CA2140141A1

CA2140141A1 - Automated system and method for processing biological fluid

Info

Publication number: CA2140141A1
Application number: CA002140141A
Authority: CA
Inventors: Eric J. Krasnoff; Thomas J. Bormann; Thomas C. Gsell; Frank R. Pascale; Vlado I. Matkovich
Original assignee: Individual
Current assignee: Pall Corp
Priority date: 1992-07-13
Filing date: 1993-07-13
Publication date: 1994-01-20
Also published as: AU674692B2; BE1006620A5; FI950128A; SE514880C2; ITTO930518A0; ATA904293A; US6106727A; IT1270457B; CH685922A5; US5690815A; PL307164A1; AT406638B; ITTO930518A1; GB2284909A; AU4674493A; CN1084426A; SE9500080D0; GB2284909B; JPH07509153A; NL9320039A

Abstract

An automated system for processing biological fluid includes a pressure differential generator; a biological fluid processing assembly, and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly. The automated system may include at least one porous medium in a housing to form a filter assembly, such as a red cell barrier assembly, a leukocyte depletion filter assembly and a red cell barrier leukocyte depletion filter assembly.

Description

21~01 ll WO 94~01193 PCI`/US93/06547 AlrTO~TBD 8Y8T}~ - n FOR
NG B~OI.OGICAI. E~I~ID
..

Ter-hnical Field:
This invention relates to a system for automatically ~ G~c_sing biological fluid and, particularly, to im~o~d methods and apparatuses for preparing, from donated biological fluid such as whole blood, pA~e~ red cells (hereinaft OE PRC), a platelet r-lspDns;on, ~ ly ~-ol.o~ .ated as platelet con~e,.~ ~e (hereinafter PC~, and plasma.

Bac~ ulld of the Invention Donated whole blood may be separated into its various components and analogous ~L Gd~cts, thereby making these different blood products avAilAhle as a transfusion product. For example, a plastic collection bag con~in;~g whole blood may be ~.~ ifuged to form (1) a ~u~e~.atant layer of platelet-rich plasma (PRP) and a sediment layer of r~ red cells (PRC) with a buffy coat (BC) therebetween or (2) a s^~iment layer of platelet-poor plasma (PPP), a rs~iment layer of PRC, and an intermediate layer such as buffy coat (BC~. A bag cont~;n;ng PRP may be centrifuged to form a supernatant layer of plasma and a r-~ iment platelet-con~A;n;n~ layer that may be ~ se~ to formplatelet con-r--~ate (PC). Similarly, a bag cont~iing buffy coat may be ce.lLlifuged to form a 3~e~1.atant layer including platelets and a sediment layer including red cells and the ~eL--atant layer may be separated and ~lo~essed to form PC.

