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Publication numberUS3448041 A
Publication typeGrant
Publication dateJun 3, 1969
Filing dateJun 14, 1965
Priority dateJun 14, 1965
Also published asDE1617790A1, DE1617790B2, DE1617790C3
Publication numberUS 3448041 A, US 3448041A, US-A-3448041, US3448041 A, US3448041A
InventorsRoy L Swank
Original AssigneeRoy L Swank
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method and apparatus for treating blood preliminary to its use in transfusions
US 3448041 A
Abstract  available in
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

June 3, 1969 R. L. SWANK 3, 8,041

METHOD AND APPARATUS FOR TREATING BLOOD PRELIMINARR To ITS USE IN TRANSFUSIONS Sheet Filed June 14. 1965 d Wm: 3: mm 69 4.0 w mm x 3 80 5 M 82253? 525; 2 w 8:352: M .Bk 6? $22 Q25: $265 963 m T N m 2: .o A lmvm omm w w .Bk -oom aoo i amzmto QPSEE.

GZQQQEmQ ww mopm 600 5 NN H mm A w v a mm on INVENTOR. R0) L SIM/VA 3,448,041 INARY R. L. SOYWANK METHOD AND APPARATUS FOR TREATING BLOOD PRELIM TO ITS USE IN TRANSFUSIONS Filed June 14, 1965 Sheet RoyLSu/an k NQ my IN VE N TOR R. L. SWANK June 3, 1969 ,448,041

METHOD AND APPARATUS FOR TREATING BLOOD PRELIMINARY Sheet Filed June 14. 1965 wzomnzi I mum a0 mwhmzsc O- QN Om O Om Ow o l O N l I o o m on H HHHSSBHd INVENTOR. I70) L. SW/J/VK United States Patent Int. Cl. B01d /00 US. Cl. 21023 11 Claims ABSTRACT OF THE DISCLOSURE Stored, human blood'is treated preliminary to blood transfusions by passing it through a mat of glass wool or other fibrous material. The fibrous material removes from the blood the storage-generated platelet-leucocyte aggregates present therein.

This application is a continuation-in-part of the patent application of Roy L. Swank, Ser. No. 107,844, filed May 4, 1961, now abandoned, for Method and Apparatus for Treating Blood Preliminary to Its Use in Transfusions.

This invention relates to method and apparatus for treating blood preliminary to its use in transfusions.

In general surgical and medical transfusions, and in heart surgery, it has become routine to employ blood bank blood. This is prepared by withdrawing the blood from donors, adding a preservative comprising heparin, or acid-citrate-dextrose (ACD) solution, and then storing the blood under carefully controlled conditions until its use is required.

Whether it is used directly in transfusions or for priming heart-lung apparatus, there have been observed in the patient an ensuing cessation of circulation and various other reactions not attributable to mismatching of blood types. Although the cause of this regrettable result has been unknown, it has been recognized as a function of blood storage duration. Accordingly, it has been common practice to discard blood bank blood after it has been in storage for a period of 21 days.

It is the general object of this invention to provide method and apparatus for treating blood to be used in transfusions and heart surgery which will overcome the foregoing problem, reducing the likelihood of transfusion reactions due to circulatory failure and related reactions, and enabling the use of blood bank blood even though it has been stored for long periods of time.

In the drawings:

FIG. 1 is an exploded perspective view of a micro-filter assembly employed in testing blood in accordance with the presently described invention;

FIG. 2 is a graph illustrating the filtering characteristics of citrated (ACD) blood after varying storage periods, but without having been treated by the presently described method;

FIG. 3 is a longitudinal sectional view of apparatus employed in treating blood by the presently described method;

FIGS. 4 and 5 are graphs illustrating the filterability of citrated and heparinized bloods which have been treated in the apparatus of FIG. 3, using various types of treating materials.

FIGS. 6 and 7 are elevational and longitudinal sectional views, respectively, of a modified form of apparatus employed in treating blood by the method of the invention;

FIG. 8 is a transverse section along line 8-8 of FIG. 7, illustrating the construction and mode of application of a packing-retaining ring employed in the apparatus of FIG. 7;


FIG. 9 is a plan view of an alternate retaining ring which may be employed in the apparatus of FIGS. 6 and 7;

FIG. 10 is an enlarged diagrammatic illustration of a blood sample, illustrating the appearance of its storage altered components.

