CA1265008A

CA1265008A - System, apparatus and method for continuously fractionating blood in situ

Info

Publication number: CA1265008A
Application number: CA000460913A
Authority: CA
Inventors: Ardis R. Lavender
Original assignee: Individual
Current assignee: Individual
Priority date: 1983-08-15
Filing date: 1984-08-13
Publication date: 1990-01-30
Anticipated expiration: 2007-01-30
Also published as: NO843225L; ES293407U; EP0246676A1; ES553762A0; EP0139376B1; US4980068A; EP0246675A1; JPS6058157A; FI843210A0; CA1265008C; ES293409U; DK391984A; ES293407Y; ZA846342B; ES293408Y; AU3185784A; EP0139376A1; NZ209172A; ES293408U; ES8801586A1

Abstract

ABSTRACT OF THE DISCLOSURE
A system, method and device for continuously fractionating blood in situ. The fractionating device is connected in a closed loop to the donor and includes interleaved blood plates and blood fraction plates separated by a semipermeable membrane. Grooves in the plates direct blood flow and blood fraction collection.
Uniform distribution among the plates and intraplate is obtained by manifolds.

Description

5()~313 Bac_ground of the Invention There are many reasons for fractionating blood to separate various components thereof, one of the most important being to obtain plasma. Plasma has been found to be efficacious in the treatment of various disease states and is generally useful since it may be stored for long periods in cornparison to whole blood which has a rather short shelf life.
When harvesting plasma from a donor, it is preferred to return the formed elements of the blood including red blood cells, white blood cells and platelets to the donor so that frequent plasma harvestings may be effected. Traditionally, plasma is harvested by transferring blood from a donor into a blood bag and thereafter centrifuging the blood to separate the plasma from the formed elements of the blood. Then the plasma is separated from the formed elements of the blood, the formed elements are thereafter reconstituted with a saline solution and reintroduced to the donor. Because of a variety of reasons, generally each donor must undergo two such operations for each plasma donation.
~ The traditional manner of harvesting~plasma involves~severa~l~risks and dlscomforts to the donor. A
principal risk is the chance that the reconstituted blood returned to the~donor will not be the donor's, a situation which has in the past resulted in fatalities.
Other attendant risks are~those of infection and the like. The discomfort involves, among other things, the :
~Inordlnate length~of time required to permit two S(3~:~8 sa~ples of blood to be taken with the re~3llired centrifuging of each sample, the large vol~me of blood remo~7ed for processing, the reconstitutilly of ~he formed elements into a saline solution ~nd reintroducing same to Lhe ~1onor. It is cl ar tr,at a simpler, safer, speed;er system for harvesting plasma is needed and has been needed for a considerable length of time.
One such proposed alternative to the above-described traditional method of harvesting plasma is described in the Blatt et al. U.S. Patent No.
3,705,100 issued December 5, 1972, which patent discloses an apparatus and method for harvesting plasma from whole blood which includes a cylinder having a reservoir and on the bottom of the cylinder a spiral flow path formed by a spiral groove which sits on top of a membrane having a predetermined pore size. Blood in the reservoir is forced through the spiral path by means of a pressurized gas driving fluid. A second ~ embodlment of the apparatus is disclosed in which a hypodermic syringe is used to withdraw blood from a patient and thereafter introduce the blood into the same~sort of splral flow path as previously described.
The Blatt et al. apparatus and process is not utillzed for the commercial production of pldsma~ The Blatt et al. process and method ~is, like the described prior art, a batch process and requires wi'hdrawing blood from~a donor, treating it and thereafter reintroducing the blood lnto the donor with all the attendant risks and time delays previously described ' `~

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Accordingly, none of the serious drawbacks of the prior art have been solved by -the Blatt et al. disclosure.
_ummary of the Inventio This invention relates to a system, apparatus and method for continuously fractionating blood in situ. The fractionating device, per_se, is small and relatively inexpensive in contradistinction to the available prior art devices which are complicated and costly. ~ost advantageously, the inventive system, apparatus and method permits blood to be taken from a donor and returned to the donor in a closed loop, thereby obviating any chance of returning incorrect blood, reducing the time necessary for plasma harvesting and reducing the cost of the equipment and labor necessary to obtain blood plasma.
The present invention provides a device for continuously producing a blood fraction, comprising a stack of at least two plates having at least one surface with a blood flow channel therein facing a surface with a collection channel therein separated by a semipermeable membrane selectively permeable to the blood fraction, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a longitudinally extending blood flow path, each blood flow channel having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof, each collection channel being substantially in registry with the transfer portion of the facing blood channel for receiving the blood fraction passing through the membrane, and a fraction outlet for conducting the blood fraction from each collection channel, whereby the blood raction continuously transfers from blood pa~s1ng through the transfer portion of each blood flow channel through the membrane to the adjacent collection channel to the fract~ion outlet.

~5~)8 The present invention also provides a device for contin-uously producing plasma, comprising a stack of at least two plates having at least one surface with a blood flow channel therein facing a surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of fro~ about 0.1 mlcrons to about 1.5 microns, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a long-itudinally extending blood flow path, each blood flow channellO having a distribution portion for uniformly distributing blood transversely of the bIood flow path and a transfer portion extending longitudinally thereof, each plasma collection channel being substantially in registry with the transfer portion of the facing blood flow channel for receiving plasma passing through ~he membrane, and a plasma outlet for conducting plasma from each plasma collection channel, whereby plasma continuously transfers from blood passing through the transer portion of each blood flow channel through the membrane ::
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12~50()8 The present invention also provides a device for continuously producing plasma, comprising a stack of at least two plates having at least one surface with a blood flow channel therein facing a surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a longitudinally extending blood flow path, each blood flow channel having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof tapered from inlet to outlet to maintain the blood flow velocity and shear substantially constant as plasma is transferred from the blood, each plasma collection channel being tapered and substantially in registry with the tapered transfer portion of the facing blood flow channel for receiving plasma passing through the membrane, ~0 and a plasma outlet for conducting plasma from each plasma collection channel, whereby plasma continuously transfers from blood passing through the transfer portion of each blood flow channel thr.ough the membrane to the adjacent plasma co1lection channel to the plasma outlet. ~;

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The present invention also provides a device for continuously producing plasma, comorising a stack or at least two plates having at least one surrace with a blooa flow channel therein facing a surface with a plasma collection channel therein separated by a semipermeable membrane havlng a pore si2e in the range of from about 0.1 microns to about 1.5 microns, an inlet for conducting blooa to each blood flow channel and an outlet for conduct~ng blood therefrom to establish a longitudinally extending blood flow path, each blood ~low channel having a distribution portion for uniformly aistributing blood txansversely of the blood flow path and a transfer portion e~tending longitudinaLly thereo~, each plasma collection channel being substantially in registry with t~e transfer portion of the facing bl~od flow channel or receiving:plasma passing through the membrane, means associated with each plasma collection channeL

for minimizing transmembrane pressure to reduce the 20 .
: rate at which red blood cells.plug the membrane, and a plasma outlet for conducting plasma from each plasma colle~tion hannel, whereby plasma continuously transfers from blood passing in the transfer portion of' : ~ ~ 6 ~j5~3~

each blood flow ch~nnel thro~gh the me.~brane to tne adjacent plas~a collection channel to the plasmz outlet.
The present inven-tion further provides device for continuously produciny plasma, comprising a stack of at least two plates having at least one substantially flat sur_ace with a blood.flow channel therein facing a substantially flat surface wi.h a plasma collection channel therein separated by a 1~ semipermeable membrane having a pore size in the range o fxom about O.l.microns to about 1.5 microns, an inlet extending through the end surface of each plate having a blood flow channel therein for conducting blood to the blood flow channel ana an outlet extending through the end surface of the plate for conducting blood therefrom to establish a longitudinally extending blood flow path, e~ch of the blood flow channels having a aistribution portion for uniformly,~distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof, each of the plasma collection channels being substantially in registry with the transfer portion of the facing blood flow channel for receiving plasma passing through the membrane, and a plasma outlet for conducting plasma from each of the plasma collection channels, whereby plasma continuously transfers from blood passing through the transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to the plasma outlet.