2 1 4 0 1~1 pCT/US93/~ ~7 The separation of whole blood into components as described above may also produce leukocyte contaminated components. It is desirable to reduce the leukocyte conc~ Lion of each of the blood components by at least 70%, since the ~e~el.~e of leukocytes may adversely affect the storage life of the components, and/or cause undesirable effects when they are transfused into a patient.
Accordingly, blood com~c -nts may be lel~ocyte depleted, preferably by passing them thLouyh a ~G~ ~5 medium ~uch as a leukocyte depletion medium.
Additionally, ~L~ ng of blood to provide blood components, particularly to provide leukocyte depleted blood ~ ~ducts, may lead to the ~L~-ence of lS gas or air, in particular oxygen, in the blood components or in the cont~in~ holding the blood components, e.g., a storage container such as a - satellite bag. This may lead to an impairment of the quality of the blood components and may decrease 20 their storage life. Furthermore, the presence of air or gas in the satellite bag may present a risk factor to a patient's being transfused with a blood component.
For this reason, the separation of blood into 25 components has substantial therapeutic and monetary value, placing additional pressure on blood banks to increase component yield and reduce costs per unit of plOC~ =5~ biological fluid.
In view of this, there is a growing need for an 30 efficient system and method for separating a biological fluid (e.g., whole blood) into its components. Blood bank per~onn~l have by attempting L
to increase the yields of blood components in a variety of ways. Hc e~e~, any saving resulting from 35 increasing the yield may be offset by the increased 21401~1 PCT/US93/~ ~7 labor cost, if the operator of the processing system must continuously and carefully monitor the system to increase the yield.
However, increasing the yield may be counte~G~ctive. For example, ex~e_sing more ~ eLl.atant PRP from the collection con~Ain~r to increase the yield of platelets in the satellite container may result in the r~-r~e of red cells into the satellite container. Since red cells are undesirable, the ~u~e~n~ ant fluid must be ~ A~ded or ~ecel.LLifuged ~o that the red cell~ may be separated from the platelets.
Accordingly, the previously described methods reflect a generally unsatis f ying compromise between the pr~s~in~ need to m~ximize the yield of the historically valuable blood comp~ ts such as PC, plasma, and red cells from whole blood samples, and provide for leukocyte depletion, while minimizing the effort and ~ ? involved.
- 20 Because of the high cost and limited availability of blood comronents, a device comprising a porous medium used to deplete leukocytes from biological fluid ~ deliver the highest roccihle p,~o~Lion of the component ~ t 2S in the donated blood and, at the same time, particularly when used in automated system, decrease or eliminate operator inte~ Lion during the ~ocessing. An ideal device for the leukocyte depletion of a blood component would be ;n~ ive, relatively small, and be capable of rapidly ~so~sing blood components obtA~n~d rom about one unit or more of biological fluid (e.g., donated whole blood). Preferably, when the leukocyte - depletion device is used in an automated system, the components may be separated and leukocyte depleted 21~01~1 -PCT/US93106~7 in, for example, less than about one hour. Ideally, automatically processing blood while utilizing this device would reduce the leukocyte content to the lowest possible level, while maximizing the yield of a valuable blood component while minimizing an ~ ive, ~orhicticated~ labor intensive effort by the v~e~a~or of the system. The yield of the blood component ~ho~ be maximized while at the 6ame time delivering a viable and physiologically active component e.g., by minimizing damage due to ~o~es~ing, and/or the pre-^nce of air or gas.

- Disclosure In the devices and methods of this invention, a biological fluid may be y~vC~-~6e~. For example, a lS biological fluid may be pA~re~ from one location to another and/or separated into one or more components or fractions. Typically, a biological fluia is rASCe~ tl~ouy}- a porous medium.
In those aspects inC~ ng separation of a biological fluid such as whole blood into one or more com~o.,~-Ls, the separation is typically carried out within about 6 to 8 hours of the time the blood is drawn. Typically, the eparated component is rA~se~ through a porous medium ~uch as a leukocyte depletion porous medium, during this interval.
Thus, in accordance with the invention, as a biological fluid is transferred from the bag contAining it, leukocytes may be removed by the a~. G~l iate yv~ OU5 medium, and leukocyte-depleted biological fluid may be collected in a satellite bag, without, or with minimal, operator inte~.Lion. In accordance with the invention, a fiyfitem is provided whereby a biological fluid such as whole blood is automatically ~lVC~ to form W094/01193 PCT/US93/~ ~7 any desired component or fraction, such as platelet-rich plasma (P~P) and PRC.
Procecses and systems according to the ~ invention may also include a red cell barrier medium that allows the rA-C--ge of one com~v..e~.L of the biological fluid, but ~lows or even stops the flow of red cell conta;n~g fluid and ~le~.Ls the ra~-^ge of red cells to the satellite bag, thereby minimizing or even eliminating the need for con~;n~o~lC monitoring by an o~_~Lor and increasing the efficiency with which a biological fluid such as - whole blood or PRP or buffy coat is separated into one or more components.
The following definitions are used in refele..~e to the invention:
(A) Blood ~oduct or Biological Fluid: refers to any treated or ~.Lleated fluid ~-c^oc;Ated with living organisms, particularly blood, including whole blood, warm or cold blood, and stored or fresh blood; treated blood, such as blood diluted with a physiological solution, including but not limited to saline, nutrient, and/or an~co^gulant solutions;
one or more blood components, such as platelet ~o~-e~Lla~e (PC)~ platelet-rich plasma (PRP), fresh frozen plasma (FFP), platelet-free plasma, platelet-poor plasma (PPP), plasma, plasma derivatives such as `~yo~Ye~ipitate~ plasma fractionation ~ cts, factor conc~ -~ates; rAc~P~ red cells (P~C), or buffy coat (BC); and analogous blood products derived from blood or a blood component or derived from bone marrow. The biological fluid may inc~ P
leukocytes, or may be treated to remove leukocytes.
As used herein, blood ~Gduct or biological fluid refers to the componPnts described above, and to similar blood products or biological fluids obtAi~pA