FIG. 11 is an enlarged diagrammatic illustration of the manner in which the storage-altered blood components are removed by the operation of the presently described apparatus;

FIG. 12 is a transverse section taken along line 12-12 of FIG. 11; and

FIG. 13 is a graph illustrating the eifect of the size of blood filtering elements employed in the herein described apparatus on their efliciency in removal of the storagealtered components of the blood.

The present invention is predicated upon the discovery that when blood bank blood is stored, its leucocyte and platelet components are altered, developing characteristics which are responsible for the transfusion reactions described above. The alteration is evidenced in two ways. First, a proportion of the platelets are rendered adhesive. Second, a proportion of the platelets form aggregates with a proportion of the leucocytes. The aggregates primarily are responsible for the adverse results occurring when old blood is used in blood transfusions.

The extent of the alteration of the blood is a function of time. It is evidenced by increased resistance to filtration. This property may be tested by use of the apparatus illustrated in FIG. 1.

Thus blood may be introduced into an hydraulic pump, illustrated schematically at 10, capable of exerting a potential pressure of 500 psi. and Operated to deliver a constant flow of blood through its outlet.

The blood is pumped into a plastic block 12 contained in a housing, not illustrated, which maintains the temperature thermostatically at any desired level, for example, at body temperature.

A passageway 14 extends longitudinally through the block. One end of the passageway receives the outlet of pump 10. The other end empties into a well 16. The well is dimensioned to receive a filter screen 18 of selected pore size and made of any desired material, for example, woven plastic cloth, or metal screen of selected pore sizes.

A retaining plug 20 is threaded into the well, where it retains screen 18 in position. This plug has longitudinally through it a passageway 22 terminating in outlet nozzle 24. Blood forced by pump 10 thus passes through passageway 14, through screen 18, through passageway 22 and out through nozzle 24. The pressure required to accom plish this flow varies with the filterability of the blood, and means are provided for measuring it.

In the illustrated form, there is a transverse channel 26 which communicates with longitudinal channel 14 upstream from filter 18. A suitable gauge 28 is inserted in the channel and measures the pressure required to establish uniform flow of blood through the screen.

When conventional blood bank citrated blood, stored for various periods but untreated by the present method, is passed through the apparatus of FIG. 1, plots such as are recorded in FIG. 2 are obtained. These illustrate the sharply decreased filterability with storage time, as indicated by the pressure required to force the blood through filter 18.

The plot for each storage period of FIG. 2 is a composite of three superimposed curves. The left hand curve of each group records a control run in which normal saline is passed through the apparatus before running the stored blood. In each case a pressure of about 10 mm. of Hg is required.

The intermediate plot records the test run and clearly demonstrates that the difiiculty of filtering blood bank blood increases sharply with storage time. Thus whereas a pressure of less than 50 mm. of Hg is required to pass through a filter 18 citrated blood which has been stored but day, a pressure of 350 mm. of Hg is required to pass through the screen blood which has been stored for 8 days.

The right hand curve of each group represents the pressures required to pass normal saline through the screen following each test run after Washing with saline, but without otherwise cleaning the screen. It thus gives an indication of the amount of accumulated residue.

A sharply increased pressure is required to pass the saline through a filter which has been used to filter 8-dayold blood, as compared with one used to filter blood stored for shorter durations. This confirms that stored blood differs from fresh blood in the presence of a component which is filterable with difficulty and which clogs the screen.

By observation of the material accumulated on the screen, and by tests to be described hereinafter, it has been established that the components responsible for the increased difficulty of filtration are the leucocyte and platelet components of the blood which are altered during storage in some unknown manner and, when thus altered, are trapped by the filter. In view of the apparent correlation between the difiiculty of filtration of the stored blood containing these altered components, and the occurrence of transfusion reactions when such blood is applied in medical practice, the importance of removing these altered components prior to transfusion becomes strikingly apparent.

One method for accomplishing their removal is by passing the stored blood through or over a material which will remove selectively the altered leucocytes and platelets, using apparatus such as is illustrated in FIG. 3.

In its illustrated form, the apparatus comprises a vertically arranged tube of glass or other easily sterilizable material of sufficient length to provide the desired dwell time and capacity. At one end of the tube is an inlet port 32 through which the stored blood to be treated is introduced. At the other end is an outlet port 34 through which passes the treated blood ready for use.