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Yet another aspect of the present inve.~ti~n provides a device for con~inuouslY proaucing plzsmz, compxising a S~2C~ of at leas. t~o plztes having a~
le-st one subs~anti211y flat sur~~ce with a ~lood flow chcnnel therein facing a subst~ntizlly LlZt surface wi,h a plasm2 colleetion cnznnel therein se~arat2a by a semiperme-ole memorane having a pore size in the range o^ from abou. 0.1 microns to aDout 1.5 microns, an inlet for conducting blocd to each blood flow channel anà an outlet ror conducting blood there~rom to est2blish a longitudinally e~tending blood flow path, each or the blood flow channels having z dis.ribution por~ion for uniformly aistributing blood transversely of the blooa-flow path inlet and z transfer portion ~Ytending longituainally thereof and a combining portion for conducting blood from the transfer portion to the outlet, the distribution and the combining portions each comprising a multiple bifurcated manifold wherein the aepth of the manifold increas2s from the ~ transfer portion to the inlet or the outlet,each of the plasma collection channels being subs.antially in registry with the transfer portion of the facing blood flow channel for receiving plasma passing through the membrane, and a plasma outlet for conducting plasma from each of the plasma collection channels, whereby plasma continuously transfers from blood passing through the transfer portion of each blood flow channel through the membrane to the aajacent plasma collection channel to the plasma outlet~

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A s.ill furthe~ aspect of the present inYention provides a device for continuously producing plasmz, com~rising 2 stac~ of at least two plates having at least one sllbs~antially flat surface with a blood flow channel therein facing a substantially flat surface with a plasmz collection channel therein separated by z semipe~meable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet extending through the end surrace of each plate having a blood flow channel therein for conducting blood to the blood flow channel and an outlet e~tending through the end surface of the plate for conducting blood therefrom to establish a longitudinally extending blood flow path, each of the blood flow channels having a distribution portion for uniformly distri~uting blood transversely of the blood flow path and a transfer portion extending longitudinally thereof and a combining portion for conducting blood from the transer portion to the outlet, the distribution and ~0 the combining portions each comprising a multiple bifurcated manifold wherein the depth of the manifold increases from the transfer portion to the inlet or the outlet, each plasma collection channel being substantially in registry with the transfer portion of the ~acing blood flow channel for receiving piasma passing through the membrane and a slot in communication with the plasma collection channel extending transversely thereof, and a plasma outlet in communication with the slots for conducting plasma from the plasma collection channels, whereby plasma ~ 2~
continuously transfers from blood p~ssins through the transfer portion of each blood flow channel through the me~brane to the zdjacent plasma collec~ion channel to ~he plasma outlet.
Yet another aspect of the present inven~ion provides a device for continuously producing plasma, comprising 2 s.ac~ of plates having a plurality of subs~antially flat surfaces with some of the sur~aces having a blood flow channel therein and the others 1~ having a plasma collection channel the~ein, the facing surfaces in the stac~ having therein a blood flow cnannel ana a plasma collec~ion cnannel separated by a semipermeable membrane having 2 pore size in the range of_from about 0.1 microns to about 1.5 microns, a blood inlet extending through the end surface of each plate having a blood flow channel therein for conducting blood to the blood flow channel ana a blood outlet extendin~ through the opposite end surface of the plate for conducting blood therefrom to establish a longitudinally e~tending blood flow path, each of the blood flow channels having a distribution portion for uniformly distributing blood transversely of the blood ;
10w path and a trar.sfer portion extending longitudinally thereof,a blood inlet manifold connected to each blood inlet for distributing blood from a source thereof evenly among said blood inle~.s and a blood outlet manifold connected to eac~ blood outlet for collecting blood therefrom and combining same into a single stream, each of the plasma collection channels being substantially in registry with the transfer '~

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portion Ot the facing blood flow channel for r~ceiving pias~a passing through the membrane, a plas.~a outlet e~tending through the end surface of each plate having a plas~a collection channel therein for conducting plas~a therefrom, 2na a plasma outlet manifoLd connectea to each plasma outle-t for collec~ins plzsma thererrom and combining same into a single s~ream, wnereby plas~a continuously transrers from blood passing through the transfer portion of each blood flow 1~ channel througn the membrane to the a~jacent plasma collec~ion cnannel to the plasma outlet.
~ still further aspect of the present invention provides a device for continuously producing plasma, com~rising a stac~ of interleaved blood plates and plasma plates with each blood plate having a blood flow channel in at least one substantially flat surface thereof and with each plasma plate having a plasma collection channel in at least one substantially flat surace thereof, the stacX being constructed and ~ arranged such that each surface having therein a blood flow channel faces a surface having therein a plasma collection channel separated by a semipermeable membrane having a pore size in the range of fxom about 0.1 microns to about 1.5 microns, a blood inlet e~tending through the end surface of each blood plate for conducting blood to the blood flow channel and a blood outlet extending through the opposite end surface of the plate for conducting blood therefrom to e~tablish a longitudinally extending blood flow path, each of the blood f}ow channels having a distribution : ' , ~ . .

portion ror uniformly distrib~ting blood trans~ersel~
or the blood flow path and a trans~er portion e~tenaing longituainally theseof tapered from inlet to outlet to maint2in the blood flow velocity and shear substantially cons-2nt 2S plas~a is transferred from .he blood ana 2 combining portion for conducting blood from the transfer portion to the outlet, the distribution and the combining por.ions each comprising a multiole bifurcated manifold wherein the depth of the manifold increases from the transfer por.ion to the inlet or the outlet, a blood inlet manifold connected to the stacX and to each blood inlet for distributing ~lood from a source thereof substantially uniformly among the blood inlets and a blood outlet manifold connected to the stac~ and to each blood outlet for collecting blood therefrom and combining same into a single stream, each of the plas~a collection channels being tapered and substantially in registry with the tapered transfer portion of the facing blood flow ~ channel for receiving plasma passing through the membrane, and each of the plasma collection channels including a plurality of longitudinally extending grooves having a depth of about 3 mils terminating in a transversely extending collection slot,a plasma outlet for conducting plasma from each of the plasma collection slots, and a plasma outlet manifold connected to the stac~ and to each plasma outlet for callecting plasma therefrom and combining same into a single stream, whereby plasma continuously transfers 3~ from blood passing through the transfer portion of each .

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blood flow channel through the membrane to the adjacent plasma collection channel to the plasma outle-t.
The invention consists of certain novel features and a combination of parts hereinafter fully described, illustrated in the accompanying drawings, and particularly pointed out in the appended claims, it being understood that various changes in the details may be made without departing from the spirit, or sacrificing any of the advantages of the present invention.

Brief Description of the Drawings For the purpose of facilitating an understanding of the invention, there is illustrated in the accompanying drawings a preferred embodiment thereof, from an inspection of which, when considered in connection with the following description, the invention, its construction and operation, and many of - its advantages should be readily understood and appreciated.