_ 5 _ PCT/US93/~ ~7 by other means and with similar properties.
A "unit" typically refers to the quantity of biological fluid from a donor or derived from one unit o~ whole blood. It may also refer to the s guantity drawn during a single donation. Typically, the volume of a unit varies, the amount differing patients and donations. Multiple units of some blood components, particularly platelets and buffy coat, may be pooled or combined, typically by combining 4 or more units.
(B) PO~GU~ medium: refers to at least one porous structure th~vu~h which one or more blood - components or biological fluids pass. For example, the PRC porous medium depletes leukocytes from a red cell cont~nin~ solution or suspension, e.g., from packed red cells. The platelet or PRP porous medium refers generically to any one of the media which deplete leukocytes from the non-P~C fluids, e.g., from BC, P~P, or from PC. The red cell barrier medium as used herein is a porous medium is effective for separating the sediment red cell cont~inin~ com~Gne.,L of blood from the Du~.,atant non-red cell contA~ni~ com~-ol,~..L so that the non-red cell compo~ L may be ~e~ e~ in a container without red cells entering the cont~in~r~ e.g., when separating PRP from P~C.
As used herein, filter assembly refers to the ~ ù5 medium positioned in a suitable housing.
Suitable housings include those disclosed in U.S.
Patent Nos. 4,880,548; 4,925,572; 4,923,620;
5,100,564; 5,152,905; and U.S. Serial No.
07/846,587.
The porous media are suitable both for use with any biological fluid obtained from donated blood, including fluid obt~in~ soon after the blood is 2 1 1 0 1 ~ 1 PCT/VS93/~ ~7 drawn, typically within about 8 hours and for use with stored biological fluid. It may be desirable to include a pre-filter, e.g., to reduce clogging, particularly when filtering stored biological fluid.

A porous medium may be pre-formed, multi-lay~e~, and/or may be treated to modify the curface of the medium. If a fibrous medium i8 used, the fiber~ may be treated either before or after forming the fibrous lay-up. It is preferred to modify the fiber surfaces before forming the fibrous lay-up because a more cohesive, ~L~v~ye~ ~G~uCt is obtAire~ after hot compression to form an integral filter element.
The porous medium may include at least one of a prefilter element or layer and a filter element or layer. The porous medium may additionally include at least one element or layer to provide ~u~po~L, better drainage, and/or im~ G~e~ flow characteristics, such as more uniform flow distribution.
The ~v~ medium may be configured as a flat sheet, a ~o~l~yaLed sheet, a web, or a m~hrane.
The porous medium may be a depth filter, a single layer, or a composite of at least two fiber and/or membrane layers. Preferably, the ~Ol~uS medium forms an interfe~ ~ fit at its edges when assembled into the ho-~ci~g (C) Separation Medium: A separation medium refers to at least one ~o~ous medium effective for separating one component of a biological fluid from another component by passing the biological fluid in a cross flow or ta~gential flow manner with respect to the porous medium. The separation media according to the invention are suitable for p~c~ing `- WO94/01193 2 1 4 0 1 4 1 PCT/US93/~ ~7 at least one component of the blood product or biological f luid, particularly plasma, therethrough, but not other compQnents of the blood product or biological fluid, particularly platelets and/or red cells.
The separation medium may be pre-formed, multi-layered, and/or may be treated to modify the surface of the medium. If a fibrous medium is used, the fibers may be treated either before or after forming the fibrous lay-up. It is preferred to modify the fiber ~urfaces before forming the fibrous lay-up because a more rohPsive, ~L~G~y~r ~lC~uCt is obt~in~ after hot compression to form an integral filter element.
lS ~he ~eparation medium may be configured in any suitable fashion, such as a flat sheet, a ~o~lu~ted sheet, a web, hollow fibers, or a membrane. The separation medium may be a depth filter, a single layer, or a composite of at least two fiber and/or membrane layers.