One or more baffies 36 may be provided in the central portion of the tube. This directs the flow of blood toward the longitudinal center of the tube, preventing channeling along the side walls and insuring eifective treatment. Although the baffie may assume diverse shapes, it preferably comprises a truncated cone tapering inwardly in the downstream direction, having a central opening, and fused or glued to the inner side walls of the tube.

The tube is filled with a treating material or packing 40 which for successful application must meet several important requirements. First, it must be a finely subdivided material having surface characteristics and a size such that it selectively will collect the storage-altered components of the blood. It acts as a base to which the adhesively altered platelets and leucocytes adhere. It also acts as a base which, being of relatively small diameter as compared to the diameter of the aggregates present in the altered blood, is enveloped by the aggregates as it interrupts their flow. The aggregates thereupon overlap the base on both sides and stick to it. Also, the sticky overlapping portions of each aggregate stick to each other. This anchors the aggregates to the base.

Second, the treating material must have characteristics such as to permit free passage of the other blood components, i.e., the plasma, red cells, unaltered leucocytes and platelets, etc. This must be accomplished even though some of these other components are much larger in size than are the altered platelets, and equal in size to the leucocytes which are removed by the treating material.

The treating material, in other words, does not act as an ordinary filter in which the filter material is so tightly packed that it does not permit solid particles to pass through the passageways between the filter components.

On the contrary, it acts as a base to which some particles which are far smaller than the pores of the treating material selectively adhere, while others which are much larger pass through.

Thirdly, the treating material must have a large area of absorbing surface such as is provided by a fibrous or filamentous material, to achieve high capacity with minimum apparatus size.

Fourth, the treating material must not react adversely with the beneficial blood components and it must not introduce sediment or foreign particles into the blood.

Fifth, the treating material should not pack during the treating procedure, nor should it demonstrate excessive buildup properties.

Sixth, it should have mechanical properties such that it may be used over long operating periods without collapse or plugging, and without being affected adversely by repeated subjection to heat and chemical sterilization.

To meet the foregoing requirements, the treating or packing material should be provided in the form of filaments or fibers which may be formed into a compressible, resilient mat which may be compressed as required to produce passageways or channels of optimum size between the material components. The diameter or cross sectional area of the individual particles of the material is of primary importance in determining its suitabilty.

In general, as will be demonstrated hereinafter, the material should comprise fibers or filaments having lengths of not less than microns and diameters of less than 60 microns, preferably less than 30 microns. Such fibers are of sufficient size so that they will not pass through the filter and into the blood stream of the patient. They are sufficiently small in diameter so that the storagealtered aggregates can completely surround them with overlapping portions which stick to each other, anchoring the aggregates to the fibers.

This effect is illustrated in FIGS. 10, 11 and 12. FIG. 10 illustrates storage-altered blood including a multiplicity of red cells R and aggregates A of storage-altered platelets and leucocytes. FIG. 11 illustrates what occurs when such aggregates contact the individual fibers or filaments of the treating material 40.

It will be observed that the aggregates have dimensions relative to the passageways between the filaments such that they could pass freely through the passageways. Nevertheless, upon impact with the filaments, the aggregates form overlapping portions which stick to each other and secure the aggregates to the filaments.

Materials suitable for the present purpose thus are fibrous or filamentous polyester resins (Dacron and Kodel), filamentous polyamide resin (nylon), filamentous polyacrylic resin (Orlon), glass wool, steel wool, cotton, and cellulose (paper). However, other fibrous or filarnentous materials meeting the above noted requirements may also be used.

The reaction conditions employed when passing the blood through reaction chamber 30 are such as to accomplish removal of the storage-altered components while at the same time preserving the inherent properties of the blood required for successful use in transfusions. Thus the treating temperature should be maintained at a level at which the blood retains a flowing viscosity, but is not denatured or otherwise thermally degraded.

Pressure normally need not be applied, gravitational flow through the tube being effective.

The dwell time within the tube depends upon such factors as the identity and density of the packing material, the age of the stored blood, etc. In general, it is sufficient to remove the altered components without removing a substantial proportion of the remainder of the blood. Thus, in a typical instance, from 10-25% of the blood leucocytes and platelets may be removed, these representing the altered components, the remaining components of the blood passing unchanged through the tube and out port 34. w

The efficiency of the apparatus in removing the storagealtered components from the blood may be tested using the apparatus of FIG. 1 in the manner previously described, introducing into pump blood previously treated in tube 30, and measuring on gauge 28 the pressure required to force the blood through screen 18. The results are shown in FIG. 4 (citrated blood) and in FIG. 5 ('Heparinized blood) using various types of filters.