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FIG~RE 1 is a diagrammatic view of the system of the present invention showing the in situ fractionation of blood;
FIG. 2 is an enlarged top plan view of the blood fractionating device illustrated in Fig. 1;
FIG. 3 is a side elevational view of the de~ice illustrated in Fig. 2;
FIG. 4 is an exploded perspective view of the blood fractionating device illustrated in Fig. l;
FIG. 5 is an enlarged plan view of an internal blood fraction collection plate;
FIG. 6 is an enlarged plan view of a blood plate;
FIG. 7 is a view in section of the collection plate illustrated in Fig. 5 as seen along line 7-7 thereof;
FIG. 8 is a view in section of the collection plate illustrated in Fig. 5 as seen along line 8-8 thereof;
FIG. 9 is a view in section of the collection ~0 plate illustrated in Fig. 5 as seen along line 9-9 thereof;
FIG. 10 is an enlarged view of a portion of the collection plate illustrated in Fig. 9;
FIG. 11 is a view in section of the blood plate illustrated 1n Fig. 6 as seen along line 11-11 thereof;
FIG. 12 is a view in section of the blood plate :
illustrated in Fig. 6 as seen along llne 12-12 thereof;
FIG. 13 is a view in section of the blood plate ~ , ~ illustrated in Fig. 6 as seen along line~13-13 thereof;

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FIG. 14 is a view in section of the blood plate illustrated in Fig. 6 as seen along line 14-14 thereof;
FIG. 15 is a view in section of the blood fractionating device illustrated in Fig. 2 as seen along line 15-15 thereof;
FIG. 16 is a view in section of the blood fractionating device illustrated in Fig. 2 as seen along line 16-16 thereof;
FIG. 17 is an end elevational view of the outlet manifold of the blood fractionating device illustrated in Fig. 2;
FIG. 18 is a view in section of the blood fractionating device illustrated in Fig. 2 as seen along line 18-18 thereof; and FIG. 19 is an end elevational view of the inlet manifold of the blood fractionating device illustrated in Fig. 2.
Description of the Preferred Embodiment Referring now to Fig. 1 there is illustrated a 2Q blood fractionating system 20 which includes a blood fractionator 25 connected in a closed loop to a donor 30. The blood fractionator 25 has an inlet 26 and an outlet 36, the inlet 26 being connected to the donor 30 by a blood tube 27 connected to a catheterj needle or double lumen needle 28 inserted into an appropriate vein or artery of the donor 30. A peristaltic pump 31 having a roller 32 in contact with the blood tube 27 is positioned between the donor 30 and the inlet 26 of the blood fractionator 25 to pomp blood ~rom the donor through the tube 27 into the fractionator in the .

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direction of the arrow 33. A supply of anti-coagulant 35 is connected to the tube 27 and the flow rate of the anti-coagulant is modified by a second pump 32A to provide a predetermined flow rate, as hereinafter explained, of anti-coagulant with the blood flowing from the donor 30 to the fractionator 25. The outlet 36 of the fractionator 25 is provided with a tube 37 which conducts blood in the direction of the arrow 38 to the catheter, needle or double lumen needle 28, thereby to provide the closed loop for the system 20 of the present invention. A blood fraction collection receptacle or bag 40 is provided with a fitting ~1 which is connected by a tube 42 to the outlet 36 and more particularly the outlet port 201, see F~G. lS of the blood fractionator 25 thereby to permit a blood fraction to flow from the outlet 36 in the direction of the arrow 43 to the blood fraction collection bag or receptacle.
Although the blood fractionator 25 of the present invention along with the system 20 disclosed herein may be useful to produce a variety of blood fractions, plasma is one of the most important blood fractions needed in the medical community, and therefore, the blood fractionator 25 as well as the system 20 and method of collecting a blood fraction will hereinafter be described with respect to blood plasma only, it being understood that other blood fractions may be collected with minor modifications to the device 25 and system 20, as will be apparent to those skilled in the art .

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Referring now to Figs. 2, 3 and 4, it will be appreciated that the blood fractionator 25 is made up of a stack 45 of plates, there being provided two ex-ternal plasma plates 50 two internal blood plates 55 and an interior or internal plasma plate 60, 3n appropriate inlet manifold 65 and ou-tlet manifold 70 with each of the plasma plates and blood plates being separated by an appropriate membrane 75. As illus-trated, the blood fractionator 25 is comprised of a stack 45 of five separate plates and four membranes 75 interleaved between the plates such that each plasma plate 50, 60 faces a blood plate 55 and is separated therefrom by an appropriate membrane 75. It will be appreciated that the stack 45 could as easily be com-prised of a stack of plates in which the external plates are blood plates having two double sided plasma plates separated by an internal double sided blood plate. The number of plates also could be increased.
Referring now to the external plasma plates 50, it ~ will be appreciated that although the plates are not identical, they are mirror images of one another for the sake of brevity like numbers have been placed on like portions of each end plate 50. As seen in Fig. 4 each external plasma plate 50 is an oval member 80 with an outer flat surface 81 opposed by an inner flat surface 82. The pIate 50 is generally oval in shape and has a large inlet end 83 and a small outlet end 84.
There are opposed recesses 85 in the side edges of the oval member 80 to provide for easy handling and a large notch 86 in the small outlet end 84 havlng an end :

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i50()8 surface 86a and a small notch 87 in the larye inlet end 83 having a flat end surface 87a.
Each of the end plasma plates 50 has on the inside flat surface 82 thereof a plasrna collection channel 90 which has a trapezoidal portion 91 defined by side edges 92 and end edges 93. Toward -the small outlet end 84 of the end plasma plate 50 is a transversely extending slot 94 in fluid communication with a plurality of longitudinally extending shallow collection grooves 95 separated by ridges 96. As~
hereinafter exp]ained, the slot 94 is substantially deeper than the shallow collection grooves 95 and the portion of the grooves 95 adjacent the slot 94 are deeper than the remainder of the grooves 95 but shallower than the slot. A plasma outlet 98 in the form of an aperture extending from the end surface 86a extends through the oval member 80 and is in fluid communication with the slot 94. Finally, an oval tongue 99 surrounds the~plasma collection channel 90, ~0 for a purpose hereinafter explained.
Referring now to Figs. 6 and 11 through 14, there is illustrated a blood plate 55 which lS provided with the same configuration on both sides thereof, whereby only one side will be described for the sake of brevity.~ Each of~the blood plates 55 is identical in configuration and has in the opposed flat surfaces 102 thereof a blood flow~channel 100, the plate 55 being generally oval ln shape~and identical in size to the external plasma~plates 50 previously described. For that matter, all~of the~plates 50, 55 and 60 have the .

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same general dimensions in plan view. The blood plate 55 has an edge surface 101 and opposed ~lat side surfaces 102, it being the surfaces 102 in which the blood flow channels 100 are positioned. The blood plate 55 has a large inlet end 103 and a small outlet end 104, with recesses 105 beinq provided in the side edyes as previously discussed wlth respect to the end plasma plates 50. As in the end plasma plates 50, there is a large notch 106 in the small outlet end 103, the notch having a end surface 106a and there is a small notch 107 at the large inlet end 103~ the small notch 107 being provided with an end surface 107a. A
groove 109 extends around the periphery of both flat side surfaces 102 and each is complementary in shape to the tongue 99 in the ad~acent end plasma plate 50 and are shaped and dimensioned to receive therein the associated tongue 99 as well as the thickness of the membrane 75, as will be explained. Although shown with grooves on blood plate 55 and tongues on plates 50, the tongues and grooves can be interchanged.
Each of the blood flow channels 100 has a distribution portion 110 and a collection portion llOa in the form of a multiple bifurcated rnanifolds, these distribution and collection portions are identical in shape but not in dimensLon, as wiIl be explained, but for the case of brevity again, like numerals have been applied to like portions of the manifolds 110, llOa.
Both the distribution portion I10 and the collection portion llOa, that is the bifurcated manifolds are in , , lq :

