|Publication number||US3852194 A|
|Publication date||Dec 3, 1974|
|Filing date||Dec 11, 1972|
|Priority date||Dec 11, 1972|
|Also published as||CA974952A, CA974952A1, DE2359670A1, DE2359670C2|
|Publication number||US 3852194 A, US 3852194A, US-A-3852194, US3852194 A, US3852194A|
|Original Assignee||Corning Glass Works|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (5), Referenced by (129), Classifications (11), Legal Events (1)|
|External Links: USPTO, USPTO Assignment, Espacenet|
llnite States Patent Zine, ,lr.
[ Dec. 3, 19M
[ APPARATUS AND METHOD FOR FLUID COLLECTION AND PARTITIONING Anthony R. Zine, Jr., Corning, NY.
 Assignee: Corning Glass Works, Corning,
 Filed: Dec. 11, 1972  Appl. No.: 314,270
 US. (11...... 210/83, 2l0/DIG. 23, 2l0/DIG. 24,
233/1 A  Int. Cl B0101 21/26  Field of Search 23/258.5; 106/287 SB;
210/65, 83, 84, 512, DIG. 23;
Primary ExaminerCharles N. Hart Assistant Examiner-Robert G. Mukai Attorney, Agent, or FirmBurton R. Turner; Clarence R. Patty, Jr.
 ABSTRACT Partitioning assemblies and partitioning or sea] members, utilized with containers (adapted to serve as fluid specimen collection or fluid-retaining tubes) for effecting partitioning of two differing-density fluid phases of a centrifugally separated fluid specimen, at a position not lower than the fluid phase interface, wherein the partitioning members include a separating amount of a gel-like material. This gel-like material, by having a specific gravity intermediate those of the separated fluid phases, is adapted to move within the container in response to centrifugal force, only to the vicinity of the fluid phase interface. The gel-like material thereupon is further adapted to make a trans' versely continuous semi-rigid contact seal with an annular portion of the container inner surface to thereby effect a seal that partitions the fluid phases. The gellike material may also be used in combination with a spool member having a container-contacting outer surface and a central axial orifice, with the gel-like material making a transversely-continuous contact seal within the spool central axial orifice. Three-phase partitioning may also be accomplished by using first and second gel-like materials having specific gravities intermediate those of the first-second and secondthird differing-density phases, respectively. The partitioning 0r seal members may also be utilized in closed system (evacuated) fluid collection tubes or may be hand inserted into opened (atmospheric pressure) tubes after specimen collection. Also set forth is a method for effecting partitioning of centrifugally separated fluid phases within a container.
3 Claims, 10 Drawing Figures APPARATUS AND METHOD FOR FLUID COLLECTION AND PARTITIONING BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to an apparatus and method for the collection and partitioning of at least two phases of a muIti-phase fluid within a container. More specifically, it pertains to the collection of whole blood and, after the separation thereof, the partitioning of blood serum or blood plasma from the blood cells. If desired further fractionating and partitioning of, for example, the blood serum may be accomplished.
2. Prior Art In the standard evacuated blood sampling tubes, such as the system illustrated in US. Pat. No. 2,460,641 to Kleiner, a glass tube has one permanently closed end and the other end is closed by a rubber stopper having a pair of opposite top and bottom axial recesses separated by an intermediate diaphragm. A cup-like holder having a double ended hollow needle, with one end terminating axially within the holder and the other end terminating axially outside the holder, is used to receive the stoppered end of the glass tube, with the inner needle end being adapted to extend through the stopper diaphragm into the evacuated tube. The outer needle end is injected into the patients vein and then, by forward thrust on the tube, the puncturing of the stopper diaphragm is completed to withdraw theblood. When the desired quantity of blood has been collected in the tube, the filled tube is removed from the cup-like holder thereby obtaining a stopper-sealed collection tube housing a blood sample.
Blood or another fluid collected in the previouslydescribed collection device is then generally taken to the laboratory for processing. The contents may be utilized as whole blood or separated into a lighter phase (serum or plasma) and a heavier phase (cells). If, for example, it is desired to obtain blood serum (after an initial time period during which the filled tube assembly is allowed to stand) the filled tube assembly is placed into a centrifuge which completes separation into two blood phases. Disposed at the bottom of the tube will be a heavy phase or high density portion of the fluid consisting of packed red blood cells, while disposed at the upper part of the tube will be the lighter phase or low density portion of the fluid which is blood serum. The separated serum is then analyzed, generally after first being removed from the tube assembly by decanting and/or siphoning.
It is well known that once the blood phases are separated, if the lighter phase is not removed from the tube within a short time, interaction will occur between the separated phases and inaccurate test results will be obtained. In addition, even if the lighter phase is presently removed from the container there are the hazards of contamination of the sample and of possible mismarking of the removed sample. Furthermore, there are also hazards to the laboratory personnel who may be ex posed to disease-carrying blood samples containing, for example, hepatitic serums.
Coleman, in US. Pat. No. 3,508,653, made an advance over the blood sampling tube of Kleiner by introducing and attaching a resilient piston directly beneath the tube closure or stopper, with the piston being adapted to be punctured during the initial filling of the sampling tube. After initial centrifugation, in order to obtain the desired blood phase separation, and in re sponse to further centrifugal force, the piston is designed to move downwardly through the light blood phase, with the piston being adapted to permit upward flow of the light phase therearound, i.e., between the container inner wall surface and the outer peripheral surface of the piston. The piston, which has a wiper portion that makes an initial sealing contact with the container inner surface, loses this sealing contact during its downward movement (to permit the flow of fluid therearound) and thereafter is designed to make a final sealing contact with the container inner surface at a position not lower than a position intermediate the separated phases by stopping the downward movement by terminating the applied force. In addition, the piston, which is initially detachably secured to the stopper, requires passageway means and a vent opening therewithin to facilitate the passage of gases to permit descent of the piston but resist the passage of fluids therethrough.
While the Coleman device provides a unitary sealing member between the blood cells and the plasma or serum, it does have several shortcomings. The piston and stopper must be held in intimate contact with each other, otherwise blood which flows into any space between them during the tube filling operation will remain above the piston, and the blood cells will contaminate the lighter phase. Once these blood cells find their way above the piston wiper, they cannot be separated, since no mechanism or method has been provided to permit them to move below the piston.
In addition, there are no positive means incorporated into the Coleman device to prevent blood cells from moving upward past the piston wiper. Actual observations in the laboratory confirm that in spite of the general downward movement of the heavy phase, due to the influence of centrifugal force, some blood cells do indeed become caught up in the fast'moving light phase stream and are carried past the piston wiper into the upper chamber of the tube. As noted, once the cells find their way above the piston wiper, there is no way to return them to the lower portion of the tube.
Since the introduction of the blood sample into the tube may also permit some airto enter the tube upon withdrawal from the patient and since some gases are evolved from the blood sample, they must be vented from below the piston to eliminate the retarding effect they will have on the downwardly moving piston through a buoyancy effect. While Coleman speaks of incorporating a vent opening into the piston design, actual experience has shown that the vent cannnot readily be incorporated into the design at manufacture but is preferably made by the technician during the blood drawing operation, thereby putting the burden of creating a satisfactory vent upon the skill of the operator. The needle puncture in the piston diaphragm (for the filling of the tube) serves as a vent for air and gases during piston descent. An improperly punctured diaphragm vent may either refuse to operate at all or may rupture and blow out when the piston impacts the fluid surface during centrifugation and thus completely loses its ability to act as a seal between the light and heavy blood phases during piston descent. In either instance, unfortunately the separation step becomes aborted.