In FIG. 4 the group of curves at 52 is obtained when glass wool is used as the packing. In this group the left hand curve represents the pressure required to pass normal saline through the apparatus before the test; the intermediate curve, the pressure required to force the treated blood sample through the screen; and the right hand curve, the pressure required to force normal saline through the screen after the test. It will be seen that this group of curves is substantially identical with that of the first group of FIG. 2, indicating that the treated blood has the filtration qualities of fresh blood.

The group of curves illustrated at 54 is obtained when either filamentous polyamide resin (nylon), filamentous polyacrylic resin (Orlon) or filamentous polyester resin (Dacron) is employed as the treating material. These materials, like glass wool, are eminently suitable for the present purpose.

The group of curves indicated at 56 represents those obtained using a different type of filamentous polyacrylic resin (modacrylic resin) and thoseillustrated in group 58 typify the results obtained when a different type of filamentous polyester resin (Kodel) is employed. Although the pressures required to pass the blood through the screen after exposure to these fibrous materials is somewhat greater than in the case of glass wool, they still are usable.

Similar results are obtained when heparinized blood first is treated in the apparatus of FIG. 3 and then passed through the filtering test apparatus of FIG. 1. In FIG. 5 two groups of test results are illustrated for heparinized blood, one after a storage period of day; and the other after a storage period of 1 day. Control curves indicated at 62 are typical of untreated heparinized blood after a storage period of but day. When heparinized blood is passed through a glass wool packing in the apparatus of FIG. 3 and then tested in the apparatus of FIG. 1, the curves of group 64 are obtained. These indicate efiicient removal of the storage-altered components.

When heparinized blood is stored for 1 day, more sharply contrasting results are obtained. In the case of untreated blood (control), illustrated in curves 66, marked alteration of the components is evidenced by the sharply increased pressure required to force the blood through screen 18. When glass wool is employed as a treating agent, curves 68 are obtained. These clearly indicate the efiiciency of this material in removing storage-altered components.

An alternate form of the blood treating apparatus of the invention is illustrated in FIGS. 6-9. Its purpose and function broadly are similar to the purpose and function of the apparatus of FIG. 3. However, it has several advantages.

First, it is provided with means for filtering out any blood clots which may be present. This is important since the presence of clots in the filter demonstrably and adversely affects the performance of the latter in removing the storage-altered components of the blood.

Second, it provides means for compressing and restraining the filamentous Dacron or other blood treating material to a degree at which it performs most satisfactorily.

Third, it includes means for filtering out from the treated blood any small particles of packing material which inadvertently might become entrained in the treated blood stream and which if left would adversely affect the patient.

Fourth, it is readily disassembleable for cleaning and sterilization, although alternatively it may be manufactured as an integral, sealed unit which may be discarded after a single use.

The improved form of the apparatus accordingly comprises a vertically arranged tube 70 of glass, plastic or other easily sterilized material. The upper end of the tube is open, but mounts a removable cap 72. fitted with a sealing O-ring 74 and provided with a central infeed connection 76.

The central portion of the bore of tube 70 is formed with an annular shoulder 78. The lower portion of the tube is formed with another annular shoulder and a tapered chamber 82 which delivers the treated blood to a centrally located outfeed connection 84.

A baflle 86 having a central opening 88 seats and is supported on shoulder 78. The upper surface of the battle is conical and guides the raw blood through central opening 88 to locate it centrally of the tube for most efficient treatment.

Bafile 86 in turn supports a filter screen 90 made of stainless steel or other relatively coarse mesh material sized to remove any blood clots which may be present, but without removing, at least to any substantial degree, the aggregates resulting from the consolidation of the storage-altered leucocytes and platelets.

Screen 90 is folded reversely, as is evident particularly in FIG. 7, to provide a relatively large filter area. Its lower margin is formed with an outwardly directed flange which receives a seal ring 92 This seats in an annular, cooperating recess 94 in the inner side wall of tube 70. It secures the screen removably in place, held snugly against the upper margins of batfie 86.