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~i50~)8 fluid communication with a transfer portion 160, all for a purpose hereinafter explained.
Referring now to the large inlet end 103 of the blood plate 55, there i5 an inlet aperture 112 extending through the end surface 107a of the notch 107 and extending longitudinally of the blood plate 55.
The inlet 112 has a counterbore portion 113 at one end thereof and communicates with an aperture 114 which extends through the plate 55, as best seen in Figs. 6 and 11, so as to provide communication between the inlet manifold 65 and the blood flow channel 100 on both sides of the plate 55. As noticed, the inside facing surface 114a of the aperture 114 is rounded at the juncture with the bifurcated manifold 110 to prevent contact of the blood flowing therethrough with a sharp edge for a purpose, as will hereinafter be set forth.
The manifolds 110 and llOa on each end of the blood plate 55 are multiple bifurcated manifolds in which each path is divided twice and there are five such divisions resulting in a single blood stream entering through inlet 112 being divided into 32 blood streams, as hereinafter set forth, at the delivery end of the manifold 110. Specifically, blood flowing through the aperture 114 enters the blood flow channel 100 at the main channel 115 and there is split at the first bifurcation into two channels 116 with the surfaces 117 ~being rounded or~arcuate so as to prevent the impingment of the blood into corners which results in stagnation and less smooth distribution and flow.
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Each of the channels 116 curves as at 118 into a secondary channel 119 which is again bifurcated into channels 121, both the arcuate portions 122 and 123 being formed to prevent stagnation and increase s~ooth flow of blood through the manifold 110. From the channels 121 the blood into the tertiary channel 129 where it is again bifurcated into channels 131 and channels 131 are again provided with arcuate surfaces 132 and 133 for the same purposes as previously described. The blood flows from channels 131 into the fourth tier of channels 149 where they are again bifurcated into channels 141, the channels 141 being provided with smooth arcuate surfaces 142 and 143 to prevent stagnation of blood as it flows through the distribution portion of the blood flow channel 100. A
fifth tier channel 14~ receives the blood from the channels 141 and is bifurcated as at 151 into two additional streams, thereby making the five bifurcations previously described with each of the channels 151 having rounded or arcuate smooth surfaces 152 and 153: to prevent any stagnation of blood and to enhance the~ flow characteristics thereof. Each of the bifurcated channels 151 has an entrance 155 to the transfer portion 160 of the blood flow channel 100. As before indicated there are 32 entrances 155 to the : transfer portion 160.
As best seen in Eig. 11, the bifurcated manifolds 110, llOa have a contlnuous:ly changing depth with the manifolds being deeper at the inlet 112 or outlet 112a and being:shallower at the junctures with the transfer :::
~ portion 160 of the blood flow channeI 100. It is - ,, preferred that this gradation in depth be uniform so that the depth of the manifolds 110, llOa will be the same along a plane transverse to the longitudinally established flow path through the plate 55.
Preferably, the varying depth of the manifolds 110, llOa is such that the depth of the manifolds at the juncture with the transfer portion 160 is exactly the same as the depth of the transfer portion.
The transfer portion 160 is generally trapezoidal in plan view and is defined by side edges 161 and end edges 162 with a generally flat uniformly deep surface 163 which is shallow and as hereinbefore set forth of the same depth as the entrances 155 from both the collection and distribution portions of manifolds 110, llOa. Because the transfer portion 160 of the blood flow channel 100 is trapezoidal in shape, that is it tapers from the inlet end 103 to the outlet end 104 of the plate 55, the transverse dimension of the collection manifold llOa is less than the transverse ~0 dimension of the distribution manifold 110. However, the configuration of the collection manifold llOa is precisely the same as the configuratlon of the distribution manifold 110; therefore, like numerals have been placed on like portlons to prevent repetitive description. Suffice it to say that the entrances 155 of the co~llection manifold llOa at the end of the transfer portion 160 are identical in configuration and number but~smaller in overall transverse dimension than the entrances 155 from the manifold 110. The same five , ~ 30 bifurcations are~ i~n the manifold llOa as in the ~2~j5~
manifold 110 and the vertically extending aperture 114 with the same arcuate surface 114a connects the outlet 112a to the collection manifold llOa, the outlet 112a being provided in the end edge 106a of the no-tch 106 and having a counterbore portion 113a of the same size and dimension as the counterbore 113 at the inlet end 103.
Similarly, the collection manifold llOa has a varying depth in the same manner as the distribution manifold 110, that is the depth of the entrances 155 is the same as the depth of the transfer portion 160 and the depth of the manifold increases uniformly from the entrances 155 toward the aperture 114. Again, the increase in depth is preferably uniform so that the depth of the manifold llOa would be exactly the same along a plane transverse to the longitudinally established blood flow path of the blood plate 155.
Accordingly, it is seen that the blood plate 55 has provided blood flow channels 100 on both sides ~0 thereof and each blood flow channel 100 is identical and has a distribution portion in the form of a multiple bifurcated manifold 110, a transfer portion 160 and a collection portion in the form of a multiple bifurcated manifold llOa. The blood flow is established longitudinally of the plate and flows from the inlet 112.through the end surface 107a of the notch lQ7 and exits through the outlet 112a through the end surface 106a of the notch 106 which is opposite to the notch 107.

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The multiple bifurcations of the manifolds 110 and llOa are most easily seen in reference to Figs. 12 and 14. Fig. 12 is taken along a portion of the manifold 110 where there are four channels 129 and Fig. 14 is taken along the entrances 155 of the manifold 110 wherein there are thirty-two channels. As seen therefore, the blood flow has been bifurcated five times so that from a single blood stream at the inlet 112 it is divided twice five times, there being two channels 116, four channels 121, eight channels 131, sixteen channels 141 and thirty~two channels 151 which terminate in the entrances 155. These five bifurcations repeated on the collection manifold llOa to combine, in a uniform manner, the thirty-two streams entering the collection manifold llOa from the transfer portion 160 to a single outlet stream in the outlet 112a. Figure 13 clearly illustrated the two transfer portions 160 of the blood flow channel 100 which consist of a shallow trapezoidal shaped groove, the trapezoidal shape being for a purpose hereinafter set forth.
Referrin~ now to Figs. 5, 7-10, there is shown the internal plasma plate 60 having the same configuration on both sides of the plate and more particularly the plate 60 has opposed flat surfaces 171 and a peripheral ;- edge surface 172. There is a large end 173 which corresponds to the inlet 26 and a small end 174 which corresponds to the outlet 36. In the side of the edge surfaces 172 are two finger recesses 175 of the same size and dimension as the previously described recesses - - ~

12~i~1)(3~3 85 and 105. At the outlet end 36 corresponding to the small end 174 is a large notch 176 of the same size and configuration as the previously described notches 86 and 106 respectively in the end plasma plates 50 and the blood plates 55. The large notch ]76 has an end surface 176a. Opposite the large notch 176 is a smaller notch 177 in the inlet 26 of the device 25 which corresponds to the small end 173 of the plate 60.
Notch 177 is of the same size and dimension as the previously described notches 87 and 107 and is provided with an end surface 177a. A tongue 179 extends around the periphery of each side surface 171 of the plate 60 and is constructed and arranged to fit within one of the notches 109 in the blood plates 55.
A plasma collection channel 180 is in both side surfaces 171 of the plate 60 and is of the same ~ize and dimension and is similarly constructed to the plasma collection channel 90 in the end plasma plates 50. Specifically, the plasma collection channel 180 ~0 includes a slot 181 which extends entirely through the plate 60 and opens onto both opposed substantially flat surfaces 171. An aperture 182 forms the plasma outlet which extends through the surface 176a of the notch 176 and has a counterbore area 183 for receiving a suitable fixture from the tubing 42 which leads to the plasma collection receptacle or bag 40. It is noted that in plan vlew, the plasms outlet 182 lS in vertical alignment with the plasma outlets 98 of the end plasma plates 50; however, ln Fig. 5 the plasma plate 60 is reversed so that while it appears the plasma outlet 182 ~`' ~