Brief Descrimtion of the Drawin7s Figure 1 is an embodiment of a biological fluid o~e~sing system according to the invention.
Figure 2 is another embodiment of a biological fluid ~Iv~esc;ng system according to the invention.
Figure 3 is an optional biological fluid processing assembly segment which includes a separation medium.
Figure 4 is an optional biological fluid pro~e_sing assembly segment which includes a gas inlet and a gas outlet.
Figure 5 is a flow chart of an exemplary initial sequence according to the invention.
Figure 6 is a flow chart of an exemplary ~?CQ~

2 1 4 0 1~ pCT/US93/~ ~7 sequence according to the invention.
Figure 7 is a flow chart of an exemplary third sequence according to the invention.
Figure 8 is a flow chart of an optional priming seguence.
Figure 9 is a flow chart of an exemplary sequence sccording to the invention.
Figure 10 is a flow chart of an optional venting seguence according to the il-v~-Lion.
Figure 11 is a flow chart of an exemplary sequence according to the invention.
Figure 12 is a ~e~e_~ive view of a first emh~iment of a differential pressure generator for use with embodiments of a biological fluid ~G,~ing gygtem according to the i,.~el.Lion.
S Figure 13 is a ~e~e_~ive view of a cecon~
embodiment of the differential ~e~ e generator according to the invention.
Figure lA i8 a partially cross-sect~on~l side elevation of a third embodiment of the differential pressure yOl.el~Lor according to the i..vel.~ion.
Figure 15 is a partially cross-sectional side elevation of the third embodiment of the differential pressure ~e..e~or of Figure 14.
Figure 16 is a top view of the third em~hoAiment of the differential pressure generator of Figure 13.
Figure 17 is a front view of an embodiment of a biological fluid ~o~essing system according to the - invention.
Figure 18 is a ~e~Lesentational block diagram of an embodiment of the biological fluid processing system according to the invention.
Figure 19 is a flow chart of an exemplary sequence according to the invention.
Figure 20 is a flow chart of an exemplary PCT/US93/~ ~7 sequence according to the invention.
Figure 2l is a flow chart of an exemplary sequence according to the invention.
Figure 22 is a flow chart of an exemplary sequence according to the invention.
- Figure 23 is a block diagram of an emhoA;ment of a portion of the biological fluid ~lG~essing system according to the i"v~.lLion.
Figure 24 is a partially cross-sectional view of a fourth embodiment of an ~-qure differential generator according to the invention.
Figure 25 is a view ~f the fourth embodiment of Figure 24.
Figure 26 is a view of a motor mount of the fourth embodiment of Figure 24.
Figure 27 is a view of a kneader block and a ~eA~r fist of the fourth embodiment of Figure 24.
Figure 28 is a partially cross-sectional view of a preferred emhoAiment of an pressure differential generator according to the invention.
Figure 29 is a top view of the preferred embodiment shown in Figure 28.
Figure 30 is a partial cross-sectional view of the preferred emhoAiment of the ~ e 2S differential generator coupled to a portion of a co~ ol unit.
Figure 3l is another emhoAiment of a biological fluid ~Lo~eæsing system according to the invention.
Figure 32 is an explanatory view of an embodiment of a ~ e ~~Le differential y~.~ator according to the invention.

Modes for CarrYing out the Invention The present invention involves a biological fluid ~o~essing system comprising a ~Les~e WO94/01193 PCT/US93J~547 differential generator; a biological fluid processing assembly including a first container such as a collection cont~i n~r operatively associated - with the ~e~Le differential generator, a ~?cQn~
container in fluid communication with the collection cont~iner, and a porous medium interposed between the collection container and the -eco~ container;
and an automated ~G1~LLO1 arrangement coupled to at least one of the pressure differential generator and the biological fluid ~ro~e--sing assembly to ~OI.~ ol flow between the collection contA;~r and the FeCQ
cont~in~r~
In a preferred e_ho~iment~ the biological fluid ~lGc~__ing assembly inCl~Aes a first porous medium, comprising at least one of a l~koçyte depletion medium, a red cell barrier medium, and a combined leukocyte depletion red cell barrier medium; and/or a ~eCQn~ porous medium, which may be a leukocyte depletion medium which may, optionally, include a microay~Leyate filter element and/or a gel pre-filter element.
The in~ention also includes a method for automatically ~lG~e sing a biological fluid comprising expressing a biological fluid from a first contA;n~r to at least one ~O~G~S medium cuch as a leukocyte depletion medium, a red cell barrier medium, a red cell barrier leukocyte medium, and a separation medium. The method may also include ~ G~e_sing the fluid U~ough additional contAin~rs~
flow paths, and porous media, and the system may be designed to process more than one separate unit at the same time.
Preferably, the method comprises eX~ cing a biological fluid from a first con~ er to a first porous medium comprising a red cell barrier medium;