Shoulder 80 supports a second, relatively coarse mesh screen 96 which, like screen 90, may be made of stainless steel or other stable, corrosion resistant material. Screen 96 supports a filter element 98' which preferably comprises a disc of polyurethane, styrofoam, or other foamed plastic. It also insures that the packing material will not touch outlet 84.

Disc 98 in turn supports a predetermined quantity of the fibrous blood treating agent 100. As explained above, this agent comprises fibrous or filamentous polyester, polyamide or polyacrylic resins; glass wool; or like materials having the ability selectively to adhere the storagealtered components of the blood.

A retainer 102 is fitted into the bore of tube 20. It is dimensioned for adjustment longitudinally of the tube as required to pack the filamentous treating material 100 to the density required for optimum operation of the unit.

Two forms of retainer 102 are illustrated: the form of FIGS. 7 and 8, and the form of FIG. 9. Both may be made of plastic, stainless steel, glass, or other suitable structural material which is inert to blood and easily cleaned.

The retainer of FIGS. 7 and 8, indicated at 102, comprises a ring dimensioned for a press-fit into the interior of the tube. It is desirable to fabricate the ring of a resilient material so that its inherent resiliency will help maintain it releasably in place.

Still further, before inserting the ring, its periphery may be treated with chloroform, or an adhesive material which assists in holding it in place. It is further retained by the spring action of cross bars 104 arranged at right angles in cruciform relation.

The retaining ring 106 of FIG. 9 is similar, with the exception that the ring is interrupted into four arcuate segments, each of which is fixed transversely to one of cross arms 108. When the cross arms are fabricated of resilient material, the arrangement of the exterior ring affords free play to the resiliency of the arms so that a snug fit of the ring within the tube is obtained.

The operation of the treating apparatus of FIGS. 6-9 thus is as follows:

Stored blood introduced into inlet connection 76 passes first through filter screen 90. This removes any blood clots which may be present.

The blood then is channeled by bafile 86 to the central portion of the filamentous or fibrous treating agent 1011 maintained in the desired degree of compression by retainer 102 or 106. The packing material removes the storage-altered blood components in the manner which has been described.

The treated blood then passes through filter disc 98 which removes any small pieces of packing material which inadvertently may have been introduced into the blood flow. The fully treated blood then passes through support screen 80, through outlet connection 84 and thence to conduits which relay it to the patient.

By filling the apparatus of FIGS. 69 with packing materials of varying identity and varying cross sectional dimensions, the effect of these two variables on the efiiciency of the blood treatment readily may be determined.

The determination was made by packing the treating tube with various fibrous materials in the form of filaments or fibers of known diameter. Blood bank blood, outdated by several weeks, was passed through the apparatus gravitationally at room temperature.

The treated blood then was tested for the presence of residual, storage-altered components, i.e. adhesive paltelets and leucocytes and aggregates of the same by passing it through the test apparatus of FIG. 1 and measuring the developed filtration pressure. The results follow in the table, and are graphed in FIG. 13.

TABLE Average fiber Filtration diameter pressure Material (microns) (mm.Hg)

Nylon 5816 180 421-4 96 Nil 25 Kodel 20:1;5 25 Cellulose (defiberized paper) and smaller It will be observed from the table and graph that the efiiciency of the treatment is affected markedly by the diameter of the packing fibers. To be efi'ective, the fibers should have diameters of less than microns, preferably less than 30 microns. As the diameter decreases, 0

the efiiciency of the altered blood component removal increases dramatically.

This is believed due to the fact that fibrous materials having diameters of more than 60 microns do not afford suflicient surface for adherence of the altered blood components. In addition, the diameters are so large that the overlapping bonding efiect illustrated in FIGS. 11 and 12 can not occur.

The data further illustrate that the above noted eifect is common to fibrous materials of diverse classes, i.e., filamentous synthetic fibers, glass wool, cotton wool, steel Wool and even cellulose fibers.

Thus it is apparent that by the present invention, I have provided method and apparatus for treating blood for the removal of components which are produced during blood bank storage and which may be responsible for undesirable transfusion reactions. The method is carried out easily in conjunction with conventional transfusion and heart-lung machine techniques. In addition, it enables use of blood which has been in storage for many days and which prior to my discovery would have been discarded as unusable.