Lawhead, in US. Pat. application Ser. No. 228,573 filed Feb. 23, 1972, made an advance over the method and apparatus of Coleman by introducing spools or partitioning assemblies for use with rigid tubular containers for effecting either the physical or complete physical and chemical partitioning of two centrifugally separated fluid phases. These spools have a central axial orifice, a resilient, annular, container-contacting wiper portion and an integral annular skirt portion. By having specific gravities intermediate those of the separated fluid phases, the spools are adapted to move downwardly in the tubular containers, in response to centrifugal force, only to the vicinity of the fluid phase interface, with fluid flow occurring freely only through the spool central axial orifice. Partitioning of the separated phases is effected by the combination of the spool in conjunction with either a natural plug of the heavy phase fluid or afloat me'mber'having a similar specific gravity.
While the Lawhead device produces excellent sealing between the separated phases, it does require different diameter parts for different diameter tubes, which of course is an economic disadvantage in a low unit cost system.
Weichselbaum, in US. Pat. No. 3,464,890, sets forth a method of separating plasma from whole blood which comprises bringing into contact with the blood a separating amount of inert particulate material, e.g., polystyrene beads having a coating of anti-coagulant and having a specific gravity intermediate that of plasma and blood. This loose material is placed into the blood sample prior to phase separation and upon separation these particles tend to establish a barrier between the plasma and cells. This system, however, will not tolerate any subsequent jarring or unusual motion since this will tend to destroy the barrier. Furthermore, this system will not tolerate shipping and cannot be utilized for mailing to testing laboratories.
Adler, in US. Pat. No. 3,647,070, sets forth a method and apparatus for a barrier at the interface between plasma and packed cells in centrifuged blood samples, which barrier means are adapted to sink through the plasma layer, and upon being wetted and expanded by the plasma, expanded into firm contact with each other and the walls of the container to form a barrier. While this system appears to be quite workable, it is limited to post centrifugation insertion of the barrier means which is a definite disadvantage from the cost, time and contamination standpoint. I
The use of silicones for centrifuge fractionating of blood samples is well known and is set forth in articles by Seal, S. H. in Cancer. 1959 12:590-595; McCrea, L. E. in J. ufUrol. 1961. 85: 1006-1010; as well as Morgan M. C. and Szafir j. J. in Blood. 1961. 18:89-94. These articles basically describe the use of silicone fluids (blended to specific gravities intermediate those of the two phases sought to be separated) with blood samples, with the silicone fluid, upon centrifugation, forming a fluid barrier between the desired two phases. However, since the barrier is only a fluid barrier the desired phase cannot be removed by decanting and even in pipetting there is a problem of possible contamination of the removed phase with silicones. Furthermore, these liquid barriers will neither tolerate any subsequent jarring nor are they adaptable to shipping. 1
SUMMARY OF THE INVENTION The instant invention, both in terms of apparatus and method, responds to each of the previously-described prior art shortcomings in a manner so as to completely eliminate any further concern regarding such problems.
The several embodiments of the partitioning assemblies and partitioning or seal members of this invention are utilized with containers that are adapted to serve as fluid collection or fluid retaining tubes.
The partitioning or seal members include a predetermined or separating amount of a gel-like material, preferably hydrophobic, substantially thixotropic and generally inert to the separated fluid phases that are to be partitioned. This gellike material, such as a mixture of a silicone fluid and hydrophobic silicon dioxide powder, which has a specific gravity intermediate those of the fluid phases, is positioned within the container either before or after fluid collection. Due to its specific gravity, the gel-like material is adapted to move within the container in response to centrifugation, with the gel-like material being adapted to stop moving when it reaches the vicinity of the fluid phase interface. The gel-like material thereupon is further adapted to make a transversely-continuous, semi-rigid, contact seal with an annular portion of the container inner surface, thereby effecting a seal that physically and chemically partitions the fluid phases.
While the gel-like material may be used by itself to form a semi-rigid partitioning or seal member, it may also be used in combination with a spool member having a container-contacting outer surface portion and a central axial orifice. The spool member, which is preferably initially positioned below the container stopper or closure, by having a specific gravity that is intermediate those of the separated fluid phases, is adapted to move downwardly within the container in response to centrifugal force. The fluid phases flow freely only through the spool central axial orifice, with the spool being adapted to stop moving downwardly when it reaches the vicinity of the fluid phase interface. The gel-like material, which in this combination is preferably initially located adjacent to the bottom of the container, by reason of its specific gravity, moves upwardly within the container and is adapted to make a transversely continuous semi-rigid contact seal with at least an annular surface portion of the spool central axial orifice.
The partitioning or seal members of this invention may also be utilized to partition at least three differing density phases of a separated multi-phase fluid specimen at positions substantially at the interfaces of these fluid phases. This three-phase partitioning may be accomplished by using first and second gel-like material having specific gravities intermediate those of the firstsecond and second-third differing density phases, respectively. These gel-like materials are adapted to make separate transversely-continuous, semirigid, contact seals with different annular portions of the container inner surface thereby effecting seals that partition the three separated phases.
.The partitioning assemblies and partitioning or seal members of this invention may be utilized in several different operational sequences. One operational sequence applies specifically to a fluid collection and partitioning assembly that is intended to remain closed (vacuum sealed) from the time of manufacture through sampling, preparation and centrifugation of its contents until the lighter phase is removed after centrifugation.
In another operational sequence, the partitioning or seal member is hand-inserted or dispensed into an opened collection tube (i.e., at atmospheric pressure) after sample collection, prior to centrifugation.
In the closed system concept sequence, the gel-like material may be positioned anywhere within the collection tube, while in the hand-insertion concept sequence, the gel-like material is preferably dispensed into the tube either as a floating capsule or positioned on the side of the tube below the tube closure.
When three or more phase partitionings are desired, both closed system and hand insertion concept sequences, as well as combinations thereof, may be employed, with one or more centrifugation steps being required.
One method of establishing the partitioning of heavier phase from the lighter phase of a centrifugally separated fluid specimen within a container involves providing the container with a predetermined amount of a gel-like material having a specific gravity intermediate those of the separated phases. Moving the gel-like material within the container through at least one of the fluid phases (in response to centrifugal force) establishes a flow of at least one of the fluid phases within the container. A transversely-continuous semi-rigid contact seal is established with an annular portion of the container inner surface when the gellike material reaches a position in the vicinity of the fluid phase interface thereby partitioning the lighter and heavier fluid phases. Thereafter the applied force is terminated.
Other advantages and features of the instant invention will be understood from the following description in conjunction with the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. I illustrates one of the fluid collection and parti tioning assemblies of this invention, ready for use, with the partitioning or seal member in the form of a gel-like material being initially position adjacent to the normally closed end of the tubular container.
FIG. 2 is the assembly of FIG. I after theintroduction of a homogenized fluid sample thereinto.
FIG. 3 illustrates the assembly of FIG. 2 shortly after the start of centrifugation, which begins to separate the homogenized sample into at least two differing-density fluid phases, with the gel-like material beginning to move away from its initial position.
FIG. 4 illustrates that in the assembly of FIG. 3, as centrifugation continues, the gel-like material is approaching the interface between the two differingdensity fluid phases.
FIG. 5 illustrates the assembly of FIG. 4i upon the completion of centrifugation, with the gel-like material being located at the interface between the differingdensity fluid phases and making a transversely continuous contact partition or seal to thereby physically and chemically partition the two separated phases.
FIG. 6 illustrates another embodiment of the fluid collection and partitioning assemblies of this invention, having a spool poised beneath the closure member of the container and having a predetermined amount of gel-like material positioned adjacent to the naturally closed end of the container, with the differing density fluid being disposed therebetween.
