rotate about an axi~ parallel to axis 44g. Thus, j the rlb 212g mates wlth a groove 214g ln end 70g of th;e unit, rather than ln the top portlon. Pressurizing aperture 84g is formed in the wall 73g of container 60g, rather than in the plate 206g o~ valve 200g. Mean~ 360 are then provided on leg 210g to seal off aperture 84~ untll the valve 1~ rotated, and such means can be a clo ure member ldentlcal to closure member 230g mounted on valve ~tem 208g, as described ln the pre~iou~ embod~ments.
Closure member 230g serves in thls embodlment to temporarlly block or ~eal of~ the dispen~ing platform 102g, and wall 92g from whl~h the platform depends may be reces~ed to accommodate member 230g. To assist in prouiding a vacuum seal, the stem 208g and the leg 210g each have a rib 364 ` protruding away from the valve body, and a matlng groove 366 is formed in th~ walls oP ~ompartment 4?g to receive the rlbs.
.
In operatlon, the partitlonlng gel 30~ i5 located in~ide the chamber 82g and between the value stem and valve leg, adJacent to valve plate 206~, prior to cent~ifuglng, 80 that chamber 82g i8 used to accommodate part of the sample as collected and at lea~t a portlon o~ the ~erum a~ter centrlfuglng.
. ~ .
The gel 30g 1~ agaln posltloned in the ~erum-collec~ing portion ad~acent compartment end 48g. Aa be~ore, the ,centrifugal force ., ~1 ' ' . ' ~ _ . .
is applied along axis 44g ~rom the chamber 82g toward end 66g~
causing the gel to move out o~ chamber 82g into compartment 42g where it separates the serum from the blood cells~ This provides the advantage Or shortening the overall length of the~container 60g. Dispensing of separated serum is achieved by rotating the valve ZOOg and pressurizlng the interior of ch~amber 82g 'hrough aperture 84g, as described for the preceding embodiments.
' Septum 350, Fiæ. 23, which can be used in any of I the embodlments of the invention, is provided with means to improve its sealing performance, particularly during centri-fuging. That is 3 as with conventional septums it has a neck portion 352 and a head por~ion 354. However, the J'unction of the'neck and head portions features- an annular undercut or groove 356 extending ~he en~lre circumference of the septum.
This groove permlts the formation of a more flexible lip 358 in neck portion 352~ and thererore extra sealing power against the inner wall of comparkment 42g, insuring that the seal will be malntained when the vacuum is drawn on the body 60g, and when the centri~uge force ls directed against the septum in a directlon tending to force the septum out.
It will be appreclated that the embodiment o~
Flg. 23 can also be used as a detached dispensing chamber adapted for lnsertion into or over a serum-containing compartment or tube in the manner ~hown'in'Fi~s. 21 or 22~ before or after centrifuging.
' The inventlon ha~ been defined in detail with reference to certain pre~erred embodlments thereof, but it wlll be understood that variations 'and modirications can' - be effected within the spirit and scope of the invention.
, .._
Claims (6)
1. Dispensing apparatus for use with a blood serum separation device comprising a separation compartment open at at least one end of the compartment; the apparatus comprising a generally cylindrical dispensing chamber having a platform at one side thereof suitable for the formation of drops, and a central axis, said platform having an aperture in fluid communi-cation with said chamber, the maximum dimension of the aperture being sufficiently small as to prevent flow of the serum under gravity;
a passageway capable of fluidly connecting the separation compartment to the chamber;
and a rotatable valve mounted within said chamber for rotation about the axis of the chamber, said valve including means for temporarily blocking flow of serum through said passageway into said chamber.
a passageway capable of fluidly connecting the separation compartment to the chamber;
and a rotatable valve mounted within said chamber for rotation about the axis of the chamber, said valve including means for temporarily blocking flow of serum through said passageway into said chamber.