Having thus described my invention in preferred embodiments, what I claim as new and desire to protect by Letters Patent is:

1. The method of treating, preliminary to medical application, stored human blood containing platelet-leucocyte aggregates, the method comprising:

(a) passing the blood through a mat of fibrous material having a large surface area, being non-degrading to the blood, and characterized by the ability selectively to adhere the aggregates, the fibers of said mat having average diameters of less than 60 microns,

(b) the passageways between the mat components being wider than the diameters of the aggregates,

(c) the blood being maintained in contact with the mat at a temperature at which the blood has a flowing viscosity but below the temperature at which it is subjected to undesirable thermal alteration,

(d) for a time suificient to remove selectively a substantial proportion of the aggregates, while leaving behind a substantial amount of nonaggregated platelets and leucocytes.

2. The method of claim 1, wherein said fibers are selected from the group consisting of fibrous polyester resin, polyamide resin, polyacrylic resin, glass, steel, cotton and cellulose.

3. The method of claim 1, wherein the blood is passed through the mat by gravitational flow.

4. The method of claim 1 including the step of compressing the mat during the treatment sufiiciently to obtain optimum pore size for adherence of the aggregates to the fibrous elements of the packing.

5. The method of claim 1 wherein the fibers have average diameters of less than 30 microns.

6. The method of claim 5 wherein the fibrous material comprises filamentous polyester resin.

7. The method of claim 5 wherein the fibrous material comprises filamentous polyamide resin.

8. The method of claim 5 wherein the fibrous material comprises filamentous polyacrylic resin.

9. The method of claim 5 wherein the fibrous material comprises glass wool.

10. The method of claim 5 wherein the fibrous material comprises steel wool.

11. Apparatus for treating, preliminary to medical application, stored human blood containing storage-altered components, the apparatus comprising:

(a) a hollow tube having an open infeed end and an outfeed end terminating in an outfeed connection,

(b) a cap having a central infeed connection removably sealed across the open end of the tube,

(c) a support screen seated in the tube across its outfeed end,

(d) a disc of foamed plastic supported on the support screen,

(e) a quantity of fibrous packing supported on the disc,

(f) the pores of the disc being of a size predetermined to pass the blood but to retain any particles of the packing material,

g) a retaining ring seated against the inner side walls of the tube and pressing against the packing, maintaining the same in a predetermined condition of compression,

(h) a bafiie element having a central guide opening seated in the tube above the retaining ring for guiding the blood into the packing, centrally thereof,

(i) and blood clot filter means positioned in the tube upstream from the bafile means.

2,644,586 7/1953 Cutter 210314 2,660,167 11/1953 Polacco 210446X (Other references on following page) 9 10 2,676,128 4/1954 Piccard 55-528 X Johnson: PSEBM, 102: 2, November 1959, pp. 2,720,278 10/1955 Wiley 210-496X 333-335.

FOREIGN PATENTS Rose: Sc1ence, 98: 2534, July 23, 1943, p. 92.

Siedentopf et a1.: Science, Sept. 25, 1942, p. 303.

3,892 8/1883 Great Britain.

588,224 5/1945 Great Britain. 5 p

OTHER REFERENCES Cooksey et a1.: Disposable, Fine Mesh Filter for Blood ogress, vol. 53, No. 7, July 1957, pp. 313419.

REUBEN FRIEDMAN, Primary Examiner.

and Plasma, J A,M A Ju e 1943, 7 g F. A. SPEAR, JR., Assistant Examiner.

F1 111' B 't' h J. Ex t1. P th., vol. 7, 1926, 10 281-385 n is P a pp US. (:1. X.'R.

Humphrey, et 211.: Air Sterilization by Fibrous Media, 210 316, 317, 335, 339, 350, 446, 496, 500, 502 Ind. & Eng. Chem, vol. 47, 1955, pp. 921-930.

Wrotnowski: Nonwoven Filter Media, Chem. Eng.

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U.S. Classification210/774, 210/496, 604/6.9, 210/317, 210/502.1, 604/252, 210/339, 210/316, 210/446, 210/335, 210/350
International ClassificationA61K35/14, A61M1/36, A61M5/165
Cooperative ClassificationA61K35/14, A61M1/3679, A61M2202/04, A61M5/165
European ClassificationA61K35/14, A61M1/36P, A61M5/165
Legal Events
Jul 21, 1986ASAssignment
Effective date: 19771005
May 5, 1986ASAssignment
Effective date: 19860430