FIG. 7 illustrates the assembly of FIG. 6 upon the completion of centrifugation, with the spool and gellike material being located at the interface between the differing density fluid phases and coacting to make a transversely-continuous contact seal to thereby partition these phases.
FIG. 8 is a sectional view, partially broken away. of one of the fluid collection and partitioning assemblies of this invention wherein the gel-like material is dispensed into the fluid collection assembly after the fluid collection is completed.
FIG. 9 is a sectional view, partially broken away, of another embodiment of the fluid collection and partitioning assemblies of this invention, having separatelypositioned first and second gel-like materials of differing densities and at least a three-phase fluid specimen disposed therebetween.
FIG. It) illustrates an assembly, such as that of FIG. 9, upon the completion of centrifugation, with the first and second gel-like materials being located in the form of transversely continuous partitioning members or contact seals at the interfaces between the first-second and the second-third differing density phases, respectively.
' DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring now to the drawings :in detail, FIGS. 1-5 illustrate one of the fluid collection and partitioning assemblies or container assemblies of this invention both in terms of the various components in correct relation ship to each other as well as the operational sequence of the various parts thereof.
FIGS. I-5 depict a fluid collection and partitioning assembly, more specifically, a blood collection and partitioning assembly or container assembly II consisting of a container or collection tube 12; a predetermined amount of a gel-like material 30; and a stopper or closure 2Q; all of which will now be described in more detail.
Collection tube I2, which is preferably made of glass, plastic or other material, and which is preferably also transparent, has a normally closed. bottom end M and an open upper end I6 for receiving a self-sealing stop per or closure 20 formed of medical grade butyl rubber or other suitable material. Closure 20 may be of the shape and material described herein or it may be of other suitable known types. Stopper 20 as shown, is shaped so as to have a flanged end. 22 which abuts and overlies annular end face I8 of collection tube open end 16. Stopper 20 is further provided with a diaphragm or septum 24lwhich forms a transverselycontinuous seal with an annular surface portion of tube inner wall surface I3. Stopper 20, together with collection tube I2, defines a sealed, closed fluid receiving chamber 26, which in the arrangement shown in F I6. I is adapted, (after previously having been evacuated) to maintain a negativepressure (vacuum) of about 24 inches Hg for an extended period of time. Thus. stopper 26), serves as a sealing closure to preserve the interior vacuum and provides a septum 24 through which the sampling needle (not shown) can reach chamber 26 without destroying its integrity. No invention is claimed for either the previously described collection tube 12 or stopper 20, per se.
Again, as shown in FIG. I, a predetermined amount of a gel-like material 30 preferably is initially positioned adjacent to closed end M of tube 112. This pre determined or separating amount (such as about 1 ml) of gel-like material 30 preferably is hydrophobic, thixotropic and generally inert to body fluids. One example of such a gel-like material is a mixture ofa silicone fluid and very fine hydrophobic silicon dioxide powder. I-Iydrophobic silicon dioxide (SiO may be defined as silicon dioxide that is treated so as to repel water, with one example of a hydrophobic silicon dioxide powder being Silanox 101 (manufactured by the Cabot Corporation of Boston, Massachusetts and described in Cabot brochure SGEN-l) hydrophobic fumed silicon dioxide, which is a fumed silicon dioxide having trimethyls'ilyl groups bonded to the surface thereof. Another example of a hydrophobic silicon dioxide powder is AEROSIL R972 (sold by DEGUSSA INC. Pigments Div., New York, NY. and described in Technical Bulletin 31 wherein the silicon dioxide is rendered hydrophobic by reacting the silanol groups on the surface with dimethyl dichlorsilane.
Silicon fluid may be defined as a polysiloxane liquid such as for example DOW Corning 360 Medical Fluid (a dimethyl polysiloxane liquid manufactured by the DOW CORNING Corporation of Midland, Michigan and described in DOW CORNING Bulletins CPO-1072, March, 1972 and CPO-158-1, March 1972). Other examples of silicone fluids are DOW CORNING 200 and 510 (a methylphenyl polysiloxane) fluids.
The following specific example of a gel-like material is given in illustration of the present invention and is not intended to be limiting on the invention. One hundred grams of DOW CORNING 360 Medical Fluid (350 centistokes; specific gravity about 0.97) were mixed with 15.7 grams of Silanox 101 silanemodified silicon dioxide (specific gravity about 2.2) to produce 115.7 grams of a gel-like material having a specific gravity of about 1.05.
Table 1 illustrates, among others, a number of mixtures of gel-like materials that may be utilized in this invention:
Sample about 1.06, with the preferred range being 1.04-1.055.
With reference to one of the operational sequences of this invention, FIG. 1 illustrates fluid collection and partitioning assembly 11, ready for use, with stopper 20 together with collection tube 12 defining a sealed, closed evacuated fluid receiving chamber 26. Con tained within chamber 26 is gel-like material 30 which is positioned adjacent to normally closed end 14 of tube 12.
The FIG. 2 assembly depicts the FIG. 1 assembly with the addition of a multi-phase fluid sample 34, such as whole blood. After a correct venipuncture has been made on the patient, the inner or butt end of the needle (not shown) is pushed through stopper diaphragm portion 24, thereby permitting the vacuum within the assembly to draw blood freely into tube 12.
FIG. 3 illustrates the assembly of FIG. 2 shortly after the start of centrifugation which begins to separate homogeneous fluid sample 34 into a lighter phase 38 and a heavier phase 42. The interface 44 between lighter and heavier phases 38 and 42, respectively, is shown, for the sake of clarity, in the form of a dash on either 'side of tube 12. During centrifugation, heavier phase tial position.
The FIG. 4 assembly shows the FIG. 3 assembly, as centrifugation continues, with gel-like material 30 still in an elongated form, but now fully removed from its initialposition, with the upper end of gel-like material 5111- Viscosity Grams of Grams of Grams of Resulting No. cone (centistokes) Silicone S-101 R-972 S.G.
Table l DC-360 is DOW CORNING 360 Medical Fluid. DC-SlO is DOW CORNING 510 Fluid. S-lOl is Silanox" 101 hydrophobic 510,. R-972 is DEGUSSA R 972 hydrophobic Si0,.
It should be noted that the specific gravity (S.G.) of whole blood is 1.05l.06 while the S.G. of the light phase (blood serum) is 1.02-1.03 and the S.G. of the heavy phase (blood cells) is 1.08-1.09. Therefore the specific gravity of gel-like material 30 has to be below that of the heavy phase and above that of the light phase, i.e., generally in the range from about 1.035 to 30 being located in the vicinity of fluid phase interface 44. It should be noted that a thin layer 32 of gel-like material remains at its initial position, i.e., at tube bottom 14.
It should be noted that due to the resilience of the gel-like material 30, movement of fluid can occur in either direction. i.e., red blood cells. fibrin or other heavy-phase bodies can usually move downwardly through gel-like material 30 under the persuasion of centrifugal force. At the same time, any lighter phase fluid remaining below gel-like material 30, again under the persuasion of centrifugal force, can usually move upwardly through material 30. The operation of the instant invention is such that it does not differentiate be tween gases and liquids and permits both to flow through material 30 without prejudice. The flow, either of gases or liquids, is neither restricted nor otherwise influenced in any way by the gel-like material 30. Each phase is free to seek its own flow path and its ultimate position within tube I2 is influenced solely by the persuasion of centrifugal force.