-~ ~x~so~
is displaced, it is seen, particularly from Fig. 4, that the plasma outlet 182 is aligned with each o the other plasma out-lets 98 of the end plasma plates 50, for a purpose hereinafter described.
The plasma collection channel 180 further includes a trapezoidally shaped collection area 185 defined by side edges 186 and end edges 187, the trapezoidal plasma collection area being substantially the same size and dimension as the transfer portion 160 of the blood plates 55 and the same as the trape-zoidal plasma collection portion or area 91 of the end plasma plates 50. As with the end plasma plates S0, there are a plurality of longitudinaliy extending shallow collection grooves 195 separàted by ridges 196. Immediately adjacent the trans-versely e~tending slot 181 is a portion 197 of the grooves 195 which is deeper than the remainder of the grooves 195 but o~
course shallo~er than the slot 181 which extends entirely through the plate 60.
As seen, therefore, the blood fractionator 25 is comprised of a stack 45 of alternating blood plates 55 and plasma plates 50, 60 interleaved by membranes 75, the membrane 75 is selected so that the pore size of the membrane selectively passes the blood fraction to be collected. In the case of a plasma collection device, the membrane ~5 preferably has a pore size in the range of from about 0.1 microns to about 1.5 microns.
Membranes are commercially available with pore sizes 0.6 microns, 0.65 microns and 1.0 microns, others may be available.
Nuclepore, Gelman, Milllpore ~

26 ~ .

z"

5~

and Sartorius produce membranes suitable ~or blood plasma harvesting. Other blood fractions which are of interest and which may be separated by the fractionator 25 are protei"-free filtrates and protein fractions and membranes useful for these purposes would necessarily have pore sizes in the range of from about 50 Angstrom to about 0.05 microns. These mernbranes, also are readily available as will be appreciated by those skilled in the art.
The stack 45 is sealed in part and clearly aligned by the tongue and groove mechanism previously described. For instance, the end plasma plates 50 have the tongues 99 while the blood plates 55 are provided with the grooves 109 and the central plasma plate 60 has the tongues 179, all of which are shaped, constructed and arranged to fit one within the other while accommodating therein membrane 175 which, as illustrated in Figs. 15-18, extends from edge to edge of the various plates. The usefulness of the tongue and groove construction i~s that the membranes 75 remain imperforate which is critical to the design of the blood fractionator 25 and to the operation of the system 20 since membrane rupture or leakage can result in serious problems. Furthermore, an imperforate membrane effectively constructs blood flow channels without the need for gaskets or other fluid separating components. In any event, utmost care is taken to ensure the leak free nature of the membranes 75 and to this end, the design`~of a device which provides an imperforate membrane 75 is a significant advantage.

i5~()8 Completing the blood fractionator 25 and coacting with the stack 45 are the blood inlet manifold 65 and the blood and plasma outlet manifold 70. The function of the blood inlet manifold is extremely important and is to uniformly distribute the blood from the donor 30 which enters the blood fractionator 25 through the inlet 26 and particularly through the tube 27 among the blood plates 55. In the preferred embodiment, there are two blood plates 55, --hereby the function of the blood inlet manifold 65 is to uniformly distribute the blood flow from the donor 30 evenly between the two blood plates 55 and specifically to the respective inlets 112 of each plate leading to the associated multiple bifurcated manifolds 110. The blood inlet manifold 65 is received in the aligned series of notches 97, 107 and 177 and, as best seen in Fig. 19, the blood inlet manifold is comprised of a solid block, preferably of plastic 210, having a blood inlet port 211, a bifurcated passageway 213 and two flttings 214 ~ of a size and dimension to fit snugly within the counterbore portion 113 of each blood plate 55.
Referring now to the blood and plasma outlet . ~
manifold 70 illustrated particularly in Figs. 4, 15 and 17, there is a block, preferably of plastic 200 which has a:blood~outlet port 201 connected to the tubing 37 so that blood flowing from the blood fractionator 25 in the~direction of the arrow 38 returns to the donor 30.
;
The-blood outlet port 201 is in fluid communication with a blfurcated~passageway 203 which leads to two fittlngs~204~constructed:and arranged to fit within the ' , ~: ~

~ 3~

counterbore portions 113a of the two blood plates 55.
The bloc~ 200 like the block 210 is constructed and arranged snugly to fit within the appropriate opening formed by the series of notches 86, 106 and 176 of the stack 45 of plates. The outlet manifold 70 also has a plasma outlet port 202 connected to the tubing 42 which permits plasma to flow in the direction of the arrow 43 into the plasma collection receptacle or bag 40.
The plasma outlet port 202 is connected to a trifurcated passageway 206 which has connected thereto two end fittings 207 and a center fitting 208 respectively fitting into the counterbore portions of the plasma end plate outlets 98 and the counterbore portion 183 of the interior plasma plate 60. The fit of the inlet manifold 65 and the outlet manifold 70 is such as to provide a fluid tight fit between the manifold and the appropriate portions of each plate, thereby to ensure no leaks during operation. It will be appreciated that the plates are maintained in their ~ stacked configuration by the two manifolds 65 and 70 which may fixedly secured to their respective series of notches by a suitable adhesive which is biocompatible with blood and blood components or by ultrasonic welding or other methods well known in the art.
In the plasma harvesting art, there has been a long felt need to provide an easier, safer, more economical; method of harvesting plasma than that which is commercially available. There has been a ; significant amount of money both rom the private 30~ sector~and from the government dedicated to finding ~ : :

.
:

~X~i50~)~

solutions to the problem, but as of yet there has been no satisfactory solution. Problems encountered in the art are many but the most significant problem is the rapid degradation in plasma production with time for any device heretofore discovered or proposed. It is not unusual to have initial plasma production that is significant and commercially acceptable howe~er within a relatively short time, in the order of less than a half hour, plasma production falls off so dramatically that as of the present date no commercial device is a~ailable which meets the criteria heretofore set forth.
The present blood fractionator 25 and system 20 meet all the criteria set forth above and provides commercially acceptable plasma collection rates even after more than one half hour of contlnuous plasma production. When harvesting blood with a 5-plate embodiment, it is preferable that the blood flow rate from the donor 30 to the blood fractionator 25 be in the range of from about 50 milliliters per minute to about 100 milliliters per minute. Blood flow rates above lOO milliliters per minute do not significantly augment plasma flow unless additional plates are added, whereas flow rates less than about 50 milliliters per minute result in low plasma production. Clearly, blood hematocrit affects the amount of plasma produced with higher hematocrit va1ues producing less plasma due to lower filtration rate.
In human donors it is usual to encounter , hematocrit values in the range of from about 38 to ~::
:: :
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about 55 percent. The taper of the plates in the stack 45 has been calculated on the basis on a average hematocrit value of about 45 percent and is also determined, to some extent, by the length of the blood flow path and particularly by the length of the trapezoidal area of the various plates. The taper is used to maintain constant the blood flow rate as plasma transfers through the membrane 75 thereby decreasing the volume of the blood. It is also impor-tant to maintain shear constant and the taper also accomplishes this purpose. In the blood fractionator 25 described, the calculated blood flow velocity which was maintained substantially constant due to the construction of the device was about 5.7 centimeters per second with a mean shear of 6027 sec 1 In addition to the tapered blood channel to maintain constant velocity and shear, it was also discovered that in order to obtain commercially acceptable plasma collection rates over a substantial period of time, it was beneficial to provide entry acceleration of the blood from the manifold to each plate and this, of course, is provided by the inlet manifold 65. An additional important feature of the fractionator 25 is the progressive decrease in the bifurcated manifold channel depth from entry to exit, this referring to the bifurcated manifolds 110 in each ; of the blood plates 55.
St1ll another important feature of the blood fractionator 25 is the shallow parallel grooves 195 in the pl~sma plate 60 and the simllar grooves 95 in the : ~ 3~1 5~

end plates 50 which function to optimize tran5membrane pressure and to minimize flow resistance to plasma during operation of the fractionator 25. The optimization of the transmembrane pressure greatly reduces the rate at which red blood cells plug the pores of the membrane 75.
Still another important feature of the system 20 and the fractionator 25 is the vertical ïnlet manifold 65 and outlet manifold 70 which, in cooperation with other design features of the fractionator, result in a uniform blood distribution intraplate and a uniform blood distribution along each blood flow channel 100.
Another aspect of the inlet manifold 65 and the outlet manifold 70 which cooperates with tongue and groove construction of the fractionator 25 is the elegant seal of the device 25 which simplifies the internal gasketing necessary to maintain a liquid tight seal for the fractionator 25.
In a constructional example of the fractionator ~ 25, each of the plates 50, 55 and 60 is 0.19 inches thick. The wldth at the sectlon 12-12 is 3.0 inches, the width at section 13-13 is about 3.04 inches and the width at section 14-14 is about 2.85 inches. The overall length of the fractionator, absent the inlet 211 and the outlet 201 is about 4.89 inches and the overall width at its widest part is about 3.3~ inches.
The dimension of the blood transfer portion 160 of the blood transfer~ plate l45 lS aboat 3.0 inches at its widest and about 2.2~inches and its narrowest, this representing a taper in th~e order of about 8.
- : , :: .