2. The apparatus as defined in claim 1 wherein said valve includes a valve stem, said blocking means pro-jecting from said stem.
3. The device as defined in claim 1 wherein a portion of said stem is itself resilient, said stem being biased so as to fit within said chamber only under compression.
4. The device as defined in claim 1, and further including a supporting leg depending from said valve at a position generally opposite to said stem.
The apparatus as defined in claim 1 wherein said chamber further comprises:
a first wall having an inner and an outer surface, and opposed side walls extending from said inner surface to define at least one compartment having a capacity for the fluid sufficient to permit at least one drop to be dispensed there-from, said first wall having an aperture, said platform being connected to and spaced away from the said outer surface by a connecting surface, the distance between the platform and said outer surface being sufficient to prevent dispensed fluid from spreading from the platform to said outer surface, the connecting surface being inclined at an angle with respect to said platform which will confine the drop to the platform, said platform exterior surface defining a drop-contacting area which will support a drop having a volume between about 1 and about 30 µ1.
a first wall having an inner and an outer surface, and opposed side walls extending from said inner surface to define at least one compartment having a capacity for the fluid sufficient to permit at least one drop to be dispensed there-from, said first wall having an aperture, said platform being connected to and spaced away from the said outer surface by a connecting surface, the distance between the platform and said outer surface being sufficient to prevent dispensed fluid from spreading from the platform to said outer surface, the connecting surface being inclined at an angle with respect to said platform which will confine the drop to the platform, said platform exterior surface defining a drop-contacting area which will support a drop having a volume between about 1 and about 30 µ1.
6. The apparatus as defined in claim 1 wherein said chamber has an additional aperture in fluid communication with the exterior of the apparatus, whereby said chamber can be pressurized.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53955775A | 1975-01-08 | 1975-01-08 | |
| US05/581,345 US4012325A (en) | 1975-01-08 | 1975-05-27 | Biological fluid dispenser and separator |
| CA234,365A CA1033333A (en) | 1975-01-08 | 1975-08-28 | Biological fluid dispenser and separator |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1040170A true CA1040170A (en) | 1978-10-10 |
Family
ID=27164089
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA293,159A Expired CA1040170A (en) | 1975-01-08 | 1977-12-15 | Biological fluid dispenser and separator |
| CA293,158A Expired CA1040169A (en) | 1975-01-08 | 1977-12-15 | Biological fluid dispenser and separator |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA293,158A Expired CA1040169A (en) | 1975-01-08 | 1977-12-15 | Biological fluid dispenser and separator |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1040170A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017156375A1 (en) * | 2016-03-10 | 2017-09-14 | Arthrex, Inc. | Systems and methods for preparing a thrombin serum |
| US10960026B2 (en) | 2016-03-10 | 2021-03-30 | Arthrex, Inc. | Systems and methods for preparing protein enhanced serums |
-
1977
- 1977-12-15 CA CA293,159A patent/CA1040170A/en not_active Expired
- 1977-12-15 CA CA293,158A patent/CA1040169A/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017156375A1 (en) * | 2016-03-10 | 2017-09-14 | Arthrex, Inc. | Systems and methods for preparing a thrombin serum |
| US10596236B2 (en) | 2016-03-10 | 2020-03-24 | Arthrex, Inc. | Systems and methods for preparing a thrombin serum |
| US10960026B2 (en) | 2016-03-10 | 2021-03-30 | Arthrex, Inc. | Systems and methods for preparing protein enhanced serums |
| US11045526B2 (en) | 2016-03-10 | 2021-06-29 | Arthrex, Inc. | Systems and methods for preparing a thrombin serum |
| IL261057B (en) * | 2016-03-10 | 2022-08-01 | Arthrex Inc | System and methods for preparing a thrombin serum |
| US11617784B2 (en) | 2016-03-10 | 2023-04-04 | Arthrex, Inc. | Systems and methods for preparing a thrombin serum |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1040169A (en) | 1978-10-10 |
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