FIG. illustrates the assembly of FIG. 4- upon the completion of centrifugation, i.e., all the parts are now in final position. Upon the completion of centrifugation the maverick lighter components or cells of heavier phase 42 (previously in or above material 34)), still having a specific gravity greater than that of material 30, have now eased into or through material 30., with mate rial resting at a density level equivalent to its own specific gravity. As shown in FIG. 5 member 3t) has now consolidated so as to make a transverselycon'tinuous semi-rigid contact seal or partitioning member 48 with an annular surface portion of tube inner surface 13. If the homogenized test fluid 34 is whole blood, then the heavier phase 42 is now blood cells and the lighter phase may be either blood serum or blood plasma, depending upon whether or not the whole blood sample was coagulated or not coagulated, respectively.
It should be understood that the thickness or axial dimension of the transversely-continuous contact seal made by partitioning or seal member 4% is, among other things, of course also dependent upon the amount of gel-like material that is initially introduced into tube 12. In addition, the seal need not be of uniform shape or thickness across its transverse dimension 1 as long as it has at least one transversely-continuous portion. Uniformity of the seal is influenced by such factors as the viscosity of the gel-like material, the amount of material present, the speed and type (horizontal or anglehead centrifuge) of centrifugation (and resulting g-force) as well as the centrifugation time.
It should be noted that gel-like material 30, which makes up transversely-continuous semi-rigid seal member 48, is substantially thixotropic, i.e., at rest it acts substantially like a material in a thixotropic state. It is not intended that this definition of the gel-like material, which also may be described as semisolid, semi-rigid, substantially non-flowable, or resistant to flow at rest, be a limitation on the invention herein described, since the behavior of the material is, at this time, not yet completely subject to a full exacting explanation. It should suffice to say that gel-like material 30 appears to have a very high viscosity, is thermoplastic in nature, will act substantially as a fluid during centrifugation and will again set up to a gel when allowed to stand.
In the form of seal-member 48, gel-like material 30 is substantially rigid and allows decanting of the lighter fluid phase from the tube or container 32 without disrupting its seal with the tube inner surface. In addition, the partitioned sample will readily tolerate subsequent jarring and is entirely adaptable to shipping (such as to a remote laboratory for example).
While the previously-described examples of gellike materials 30 are mixtures of silicone fluids and silicone dioxide powders it must be understood that these mixtures are not to be considered as limiting this invention. Any gel-like material is useful in the context of this invention if it meets the following basic requirements:
1. Specific gravity (or density) intermediate between those of the two fluid phases sought to be sepa rated.
2. Non-interaction with the fluid phases sought to be separated.
3. Substantially non-flowable (semi-rigid) at rest.
In the previously-described examples. the silicon fluid may be thought of as a liquid or base material (an oil) and the silicon dioxide powder as a solid (a filler), with the latter serving both to adjust the specific gravity of the former to the desired value and to gel the oil, i.e., to convert it into a semi-rigid gel-like material or grease (with the terms gel-like and grease being used synonymously). Thus, as long as they meet the previously noted three basic requirements, almost any liquid and filler combination may be utilized, with examples of oils including esters of polyacids (such as dioctylsebacate, dibutylphthalate and tributylphosphate) and min eral oils (hydrocarbons). Examples of fillers include titania, zirconia, asbestos, wood flour and finely divided organic polymers (such as polyethylene, polypropylene, fluorocarbons and polyesters, etc.) In addition, depending on the specific gravity of the base material. the fillers may be used to either increase or decrease the specific gravity of the former. Furthermore, again as long as the three basic requirements are met, the gellike material may be made up of but a single component (such as a silicone) material or may be mixtures of one or more base materials and one or more fillers.
Up to this point the only operational sequence described has been one wherein gel-like material 30 is initially positioned adjacent to closed end 14 of tube 12, as shown in FIGS. 15. However, other initial placements of material 30 are entirely possible, i.e., material 30 may be placed anywhere within fluid receiving chamber 26. For example, as shown in FIG. 9, a predetermined amount of gellike material 30a may be positioned on a portion of tube inner'surface 13 below stopper 20. When used in the sequence shown in FIGS. ll-S, in lieu of material 30, upon centrifugation, gel-like material 3% (which is substantially similar to material 30), by virtue of its specific gravity (l.035l.()6) will move downwardly through lighter phase 38 (specific gravity 1024.03) and eventually rest at the density level equivalent to its own specific gravity. The end result, as shown in FIG. 5, will be substantially the same regardless of whether material 30 moves up from tube bottom M or material 31M moves down from the vicinity of stopper 20.
The operational sequences described up to now have been limited to a fluid collection and partitioning assembly Ill consisting of collection tube 12, stopper 2d and contact seal or partitioning member 48, wherein tube 12 together with stopper 20 defines a sealed, closed, evacuated fluid receiving chamber 26. This operational sequence, as shown in FIGS. 1-5, applies specifically to a fluid collection and partitioning assembly that is intended to remain closed from the time of manufacture, through sampling, preparation and centrifugation of its contents until the lighter phase is to be removed after centrifugation. Of necessity, the gel-like material must be placed into the tube (prior to the evacuation thereof) at the factory. This sequence will hereinafter be referred to as the closed system concept to differentiate it from a hand or user insertion concept.
In an operational sequence utilizing the hand insertion concept, a predetermined amount of gel-like material such as for example 30a in FIG. 9 or 30b (also substantially similar to material 30) in FIG. 8 is dispensed into an opened collection tube after sample collection, preferably either after coagulation has been completed or after partial phase separation has been effected (upon completion of coagulation). The gellike material can be inserted into an opened collection tube even before coagulation has been completed, however, since blood cells exhibit a tendency to harden on the walls of the opened tube it is preferable to delay the opening of the collection tube until coagulation has been completed therein.
With reference to the operational sequence utilizing the hand-insertion concept, FIGS. 2 and 3, sans material 30, may be utilized to illustrate a well-known evacuated blood collection tube assembly comprised of collection tube 12 and stopper 20. Once blood sample 34 has been introduced into this assembly and preferably eitherafter coagulation (FIG. 2) or after partial phase separation (FIG. 3), stopper 20 is removed and gel-like material 30a (FIG. 9), or 30b (FIG. 8) is dispensed into tube 12.' Thereafter, stopper 20, in accordance with good medical practice, preferably is placed back on tube 12 and centrifugation can begin (FIG. 2, sans material 30) or be continued (FIG. 3, sans material 30). Hereinafter, the operational sequence proceedsin a manner and with a result identical to that already described with reference to the closed system concept. Substantially similar results are obtained regardless of whether the gel-like material is dispensed directly into the fluid sample, as is material 30b in FIG.
8, or positioned on an inner surface portion of the tube, as is material 300 in FIG. 9.
FIGS. 6 and 7 disclose another embodiment of the fluid collection and partitioning assemblies of this invention wherein a predetermined amount of gel-like material 30 coacts with a spool 52to effect complete physical and chemical partitioning of two differingdensity fluid phases. The assembly shown in FIG. 6, i.e., tube 12, stopper 22, gel-like material 30, fluid 34 and spool 52, can be the result of at least two different concept sequences, namely: l a closed system concept wherein spool 52 and gel-like material 30, are both located in a sealed, closed, fluid receiving chamber 26 as shown in FIG. 1., into which fluid sample 34 has thereafter been introduced, or (2) a hand-insertion concept wherein spool 52 is introduced into a collection tube 12 (upon stopper removal) after fluid sample 34 has been collected (as shown in FIG. 2).
Spool 52, which has an annular, generally cylindrically-shaped main body portion 54 having a diameter less than the inside diameter of collection tube 12, also has an upper. outwardly-tapering, annular. resilient, wiper or outer surface portion 56 having a maximum outer free diameter greater than that of portion 54, with portion 56 being adapted to sealingly contact tube inner wall surface 13. Spool 54 also has a lower skirt portion 58 and a central axial orifice 62. Spool 52 may be of the type disclosed in co-pending US. Pat. application Ser.