-i5~

It should be understood that the taper is calculated on the basis that plasma transfer through the membrane 75 is uniform throughout the blood transfer portion 160 and on the length of the portion 160. For longer devices, the taper is necessarily greater and tapers of up to about 10 are contemplated. The length of the blood transfer area 160 is about 2.6 inches.
The passageway 114 which connects the inlets 112 with the multiple bifurcated manifold 110 has a diameter of about .125" and the entrances 155 are each about . 031 ll wide and are spaced about 0. 093 ll, center to center at the large end and .069l center to center at the small end.
Referring now to the plasma plates and particularly to Figs. 9 and 10 the depth of the longitudinally extending shallow grooves 195, and for that matter the grooves 95, are preferably about 3 mils. Each of the grooves 95, 195 as best seen in Fig.
10, are described by an arc 62 mils in radius and each of the ridges 96, 196 are about 46 mils center to center. The depth of the portions 197 of the grooves 195 and the portions of the grooves 95 unnumbered immediately adjacent the respective slots, 9~, 181, have a depth of about .052l'. This portion of the grooves is lmportant because it decreases flow resistance as the plasma or blood fraction flows into the slots. Preferably,~for grooves 95, 195, 3 mils deep, the portion 197 would be in the range of from about 04l to about .07 n, Less than about 04ll would ~ ,3 ~:

- :, - 12~

not accomplish the required reduction in blood fraction or plasma flow resistance while greater than about .07"
would enhance clogging by red cells.
Another feature of the blood fractionator 25 is the continuously decreasing depth of the multiple bifurcated manifolds 110, llOa from the inlet 112, outlet 112a to the blood transfer area 160. This is important because blood exits the multiple bifurcated manifold 110 and particularly the entrances 155 with a slight inclination toward the surface of the adjacent membrane 75 which seems to be an advantage to the present design. Because relatively high shear is important to prevent the membrane 75 from clogging with red blood cells, the blood flow channel was kept shallow. As channel height was increased, filtration rate d`ecreased.
Summarizing, there are a number of factors whLch apparently cooperate to enable a commercial device to be made which operates satisfactorily and which meets ~0 all the objects of the present invention. Of the most important features of the~present invention are the uniform intraplate distribution~of blood by the inlet manifold 65,~ the uniform transverse distribution of blood across the plates by the multiple bifurcated manifolds 110, the u~niform flow velocity and shear accomplished~by means of the tapered transfer areas 160, the shallow blood flow pat~h accomplished by the depth of the transfer~areas 160 and the immediately adjacent membrane~75,~the optlmization of transmembrane pressure by~`the~shallow~grooves 95, 195 of the plasma 3 ~

:: :

12~i5~1~3~

plates 50, 60, the reduction in the flow resistance of the plasma due to the increased depth of the grooves 195 at the portions 197 and the like portions on the end plasma plates 50, the uniform collection of the plasma by the outlet manifold 70, and the uniform condensation of the multiple streams into a single outlet stream by the multiple bifurcated manifold 110 at the outlet end 36 of the fractionator 25 and the use of a design which obviates the necessity for internal gaskets or perforations of the membrane.
Reported hereafter in Tables I, II and III are data obtained with in vitro experiments with human blood. Because of the nature of stored human blood, the hematocrit value was adjusted to 33 percent with saline. In Tables I and III, a single membrane device was used and hence the blood flow rate was 20 milliliters per minute whereas Table II reports a five layer, four channel device wherein the total blood flow rate was 80 milliliters per minute. Several different ~ design modifications are shown. Accordingly, in order to extrapolate the initial and final filtrate rates reported in Tables I and III, these values must be multiplied by four.

: :

~ 5 ~8 TABLES I, II AND III

Table I
B00191/P00181 Results All experiments in vitro with human blood, hematocrit adjusted to 33 per cent with saline.
Pump speed = 20 ml/minute Inlet Outlet Initial Final Number Pressure Pressure Filtrate Filtrate Experiments Membrane mm H mm H ml/min ml/min g 7 Nuclepore 0.6u 244 25 6.2 4.3 6 Nuclepore 1.0u 275 - 7.5 6.8 4 Gelman 0.65u 404 - 8.2 6.8 Table II
B00191/P00181 Results All experiments in vitro per Table I.
Pump speed = 80 ml/min.
Five layers with 4 blood channels in parallel.
Inlet Outlet Initial Final Number PressurePressure Filtrate Filtrate E~periments Membrane mm Hg mm Hg ml/min ml/min 8 Nuclepore 0.6u 215 - 26.1 12.9 l Nuclepore 1.0u 96 - 20.5 -15.5 12 Gelman 0.65u 239 - 25.0 20.9 Table III
B00198jP00188 Results All experiments in vitro per Table I.
Pump speed =~20 ml/min. Single layer.
InletOutlet Initial Final PressurePressure Filtrate Filtrate xperiments Membrane mm Hg mm Hg ml/min ml/min -6 Nuclepore 0.6u 154 - 4.6 3.1

2 Nuclepore 1.0u 189 - 7.3 6.5 4 Gelman 0.65u ~ 190 - 4.4 2.1 :

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~lX~;5~8 Table IV reports the results of various dog experiments, it being noted that fresh blood produced a significantly higher final plasma flow rate than did the stored blood used in the experiments reported in Tables I-III.

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~j5~8 Table IV also illustrates certain results with blood flow channels having depths of 3 mils and 4.5 mils, but as seen from the data significant differences were not seen. For a single membrane device of the type reported in Tables I-III, typical manifold entrance velocities at 114 were 4.2 centimeters per second and typical manifold exit velocities at 155 were 17.4 centimeters per second. The blood flow channel velocity was, as previously reported, 5.7 centimeters 0 per second and the blood channel mean shear was 6.027 sec . The manifold 110 flow channels, at the inlet were approximately 125 mils deep with the depth decreasing progressively, and uniformly, to 3 mils at the juncture between the ends of the manifolds 110 and the beginnings o~ the blood transfer area 160 on the one hand and the entrance to the manifold and the end of the blood transfer area on the other hand.
In the blood fractionator 25 as illustrated, there are five plates with four hlood-fraction plate pairs ~0 separated by four sheets of membrane. It is clear that larger or smaller stacks may be used without departing from the scope of the invention.
As illustrated, the system 20 is useful to provide a method of continuously fractionating blood in situ, that is continuously fractionating blood utilizing a closed loop system wlth a donor 30. The closed loop consists of the tubes 27 and 37 in combination with the double lumen needle, needles or catheter 28 and the blood fractlonator 25 enabling a method to be used in which blood is continuously pumped via the pump 31 from .