WOg4/01193 ~1~01 4 1 - PCT/US93/~ ~7 and expressing a biological fluid from the first cont~in~ to a second porous medium.
The invention includes a method for automatically processing a biological fluid comprising:
a) p~ ng a cont~inDr of biological fluid into an enclosed chamber of a differential pressure ge~ or; b) supplying a cignal from an automated ~G.~LO1 ~rrangement to the differential pressure y~.~.a~or; and c) in ~ OI~? to the signal, varying pressure within the chamber to establish fluid flow into or out of the cont~; n~, The invention also includes a method for automatically ~o~__sing a biological fluid comprising:
a) placing a cont~;~e~ of biological fluid into an enclosed chamber of a differential pressure generator; b) ~upplying a signal from an automated ~Gl~ol arrangement to the differential pressure generator; and c) in ~e_po.l-c to the signal, varying ~e~ e within the chamber to establish fluid flow into or out of the cont~in~r.
A method according to the invention includes automatic~lly ~lG~essing a biological fluid comprising:
a) estab~ ;ng flow of a first portion of a biological fluid along a first fluid flow path to at least one of a leukocyte depletion porous medium, a - red cell barrier medium, or a combined leukocyte depletion red cell barrier medium; b) generating a signal indicative of the separation of the first portion of the biological fluid and a æecQn~ =
portion, and supplying the signal to an automated ~GI1ILO1 arrangement; and c) in ~e~ol. e to the signal, terminating flow tl~ou~h the first fluid flow path.

$3~i3~ I c ~ ~ ~ r~

_W094/01193 Z1 4 0 1 4 1 PCT/USg3/~ ~7 A method for processing a biological fluid according to the invention comprises separating a biological fluid into a supernatant portion and a - sediment portion; and passing at least one of the S Dù~l..atant portion and the sediment portion tl~o~yl-at least one porous medium, wherein said passing includes initiating, monitoring, and terminating flow of the portions by an automated ~o---.ol arrangement.
The invention al80 involves a method for automatically ~o~eD~ing a biological fluid separated to form a D~ .atant layer snd a sediment layer comprising, passing the ~u~e~l.atant layer of the separated biological fluid th~G~y11 a first ~o~v~s medium, the first ~OL~US medium comprising at least one of a leukocyte depletion medium, a red cell barrier medium, and a combined leukocyte depletion red cell barrier medium; and passing the sediment layer of the separated biological fluid ~ou~ a ~con~ ~.ous medium, the -ecQn~ porous medium comprising a leukocyte depletion medium.
The invention also may involve separating the biological fluid into three layers -- the s~e~..atant and sediment layers as noted above, and an intermediate layer. In the emhoAiments of the invention in which an intermediate layer or zone is formed, the intermediate layer or zone, typically buffy coat, can be further ~GC~S~ into a s~conA
~u~eLl.atant layer and a cecon~ se~;ment layer. The S? Dn~ ~u~e~..atant layer may then be passed through a third porous medium comprising at least one of a leukocyte depletion medium, a red cell barrier medium, and a combined leukocyte depletion red cell barrier medium. The ~?con~ sediment layer may be passed through a fourth porous medium comprising a leukocyte depletion medium.