No. 228,573 filed Feb. 23, 1972 (which is a continuation in part of application Ser. No. 178,274 filed Sept. 7, 1971) and is also assigned to the assignee of this invention.
With reference to the operational sequence of the FIG. 6 and 7 embodiments. FIG. 6 shows the fluid collection and partitioning assembly immediately prior to centrifugation, while FIG. 7 depicts the assembly upon the completion of centrifugation. During centrifugation, gel-like material 30 behaves in the manner already described with reference to FIGS. 3 and 4 except that material 30 coacts with spool 52 to make a transverse ly-continuous contact seal to separate phases 38 and 42. Spool 52, which is preferably made .of a resilientmaterial such as medical grade rubber, preferably has a specific gravity intermediate those of the fluid phases to be separated (in the case of human blood the intermediate S.G.=l.035l.06). At the start of centrifugation, spool 52, because of its specific gravity, starts to move downward, away from the vicinity of stopper 20, toward lighter phase 38, which in turn flows upwardly through spool central axial orifice 62. It should be noted that all fluid flow takes place through orifice 62 and no fluid is permitted, nor can it possibly take place, between the outer surface of spool 52 and tube inner surface 13. Furthermore, fluid flow can occur through orifice 62 in either direction, depending upon the initial position of spool 52 relative to the various density components of the fluid which are to be separated. The operation of spool 52 is such that it does not differentiate between gases or liquids and each phase is free to seek its own flow path and its ultimate position within tube 12 is influenced solely by the persuasion of centrifugal force. Upon the completion of centrifugation (FIG. 7) the skirt portion 58 of spool 52 has entered heavier phase 42 and gel-like material 30, again as a result of the applied centrifugal force, has started to enter lighter phase 38 by extending at least partially through spool central axial orifice 62. Gel-like material 30 is adapted to make a transversely-continuous contact seal member 64 with at least an annular portion of orifice 62. Thus spool 52 together with gel-like material 30 forms a transversely-continuous partitioning assembly 66 with an annular surface portion of tube inner surface 13. Basically, spool 52 acts as a constriction within tube 12 since sealing of the differing density fluids from one another at tube inner surface 13 has been continuous (by reason of spool wiper 56) since spool 52 began its descent through the fluid and the separated fluid phases have never been in contact with each other in this area. Final sealing is accomplished within spool central axial orifice 62 due to the action of gel-like material 30, and is purposefully designed to occur at or just above the fluid phase interface 44 to ensure the absence of any heavy phase components within the lighter phase sample. The exact positioning of gel-like material 30 with reference to spool skirt portion 58 and orifice 62 depends upon the amount and viscosity of material 30 as well as the centrifugal force applied.
Up to this point the embodiments described have been limited to the partitioning of two differing-density fluid phases of a centrifugally separated fluid specimen at the interface of the fluid phases. Often it may be desirable to partition at least three differing-density phases of centrifugally separated muIti-phase fluid specimen at positions substantially at the interfaces of the differing-density fluid phases. This goal can be accom- 13% plished by utilizing n-l differing-density gel-like materials to partition n number of differing-density fluid phases.
FIG. 9, which is a partially broken away sectional view of another embodiment of the fluid collection and partitioning assemblies of this invention, shows a first gel-like material 39, having a first specific gravity, adjacent to tube bottom I4 and a second gel-like material 30a, having a second specific gravity, attached to tube inner wall 13 in an area below stopper 29. Art at least three-phase fluid 68 having first or heaviest density 70, second or intermediate density 72, and third or lightest density 74 fluid components is also contained within tube 12. Gel-like material 20 has a specific gravity intermediate those of first and second fluid phase components 7t), 72, respectively, while material 390 has a specific gravity intermediate those of second and third fluid phase components 72, 74 respectively.
FIG. 10 which illustrates an assembly, such as that of FIG. 9, upon the completion of centrifugation, with first and second gel-like materials 39, 39a, being located in the form of transversely-continuous semi-solid partitioning members or contact seals 48, lfla, between first-second (7tlt-72) and second-third (72-74) differing density fluid phases, respectively. As already previously described, gel-like material 30 moves upward away from tube bottom 14 and material 30a moves downward away from the area below stopper 20, under the influence of centrifugal force until they reach the fluid gradient levels, i.e., the interfaces closest to their own specific gravity.
The end result, i.e., the partitioning of fluid phases 70, 72 and 74 shown in FIG. 10 may be achieved in a number of different operational sequences. In the closed system concept technique, both materials 30 and 30a are contained (at tube bottom M and in the area below stopper 20, respectively) within a closed, evacuated fluid receiving chamber, into which fluid sample 68 is thereafter introduced (see FIG. 9). A subsequent single centrifugation step produces the partitioning shown in FIG. Ill), with both materials 30 and 30a leaving thin layers of gel-like materials 32 and 32a respectively at their initial positioning areas.
In the hand insertion concept technique, after fluid sample 68 has been collected, a first gel-like material, having a first specific gravity intermediate those of heaviest and intermediate fluid phases 70, 72, respectively, is dispensed into collection tube 12, either in the shape of material 30b (FIG. 8) or material 3th: (FIG. 9). Thereafter, the assembly is centrifuged a first time and this first gel-like material forms transverselycontinuous partitioning or seal member 4% between phases 70 and 72. Then, a second gel-like material, having a second specific gravity intermediate those of the intermediate and lightest fluid phases, 72 and 74, respectively, is dispensed into collection tube 112, again either in the shape of material 30b (FIG. 9) or material 30a (FIG. 9). After a second centrifugation, the second gel-like material forms transversely-continuous partitioning or seal member Ma between phases 72 and 74.
Several combination closed system and hand insertion" concept techniques are also possible. In one such combination, a first gel-like material, having a specific gravity intermediate those of heaviest and in-- termediate phases 7t), 72, respectively, is contained within a closed, evacuated fluid receiving chamber (FIG. I). After the introduction of fluid 68 a second gel-like material, having a specific gravity intermediate those of the intermediate and lightest phases 72, 74. re
spectively, is dispensed into collection tube 12 (either into collection tube 12 (in either of the shapes as previously noted) and a second centrifugation step then forms a second transversely-continuous member 48a between phases 72 and '74.
It should be noted that with any multi-phase fluid, having three or more phases, an initial separating of the heaviest phase from the remaining phases can be accomplished by means of either of the two phase separation techniques herein discussed, e.g. by means of partitioning or seal member 4 8 (FIG. 5) or partitioning assembly 66 (FIG. 7), using either the closed system or hand-insertion concept techniques. Further separations of the remaining phases can thereafter be accomplished by successively dispensing in gel-like materials of decreasing specific gravities and successively centrifuging the collection tube assembly. For example, a whole blood sample may be initially be separated into blood cells and blood serum and thereafter, while remaining in thesame container, the blood serum may be further fractionated into separate components. Whole human blood has a given, generally quite uniform, specific gravity between 1.05 and 1.06. Centrifuged blood however has many layers or constituents of varying specific gravities, from the heaviest at the bottom to the lightest at the top, with the greatest visible demarcation occurring at the serum/red cell interface.
The principles of this invention may be utilized in partitioning assemblies for fluids other than human blood, e.g., any fluid separable into at least two differing density phases may be separated using a gel-like material (or a gel-like material and spool combination) having a specific gravity intermediate those of the phases sought to be separated. Any gel or gel-like material that is hydrophobic, substantially thixotropic, and generally inert to the fluids to be separated, may be utilized.