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the donor 30 in a closed loop through the b]ood fractionator 25 and returned to the donor. The blood fraction is continuously produced during the operation of the method and is collected in the receptacle or blood fraction bag 40. The method optimi~es transmembrane pressure resulting in continued satisfactory blood fraction collection rates for prolonged durations. The method also includes the use of an anti-coagulant 35 which may be citrated saline or 1~ heparinized saline, or other well known anti-coagulants. The flow rate of the anti-coagulant and the blood axe fixed by the pumps 31 and 31A used in conjunction with the supply 35 of anti-coagulant. A
flow rate of 65 milliliters of blood per minute and 15 milliliters of anti-coagulant per minute for a total inlet flow rate to the fractionator 25 of about 80 milliliters per minute has been satisfactory.
By the design of the fractionator 25, the blood velocity is maintained constant through the transfer 0 area of each plate, but the blood velocity is accelerated from manifold inlet to manifold outlet. In addition, the blood shear is also maintained substantially constant from manifold inlet to manlfold " outlet.
The system 20 of the present invention, as previously described, may have other safety features not illustrated. For instance, an air bubble detection device may be included on the return tubing 37 and there may be a bIood leak detector or other such equipment elsewhere located in the system, all well kD~

, within the skill of the art. An important and unique feature of the blood fractionator 25 is the minimum volume of the device. All of the blood channels of the device 25, including both end manifolds 110, llOa, have a volume less than 2.5 ml. Volume of the plasma compartments, including manifolds, is less than 2 ml.
This feature, not present in previously described devices, minimizes blood loss by the donor and maximizes plasma recovery. The minimal amounts of plasma left in the device 25 are important to commercial utilization of the device. Accordingly, low blood and plasma retention volumes of less than 10 mls is an important commercial feature of the invention~
Total blood volume of the tubing plus fractionator 25 is estimated to be less than 20 ml.
Total membrane area of the device is 176 c~2 whereas previously described devices may use as much as 10,000 cm~ of membrane. The reduction of membrane area contributes significantly to reduction of costs.
~ This is a substantial improvement over prior art devices which require larger ~uantlties of membrane, thereby resulting in a substantially more expensive device, not suitable for a disposable device.
While there has been descrlbed what at present is considered to be~the preferred embodiment of the present invention, it will be understood that various modifications and alterations may be made therein without departing from the true scope and spirit of the present invention which is;~ntended to be covered in the claims appended hereto.

;.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A device for continuously producing plasma, comprising a stack of at least two plates having at least one surface with a blood flow channel therein facing a surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a longitudinally extending blood flow path, each blood flow channel having a distribution portion for uniformly distributing blood transversely or the blood flow path and a transfer portion extending longitudinally thereof, said transfer portion of said blood flow channel being more narrow at the outlet thereof than at the inlet thereto sufficiently to maintain blood velocity substantially constant through said transfer portion, each plasma collection channel being substantially in registry with said transfer portion of said facing blood flow channel for receiving plasma passing through said membrane, and a plasma outlet for conducting plasma from each plasma collection channel, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

2. The device of claim 1, wherein each plate in said stack of plates is flat.

3. The device of claim 1, wherein each plate has either a blood flow channel or a plasma collection channel therein.

4. The device of claim 1, wherein the two outside plates in said stack of plates each have a plasma collection channel on the inside facing surface thereof.

5. The device of claim 1, wherein at least one blood plate has a blood flow channel in each of the opposite surfaces thereof.

6. The device of claim 1, wherein at least one plasma plate has a plasma collection channel in each of the opposite surfaces thereof.

7. The device of claim 1, wherein there are five plates in said stack with at least one plate having a blood flow channel in opposite surfaces thereof and one plasma plate having a plasma collection channel in opposite surfaces thereof.

8. The device of claim 1, wherein said transfer portion of said blood flow channel is shallow having a depth in the range of from about 1 mil to about 10 mils.

9. The device of claim 8, wherein the depth of the transfer portion is about 3 mils.

10. The device of claim 1, wherein each plasma collection channel has substantially the same depth as said transfer portion of each blood collection channel.

11. The device of claim 10, wherein a plasma collection channel has a transversely extending slot at one end thereof deeper than the remaining portion of the plasma collection channel.

12. A device for continuously producing plasma, comprising a stack of at least two plates having at least one surface with a blood flow channel therein facing a surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a longitudinally extending blood flow path, each blood flow channel having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof tapered from inlet to outlet to maintain the blood flow velocity and shear substantially constant as plasma is transferred from the blood, each plasma collection channel being tapered and substantially in registry with said tapered transfer portion of said facing blood flow channel for receiving plasma passing through said membrane, and a plasma outlet for conducting plasma from each plasma collection channel, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

13. The device of claim 12, wherein said transfer portion of said blood flow channel is trapezoidal in plan view.

14. The device of claim 13, wherein the depth of the transfer portion of said blood flow channel is less than 10 mils.

15. The device of claim 13, wherein the angle of the taper from the inlet to the outlet of said transfer portion is in the range of from about 5° to about 10°.

16. The device of claim 13, wherein the angle of said taper is between about 8°.

17. The device of claim 12, wherein said plasma collection groove has substantially the same depth as the depth of the transfer portion of said blood flow channel.

18. A device for continuously producing plasma, comprising a stack of at least two plates having at least one surface with a blood flow channel therein facing a surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a longitudinally extending blood flow path, each blood flow channel having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof, said transfer portion of said blood flow channel being more narrow at the outlet thereof than at the inlet thereto sufficiently to maintain blood velocity substantially constant through said transfer portion, each plasma collection channel being substantially in registry with said transfer portion of said facing blood flow channel for receiving plasma passing through said membrane, means associated with each plasma collection channel for minimizing transmembrane pressure to reduce the rate at which red blood cells plug said membrane, and a plasma outlet for conducting plasma from each plasma collection channel, whereby plasma continuously transfers from blood passing in said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

19. The device of claim 18, wherein said plasma collection channel is of substantially the same shape and dimension as said transfer portion of said blood flow channel and has a plurality of longitudinally extending grooves therein, said grooves having a depth in the range of from about 1 mil to about 10 mils.

20. The device of claim 19, wherein the depth of said grooves is in the range of from about 3 mils to about 5 mils.

21. The device of claim 18, wherein said grooves are about 3 mils deep, are transversely spaced apart about 45 mils center-to-center and are separated by ridges about 15 mils wide.

22. The device of claim 19, and further comprising a slot at the end of said grooves connected to same, said slot being deeper than the depth of said longitudinally extending groove.

23. The device of claim 22, wherein the portion of each groove immediately adjacent said slot is deeper than the remainder of said grooves to reduce plasma flow resistance prior to entry of plasma into said slot.

24. A device for continuously producing plasma, comprising a stack of at least two plates having at least one substantially flat surface with a blood flow channel therein facing a substantially flat surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet extending through the end surface of each plate having a blood flow channel therein for conducting blood to said blood flow channel and an outlet extending through the end surface of said plate for conducting blood therefrom to establish a longitudinally extending blood flow path each of said blood flow channels having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof, said transfer portion of said blood flow channel being more narrow at the outlet thereof than at the inlet thereto sufficiently to maintain blood velocity substantially constant through said transfer portion, each of said plasma collection channels being substantially in registry with said transfer portion of said facing blood flow channel for receiving plasma passing through said membrane. and a plasma outlet for conducting plasma from each of said plasma collection channels, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

25. The device of claim 24, wherein said inlet is in the middle of said end surface.

26. The device of claim 25, wherein said inlet and outlet are longitudinally aligned.

27. The device of claim 24, wherein an aperture extends generally perpendicularly to the surface having said blood flow channel therein connecting said inlet and said blood flow channel.

28. The device of claim 27, wherein the juncture between said aperture extending generally perpendicularly from said inlet to said blood flow channel is arcuate to provide a smooth flow surface for blood flowing through said inlet to said blood flow channel.

29. The device of claim 24, and further comprising an outlet extending through the end surface of each plate having a plasma collection channel therein.

30. The device of claim 29, and further comprising a slot extending transversely to said collection channel in fluid communication therewith having a depth exceeding that of the plasma collection channel, said slot being connected to said outlet.