While the invention has been described in connection with possible forms or embodiments thereof, it is to be understood that the present disclosure is illustrative rather than restrictive and that further changes or modifications may be resorted to without departing from the spirit of invention or scope of the claims which follow.
11. A fluid collection and partitioning assembly for collecting a specimen of blood within a sealed fluid collection chamber, centrifically separating the heavier and lighter fluid phases of said blood specimen, and physically and chemically partitioning the separated phases, comprising:
a. a container having an open end and a closed end;
b. gel-like means initially positioned within said container adjacent said closed end for forming a transversely continuous contact seal with an annular surface portion within said container at a subsee. subjecting said specimen and gel-like means to a quently formed interface between said heavier and lighter phases;
said container and for defining a closed fluid collection chamber containing said gel-like means therewithin, said closure means being pierceable closure means for vacuum-sealing said open end of centrifugal force to separate said fluid specimen into a heavier phase and a lighter phase and simultaneously move said gel-like means toward the interface of said phases; and
f. establishing a continuous semi-rigid gel-like seal across the interior of said container between said by a needle for supplying blood to said closed fluid collection chamber which is adapted to draw the 0 blood specimen therewithin;
d. said gel-like means being a thixotropic material and including a mixture of a fluid which is generally inert to body fluids and a powdered inorganic filler; and
heavier phase and said lighter phase within said container.
3. A method of collecting a multiphase fluid specimen, separating said specimen into at least two differing-density phases, and partitioning said phases comprising:
a. providing an open-ended container with thixotrosaid gel-like means having a. specific gravity interlighter phase of a centrifugally separated fluid specimen within a container which comprises:
providing a container having a closed end and an open end;
initially positioning thixotropic gel-like means having a. specific gravity intermediate those of said lighter and heavier fluid phases within said container in spaced relation from said open end; evacuating and sealing said container to provide a closed fluid collection chamber therewithin; supplying a fluid specimen to said closed chamber;
pic gel-like material having a specific gravity intermediate those of the two phases of a fluid specimen to be collected and separated;
b. vacuum-sealing the open end of said container,
containing said gel-like material, with a needlepierceable closure;
c. drawing a specimen through said closure; d. applying centrifugal force to said specimen and gel-like material and simultaneously forcibly moving the phases of said specimen and said gel-like material toward relative positions within said container corresponding to their respective specific gravities;
. terminating said centrifugal force after said specimen -has separated into differing-density phases and a substantial portion of said gel-like material has reached a position intermediate said phases, and
. at such position, utilizing said gel-like material to partition said separated differing-density phases.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3508653 *||Nov 17, 1967||Apr 28, 1970||Charles M Coleman||Method and apparatus for fluid handling and separation|
|US3761408 *||May 8, 1972||Sep 25, 1973||Jae Yoon Lee||Method and apparatus for separating blood constituent components|
|US3779383 *||Apr 25, 1972||Dec 18, 1973||Becton Dickinson Co||Sealed assembly for separation of blood components and method|
|US3780935 *||Jul 10, 1972||Dec 25, 1973||Lukacs & Jacoby Ass||Serum separating method|
|US3782548 *||Dec 7, 1972||Jan 1, 1974||J Bowen||Serum skimmer|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3920549 *||Mar 18, 1974||Nov 18, 1975||Corning Glass Works||Method and apparatus for multiphase fluid collection and separation|
|US3920557 *||Feb 27, 1974||Nov 18, 1975||Becton Dickinson Co||Serum/plasma separator--beads-plus-adhesive type|
|US3929646 *||Jul 22, 1974||Dec 30, 1975||Technicon Instr||Serum separator and fibrin filter|
|US3957653 *||Apr 3, 1975||May 18, 1976||Becton, Dickinson And Company||Apparatus for collection, separation and isolation of blood|
|US3957654 *||Jun 5, 1975||May 18, 1976||Becton, Dickinson And Company||Plasma separator with barrier to eject sealant|
|US3963119 *||Sep 16, 1974||Jun 15, 1976||Lucaks And Jacoby Associates||Serum separating apparatus|
|US3976579 *||Jul 10, 1975||Aug 24, 1976||Becton, Dickinson And Company||Novel assembly|
|US3977982 *||Jan 20, 1975||Aug 31, 1976||Corning Glass Works||Controlling viscosity of silica-silicone oil gels|
|US3986962 *||Jul 10, 1975||Oct 19, 1976||Becton, Dickinson And Company||Novel assembly for separating blood|
|US3997442 *||Sep 15, 1975||Dec 14, 1976||Corning Glass Works||Method of separating and partitioning differing density phases of a multiphase fluid|
|US4012325 *||May 27, 1975||Mar 15, 1977||Eastman Kodak Company||Biological fluid dispenser and separator|
|US4018564 *||Nov 24, 1975||Apr 19, 1977||General Electric Company||Silicone composition for analyzing blood samples|
|US4050451 *||Aug 13, 1976||Sep 27, 1977||Eastman Kodak Company||Blood collection and separation device|
|US4052320 *||Jul 8, 1976||Oct 4, 1977||Eastman Kodak Company||Telescoping serum separator and dispenser|
|US4055501 *||Jan 16, 1976||Oct 25, 1977||Sherwood Medical Industries Inc.||Fluid collection device with phase partitioning means|
|US4071316 *||Dec 20, 1976||Jan 31, 1978||General Electric Company||Silicone composition for analyzing blood samples|
|US4083784 *||Apr 28, 1977||Apr 11, 1978||Corning Glass Works||Stabilized blood separating composition|
|US4088582 *||Jan 16, 1976||May 9, 1978||Sherwood Medical Industries Inc.||Blood phase separation means|
|US4091802 *||Feb 17, 1976||May 30, 1978||Eastman Kodak Company||Vented liquid collection device|
|US4101422 *||May 11, 1977||Jul 18, 1978||Emery Industries, Inc.||Copolyesters useful in blood separation assemblies|
|US4136036 *||Feb 22, 1978||Jan 23, 1979||Eastman Kodak Company||Collection and dispensing device for non-pressurized liquids|
|US4147628 *||Jan 23, 1978||Apr 3, 1979||Becton, Dickinson And Company||Blood partitioning method|
|US4169060 *||Oct 25, 1977||Sep 25, 1979||Eastman Kodak Company||Blood-collecting and serum-dispensing device|
|US4172803 *||Oct 20, 1977||Oct 30, 1979||Terumo Corporation||Liquid separating composition and apparatus for applying said composition|
|US4180465 *||Dec 19, 1975||Dec 25, 1979||Sherwood Medical Industries Inc.||Fluid collection device with phase separation means|
|US4190535 *||Jul 10, 1978||Feb 26, 1980||Corning Glass Works||Means for separating lymphocytes and monocytes from anticoagulated blood|
|US4235725 *||Aug 16, 1978||Nov 25, 1980||Owens-Illinois, Inc.||Sterile blood-collecting and separating device|
|US4246123 *||Apr 20, 1979||Jan 20, 1981||Sherwood Medical Industries Inc.||Fluid collection device with phase partitioning means|
|US4257886 *||Jan 18, 1979||Mar 24, 1981||Becton, Dickinson And Company||Apparatus for the separation of blood components|
|US4295974 *||May 5, 1980||Oct 20, 1981||Sherwood Medical Industries Inc.||Blood sample collection and phase separation device|
|US4333564 *||Jan 16, 1980||Jun 8, 1982||Sherwood Medical Industries Inc.||Method of controlling rheological properties of gel-like compositions|
|US4350593 *||Jun 25, 1979||Sep 21, 1982||Becton, Dickinson And Company||Assembly, compositions and method for separating blood|
|US4369117 *||May 12, 1980||Jan 18, 1983||American Hospital Supply Corporation||Serum separating method and apparatus|
|US4386003 *||Sep 17, 1981||May 31, 1983||Sherwood Medical Industries Inc.||Blood separating composition|
|US4534798 *||Nov 18, 1983||Aug 13, 1985||Sekisui Kagaku Kogyo Kabushiki Kaisha||Composition for partitioning blood components|
|US4555336 *||Aug 11, 1980||Nov 26, 1985||Becton, Dickinson And Company||Pour spout for container with improved pouring feature|
|US4555341 *||Aug 11, 1980||Nov 26, 1985||Becton, Dickinson And Company||Pour spout for a container with improved screening feature|
|US4567754 *||Mar 29, 1985||Feb 4, 1986||Wardlaw Stephen C||Measurement of small heavy constituent layer in stratified mixture|
|US4569764 *||May 4, 1981||Feb 11, 1986||Sherwood Medical Company||Collection device with phase partitioning means|
|US4640785 *||Dec 24, 1984||Feb 3, 1987||Becton Dickinson And Company||Separation of lymphocytes and monocytes from blood samples|
|US4707276 *||Apr 22, 1983||Nov 17, 1987||Sherwood Medical Company||Fluid collection device with phase partitioning means|
|US4751001 *||Sep 24, 1984||Jun 14, 1988||Becton Dickinson And Company||Blood partitioning apparatus|
|US4816168 *||Oct 28, 1986||Mar 28, 1989||Becton Dickinson & Company||Separation of lymphocytes and monocytes from blood samples|
|US4818386 *||Oct 8, 1987||Apr 4, 1989||Becton, Dickinson And Company||Device for separating the components of a liquid sample having higher and lower specific gravities|
|US4818418 *||Feb 3, 1988||Apr 4, 1989||Becton Dickinson And Company||Blood partitioning method|
|US4828716 *||Apr 3, 1987||May 9, 1989||Andronic Devices, Ltd.||Apparatus and method for separating phases of blood|
|US4844818 *||Oct 23, 1987||Jul 4, 1989||Becton Dickinson & Company||Method for separating the cellular components of blood samples|
|US4867887 *||Jul 12, 1988||Sep 19, 1989||Becton Dickinson And Company||Method and apparatus for separating mononuclear cells from blood|
|US4877520 *||Jun 6, 1988||Oct 31, 1989||Becton, Dickinson And Company||Device for separating the components of a liquid sample having higher and lower specific gravities|
|US4917801 *||Nov 2, 1987||Apr 17, 1990||Becton Dickinson And Company||Lymphocyte collection tube|
|US4954264 *||Feb 2, 1989||Sep 4, 1990||Becton-Dickinson And Company||Apparatus for separating mononuclear cells from blood and method of manufacturing and using the same|
|US4957638 *||May 9, 1989||Sep 18, 1990||Becton Dickinson And Company||Method for separating the cellular components of blood samples|
|US4994393 *||Feb 22, 1989||Feb 19, 1991||Becton, Dickinson And Company||Blood partitioning composition|
|US5019243 *||May 2, 1989||May 28, 1991||Mcewen James A||Apparatus for collecting blood|
|US5053134 *||Jan 17, 1990||Oct 1, 1991||Becton Dickinson And Company||Lymphocyte collection tube|
|US5169543 *||Mar 27, 1990||Dec 8, 1992||Nippon Paint Co., Ltd.||Serum separation sealant and fine resin particles using the same|
|US5265482 *||May 21, 1991||Nov 30, 1993||E. I. Du Pont De Nemours And Company||Method of sampling a container|
|US5271852 *||May 1, 1992||Dec 21, 1993||E. I. Du Pont De Nemours And Company||Centrifugal methods using a phase-separation tube|
|US5275933 *||Sep 25, 1992||Jan 4, 1994||The Board Of Trustees Of The Leland Stanford Junior University||Triple gradient process for recovering nucleated fetal cells from maternal blood|
|US5282981 *||May 1, 1992||Feb 1, 1994||E. I. Du Pont De Nemours And Company||Flow restrictor-separation device|
|US5308506 *||Dec 31, 1992||May 3, 1994||Mcewen James A||Apparatus and method for separating a sample of blood|
|US5354483 *||Oct 1, 1992||Oct 11, 1994||Andronic Technologies, Inc.||Double-ended tube for separating phases of blood|
|US5393674 *||Mar 8, 1993||Feb 28, 1995||Levine Robert A||Constitutent layer harvesting from a centrifuged sample in a tube|
|US5419835 *||Oct 13, 1993||May 30, 1995||E. I. Du Pont De Nemours And Company||Flow restrictor-separation device|
|US5437987 *||Jun 14, 1993||Aug 1, 1995||The Board Of Trustees Of The Leland Stanford Junior University||Triple gradient process with antibody panning to recover nucleated fetal cells from maternal blood|
|US5494590 *||Jun 11, 1992||Feb 27, 1996||Becton Dickinson||Method of using anticoagulant solution in blood separation|
|US5518615 *||Apr 22, 1994||May 21, 1996||Becton, Dickinson And Company||Blood compatible, shear sensitive gels|
|US5560830 *||Dec 13, 1994||Oct 1, 1996||Coleman; Charles M.||Separator float and tubular body for blood collection and separation and method of use thereof|
|US5736033 *||Dec 13, 1995||Apr 7, 1998||Coleman; Charles M.||Separator float for blood collection tubes with water swellable material|
|US5814220 *||Dec 11, 1996||Sep 29, 1998||Mitsubishi Chemical Corporation||Process for producing blood separating agent|
|US5853600 *||Sep 19, 1997||Dec 29, 1998||Beckman Instruments, Inc.||Axial spin blood separation system and method|
|US6017483 *||Jul 18, 1997||Jan 25, 2000||Becton Dickinson And Company||Receptacle with a fused coating on an interior surface and an injection molding process for forming the article|
|US6225123||Aug 14, 1997||May 1, 2001||Becton Dickinson And Company||Additive preparation and method of use thereof|
|US6238578||Dec 9, 1996||May 29, 2001||Sherwood Services Ag||Method for dispensing separator gel in a blood collection tube|
|US6376210||Jul 6, 1999||Apr 23, 2002||General Atomics||Methods and compositions for assaying analytes|
|US6458420 *||Aug 25, 1997||Oct 1, 2002||Dow Corning Toray Silicone Co., Ltd.||Water repellent for application to glass and water-repellent glass|
|US6534016||Nov 21, 2000||Mar 18, 2003||Richmond Cohen||Additive preparation and method of use thereof|
|US6610504||Apr 10, 2000||Aug 26, 2003||General Atomics||Methods of determining SAM-dependent methyltransferase activity using a mutant SAH hydrolase|
|US6793892 *||Oct 24, 2000||Sep 21, 2004||Volker Niermann||Device and method for separating components of a fluid sample|
|US7070939||Sep 26, 2001||Jul 4, 2006||The Scripps Research Institute||Methods for detecting vasculopathies and tumors|