31. A device for continuously producing plasma, comprising a stack of at least two plates having at least one substantially flat surface with a blood flow channel therein facing a substantially flat surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet for conducting blood to each blood flow channel and an outlet for conducting blood therefrom to establish a longitudinally extending blood flow path, each of said blood flow channels having a distribution portion uniformly distributing blood transversely of the blood flow path inlet and a transfer portion extending longitudinally thereof and a combining portion for conducting blood from said transfer portion to said outlet, said distribution and said combining portions each comprising a multiple bifurcated manifold wherein the depth of the manifold increases from said transfer portion to said inlet or said outlet, each of said plasma collection channels being substantially in registry with said transfer portion of said facing blood flow channel for receiving plasma passing through said membrane, and a plasma outlet for conducting plasma from each of said plasma collection channels, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

32. The device of claim 31, wherein there are five bifurcations in each of said distribution and combining portions thereby providing 32 blood streams entering said transfer portion and 32 entrances for said combining portion.

33. The device of claim 31, wherein said transfer portion of said blood flow channel has a depth in the range of between about 1 and about 10 mils.

34. The device of claim 33, wherein the depth of said manifolds equals the depth of the transfer portion where the distribution and combining portions meet the transfer portion of each blood flow channel.

35. The device of claim 34, wherein the depth of said transfer portion is about 3 mils and the depth of said manifolds increases from about 3 mils at the juncture of the manifolds and the transfer portion to about 125 mils at the outlet and the inlet.

36. The device of claim 31, wherein the depth of the manifold increases substantially uniformly from said transfer portion to said inlet or said outlet.

37. The device of claim 31, wherein each branch of said bifurcated manifold has arcuate surfaces at each change in direction of blood flow thereby to improve blood flow through said manifold.

38. A device for continuously producing plasma, comprising a stack of at least two plates having at least one substantially flat surface with a blood flow channel therein facing a substantially flat surface with a plasma collection channel therein separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, an inlet extending through the end surface of each plate having a blood flow channel therein for conducting blood to said blood flow channel and an outlet extending through the end surface of said plate for conducting blood therefrom to establish a longitudinally extending blood flow path, each of said blood flow channels having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof and a combining portion for conducting blood from said transfer portion to said outlet, said distribution and said combining portions each comprising a multiple bifurcated manifold wherein the depth of the manifold increases from said transfer portion to said inlet or said outlet, each plasma collection channel being substantially in registry with said transfer portion of said facing blood flow channel for receiving plasma passing through said membrane and a slot in communication with said plasma collection channel extending transversely thereof, and a plasma outlet in communication with said slots for conducting plasma from said plasma collection channels, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

39. The device of claim 38, wherein an aperture extends substantially perpendicularly to the surface having said blood flow channels therein connecting said inlet and said blood flow channel.

40. The device of claim 38, wherein the juncture between said aperture extending perpendicularly from said inlet to said blood flow channel is arcuate to provide a smooth flow surface for blood flowing through said inlet to said blood flow channel.

41. The device of claim 38, wherein there are five bifurcations in said distribution and combining portions thereby providing 32 blood streams entering said transfer portion and 32 entrances for said combining portion.

42. The device of claim 38, wherein each branch of said bifurcated manifold has arcuate surfaces at each change in direction of blood flow thereby to improve blood flow through said manifold.

43. The device of claim 38, wherein said transfer portion has a uniform depth in the range of from about 1 to about 10 mils, the depth of each manifold at the juncture with said transfer portion being the same as the depth of the transfer portion and the depth of said manifolds at the inlet and outlet being substantially greater.

44. A device for continuously producing plasma, comprising a stack of plates having a plurality of substantially flat surfaces with some of the surfaces having a blood flow channel therein and the others having a plasma collection channel therein, the facing surfaces in said stack having therein a blood flow channel and a plasma collection channel separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, a blood inlet extending through the end surface of each plate having a blood flow channel therein for conducting blood to said blood flow channel and a blood outlet extending through the opposite end surface of said plate for conducting blood therefrom to establish a longitudinally extending blood flow path, each of said blood flow channels having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof,a blood inlet manifold connected to each blood inlet for distributing blood from a source thereof evenly among said blood inlets and a blood outlet manifold connected to each blood outlet for collecting blood therefrom and combining same into a single stream, each of said plasma collection channels being substantially in registry with said transfer portion of said facing blood flow channel for receiving plasma passing through said membrane, a plasma outlet extending through the end surface of each plate having a plasma collection channel therein for conducting plasma therefrom, and a plasma outlet manifold connected to each plasma outlet for collecting plasma therefrom and combining same into a single stream, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

45. The device of claim 44, wherein said stack of plates contains two plates having blood flow channels in both surfaces thereof, said blood inlet manifold having a single bifurcated channel to divide a single blood stream into two blood streams of equal proportion and said blood outlet manifold has a single bifurcated channel to receive two blood streams and combine same into one blood stream.

46. The device of claim 44, wherein said stack of plates has three plates having a plasma collection channel therein, said plasma outlet manifold being constructed and arranged to combine three plasma streams into a single stream.

47. A device for continuously producing plasma, comprising a stack of interleaved blood plates and plasma plates with each blood plate having a blood flow channel in at least one substantially flat surface thereof and with each plasma plate having a plasma collection channel in at least one substantially flat surface thereof, said stack being constructed and arranged such that each surface having therein a blood flow channel faces a surface having therein a plasma collection channel separated by a semipermeable membrane having a pore size in the range of from about 0.1 microns to about 1.5 microns, a blood inlet extending through the end surface of each blood plate for conducting blood to said blood flow channel and a blood outlet extending through the opposite end surface of said plate for conducting blood therefrom to establish a longitudinally extending blood flow path, each of said blood flow channels having a distribution portion for uniformly distributing blood transversely of the blood flow path and a transfer portion extending longitudinally thereof tapered from inlet to outlet to maintain the blood flow velocity and shear substantially constant as plasma is transferred from the blood and a combining portion for conducting blood from said transfer portion to said outlet, said distribution and said combining portions each comprising a multiple bifurcated manifold wherein the depth of the manifold increases from said transfer portion to said inlet or said outlet, a blood inlet manifold connected to said stack and to each blood inlet for distributing blood from a source thereof substantially uniformly among said blood inlets and a blood outlet manifold connected to said stack and to each blood outlet for collecting blood therefrom and combining same into a single stream, each of said plasma collection channels being tapered and substantially in registry with said tapered transfer portion of said facing blood flow channel for receiving plasma passing through said membrane, and each of said plasma collection channels including a plurality of longitudinally extending grooves having a depth of about 3 mils terminating in a transversely extending collection slot,a plasma outlet for conducting plasma from each of said plasma collection slots, and a plasma outlet manifold connected to said stack and to each plasma outlet for collecting plasma therefrom and combining same into a single stream, whereby plasma continuously transfers from blood passing through said transfer portion of each blood flow channel through the membrane to the adjacent plasma collection channel to said plasma outlet.

48. The device of claim 47, wherein the two outside plates in said stack of plates are plasma plates having a plasma collection channel on the internally facing surface thereof.

49. The device of claim 48, wherein said stack of plates has five plates with two plates having blood flow channels in both surfaces thereof separated by a plate having a plasma collection channel in both surfaces thereof thereby to form a stack with two plasma plates as the outside plates each having one plasma collection channel on the inside facing surface thereof facing a blood plate having blood channels on the surfaces thereof and a plasma plate having plasma collection channels on both surfaces thereof between said blood plates.

50. The device of claim 49, wherein said membrane has a pore size in the range of from about 0.5 microns to about 1.5 microns.

51. The device of claim 47, and further comprising an aperture extending through each blood plate connecting the inlet to each blood flow channel and connecting said outlet to each blood flow channel.

52. The device of claim 47, wherein one plate in said stack of plates has a plasma collection channel in both surfaces thereof and said slot extends entirely through said plate to provide communication between said plasma collection channels.

53. A device according to any of claims 1, 18 or 24, wherein said transfer portion of said blood flow channel is more narrow at the outlet thereof than at the inlet thereto sufficiently to maintain blood velocity substantially constant through said transfer portion.

54. A device according to any of claims 31, 38 or 44, wherein said transfer portion of said blood flow channel is more narrow at the outlet thereof than at the inlet thereto sufficiently to maintain blood velocity substantially constant through said transfer portion.