|US7192729||Jan 10, 2002||Mar 20, 2007||General Atomics||Methods for assaying homocysteine|
|US7384760||Apr 30, 2004||Jun 10, 2008||General Atomics||Methods for assaying inhibitors of S-adenosylhomocysteine (SAH) hydrolase and S-adenosylmethionine (SAM)-dependent methyltransferase|
|US7673758 *||Mar 9, 2010||The Regents Of The University Of California||Collection tubes apparatus, systems, and methods|
|US8206638 *||Jun 26, 2012||The Regents Of The University Of California||Collection tubes apparatus, systems, and methods|
|US8318077 *||Nov 27, 2012||The Regents Of The University Of California||Collection tubes apparatus, systems, and methods|
|US8377395||Apr 29, 2011||Feb 19, 2013||Charles M. Coleman||Integrated blood specimen processor|
|US8394342||Mar 12, 2013||Becton, Dickinson And Company||Density phase separation device|
|US8580183||Nov 19, 2012||Nov 12, 2013||The Regents Of The University Of California||Collection tubes apparatus, systems, and methods|
|US8623278||Oct 11, 2012||Jan 7, 2014||Commissariat A L'energie Atomique Et Aux Energies Alternatives||System and method for the continuous extraction of a liquid phase of microsamples, and automated installation for taking them, for carrying out the extraction and taking measurements|
|US8747781||Jul 21, 2009||Jun 10, 2014||Becton, Dickinson And Company||Density phase separation device|
|US8794452||Aug 1, 2013||Aug 5, 2014||Becton, Dickinson And Company||Density phase separation device|
|US8950617 *||Jul 12, 2012||Feb 10, 2015||Universiti Putra Malaysia||Non-penetrative blood container and apparatus for vacuuming the same|
|US8998000||May 14, 2010||Apr 7, 2015||Becton, Dickinson And Company||Density phase separation device|
|US9079123||Aug 6, 2013||Jul 14, 2015||Becton, Dickinson And Company||Density phase separation device|
|US9333445||Jul 21, 2009||May 10, 2016||Becton, Dickinson And Company||Density phase separation device|
|US9339741||May 2, 2014||May 17, 2016||Becton, Dickinson And Company||Density phase separation device|
|US9364828||Aug 1, 2013||Jun 14, 2016||Becton, Dickinson And Company||Density phase separation device|
|US20010007315 *||Mar 9, 2001||Jul 12, 2001||Fiehler William R.||Method and apparatus for dispensing separator gel in a blood collection tube|
|US20030215389 *||Sep 26, 2001||Nov 20, 2003||Anthony Montgomery||Methods for detecting vasculopathies and tumors|
|US20040014083 *||Feb 24, 2003||Jan 22, 2004||Chong-Sheng Yuan||Detection of heteroduplex polynucleotides using mutant nucleic acid repair enzymes with attenuated catalytic activity|
|US20040059255 *||Sep 18, 2003||Mar 25, 2004||Dimitrios Manoussakis||High bias gel tube and process for making tube|
|US20050178218 *||Jan 26, 2005||Aug 18, 2005||Jean Montagu||Micro-volume blood sampling device|
|US20050244912 *||Apr 30, 2004||Nov 3, 2005||Chong-Sheng Yuan||Methods for assaying inhibitors of S-adenosylhomocysteine (SAH) hydrolase and S-adenosylmethionine (SAM)-dependent methyltransferase|
|US20060211038 *||May 23, 2006||Sep 21, 2006||Anthony Montgomery||Methods for detecting vasculopathies and tumors|
|US20070190148 *||Feb 14, 2006||Aug 16, 2007||Peter Cronin||Gel compositions, apparatuses and fluid separation methods|
|US20080047908 *||May 25, 2005||Feb 28, 2008||Eiken Kagaku Kabushiki Kaisha||Tool for Recovering Biological Samples and Method for Recovering Biological Samples|
|US20080132874 *||Nov 1, 2007||Jun 5, 2008||The Regents Of The University Of California||Collection tubes appratus, systems, and methods|
|US20080317630 *||Dec 21, 2007||Dec 25, 2008||Jean-Marc Reymond||System and method for the continuous extraction of a liquid phase of microsamples, and automated installation for taking them, for carrying out the extraction and taking measurements|
|US20100117269 *||Jan 21, 2010||May 13, 2010||The Regents Of The University Of California||Collection tubes appratus, systems, and methods|
|US20100160135 *||Jul 21, 2009||Jun 24, 2010||Becton, Dickinson And Company||Density Phase Separation Device|
|US20100288694 *||May 14, 2010||Nov 18, 2010||Becton, Dickinson And Company||Density Phase Separation Device|
|US20140018700 *||Jul 12, 2012||Jan 16, 2014||Universiti Putra Malaysia||Non-penetrative blood container and apparatus for vacuuming the same|
|DE2743882A1 *||Sep 29, 1977||Mar 30, 1978||Nippon Paint Co Ltd||Trennmittel und verfahren zum auftrennen einer blutprobe in serum- oder plasma- und gerinnsel-anteile|
|EP0046391A1 *||Aug 14, 1981||Feb 24, 1982||Sekisui Kagaku Kogyo Kabushiki Kaisha||Composition for partitioning blood components|
|EP0073551A2 *||Jan 5, 1982||Mar 9, 1983||Becton, Dickinson and Company||Sample collection container|
|EP0076051A2 *||Sep 9, 1982||Apr 6, 1983||Sherwood Medical Company||Fluid separating composition|
|EP0119692A2 *||Jan 25, 1984||Sep 26, 1984||TECHNICON INSTRUMENTS CORPORATION(a Delaware corporation)||Method and apparatus for separating blood lymphocytes from blood|
|EP0184274A2 *||Mar 20, 1985||Jun 11, 1986||Becton Dickinson and Company||Partition for a lymphocyte collection tube|
|EP0575736A2||May 7, 1993||Dec 29, 1993||Becton Dickinson and Company||Anticoagulant solution|
|EP0875756A2 *||Apr 21, 1998||Nov 4, 1998||Becton Dickinson and Company||Additive preparation and method of use thereof|
|EP2253379A1 *||Sep 19, 2003||Nov 24, 2010||Becton Dickinson and Company||High bias gel tube and process for making tube|
|EP2263801A1 *||Sep 19, 2003||Dec 22, 2010||Becton Dickinson and Company||High bias gel tube and process for making tube|
|EP2266697A1 *||Sep 19, 2003||Dec 29, 2010||Becton Dickinson and Company||High bias gel tube and process for making tube|
|EP2266698A1 *||Sep 19, 2003||Dec 29, 2010||Becton Dickinson and Company||High bias gel tube and process for making tube|
|EP2272589A1 *||Sep 19, 2003||Jan 12, 2011||Becton Dickinson and Company||High bias gel tube and process for making tube|
|EP2272590A1 *||Sep 19, 2003||Jan 12, 2011||Becton Dickinson and Company||High bias gel tube and process for making tube|
|WO2004026477A1 *||Sep 19, 2003||Apr 1, 2004||Becton Dickinson And Company||High bias gel tube and process for making tube|
|WO2009010662A2||Jun 18, 2008||Jan 22, 2009||Commissariat A L'energie Atomique||System and method for the continuous extraction of a liquid phase of microsamples, and automated installation for the withdrawal thereof, for carrying out the extraction and taking measurements that relate thereto|
|WO2009010662A3 *||Jun 18, 2008||Mar 12, 2009||Commissariat Energie Atomique||System and method for the continuous extraction of a liquid phase of microsamples, and automated installation for the withdrawal thereof, for carrying out the extraction and taking measurements that relate thereto|
|U.S. Classification||210/789, 494/38, 494/16, 494/81, 436/17|
|International Classification||G01N33/49, B04B5/02, B04B5/00, G01N33/48|
|Apr 18, 1983||AS||Assignment|
Owner name: SHERWOOD MEDICAL COMPANY
Free format text: MERGER;ASSIGNOR:SHERWOOD MEDICAL INDUSTRIES INC. (INTO);REEL/FRAME:004123/0634
Effective date: 19820412