SUBS~Il~U~E ~:-3 ` WO94/01193 2 1 4 0 1 4 1 PCT/US93/~ ~7 Exemplary automated ~iological fluid collection and processing systems are shown in Figures l, 2, 17, 18, 23, and 3l. A system according to the invention may comprise a pressure differential generator 51, e.g., an expressor, or the like, suitable for inducing fluid flow from a contA;ner such as a collection cont~; n~ 11 to other parts of the _ystem, or inducing flow from other parts of the system to collection cont~iner ll. The pressure -differential generator is operatively associated with a biological fluid processing assembly, an example of which is shown as lO in Figure l.
The individual parts which constitute a biological fluid ~loc~r~C~ng assembly lO may vary according to an intended use. In the illustrated embodiments, the biological fluid processing assembly lO may comprise a first container or collection bag ll; a needle or the like l to be inserted into or connected to the donor; a red cell barrier assembly 12; a first leukocyte depletion assembly 13, preferably suitable for removing leukocytes from a platelet-cont~ining solution or suspension, e.g., PRP; a second container (e.g., a first satellite bag) 41 suitable for receiving and/or storing a platelet-contA;n;ng solution or ~ pencion~ for example; an optional fourth container (e.g., a third satellite bag) 42 suitable for receiving and/or storing platelet co~;e,.L~ate or plasma, for example; a s~conA leukocyte depletion assembly 17, preferably suitable for removing leukocytes from a red cell cont~i ni ng solution or s~crDncion, e.g., PRC; and a third container (e.g., a second satellite bag) 18 suitable for receiving and/or storing a red cell cont~ining solution; and at least one flow co~ ol device, 61, 62, 63, 64.

SUSS7'1~U~E ~ E I

- wo g4/0ll93 2 1 i O 1 4 1 PCT/US93/~ ~7 In other embodiments, for example as illustrated in Figures 3 and 31, the biological fluid assem~ly 10 may include a separation assembly 81, preferably a ~O~ L~ifugal separation device. The biological fluid processing assembly lO may include at least one gas co-,~ol element such as a gas inlet 99, 74, and a gas outlet 98, 73, 74, ~s exemplified in Figures 1, 3 and 4.
Each of the assemblies or cont~n~rs may be in fluid communication t~uo~l, ron~l~its 20, 21, 25, 26, 27 or 28. A seal, valve, clamp, pinch clamp, or transfer leg closure or r~nnVl~ may also be positioned in or on the tubing or in the collection and/or satellite bags. Tn accor~-n~e with the ~ nt invention, the assemblies, cont~in-~s, flow ~o~,L~ol devices, gas ~o.,L~ol elements, and ro~ 1ts may be pre~iously co.~.~cted in a closed, sterile manner, or segments of the system may be inserted into a closed system in a sterile manner.
In accordance with the ~-ent invention, -sin~ a biological fluid t~v~yh the system can be automated by coupling an automated cu-,~ ol arrangement to the biological fluid p~oce3sing assembly 10 and/or to the ~er~re differential generator 51. The individual parts which constitute an automated ~o.,~ ol arrangement may vary according to an inten~ use. In the illustrated embodiments, the automated CGl~ ol arrangement may comprise a ~v-,L~ol unit 50, typically a mi~lG~o~e-ror ~o"L~oller, and one or more ~^nF~rs, and may be coupled to at least one of the pressure differential y~~ or 51 and the biological fluid ~l GCe sing assembly 10 to c~l~ol flow between the first container 11 and another container 41 and/or 18.
Each of the comron~nts of the assembly will now i _ W094/01193 2 1 ~ O 1 4 ~ PCT/US93/~ ~7 be described in more detail below.
Movement of the biological fluid through the system is effected by maint~i ni n~ a pressure differential between the container holding the biological fluid, e.g., the collection con~;ne~, and the destination of the biological fluid (e.g., a container such as a satellite bag). Exemplary means of estab1~h~ng this ~Pr~re differential may be by a mech-nic~1 member such as a plate bearing directly against the collection container, an ~ or such as a mechAnical, pneumatic or hydraulic ex~e_sor, gravity head, applying ~ re to the collection bag by hand or with a ~e_~u,e cuff, by rl~c-ing the other con~in~r (e.g., satellite bag) in a chamber (e.g., a vacuum chamber) which establi~ec a ~e~u~e differential between the collection bag and the other cont~in~r, or ffl a pump such as an in-line pump.
In accor~-nce with the invention, e~ ors which ~eneL~te substantially equal pressure o~er the entire collection bag may be used. Also included are e~e_sors which ~ e or agitate the biological fluid, and expressors which are capable of rotating on an axis, e.g., so that the u~c~ h~rge ronAnjt becomes a lower ~i~c~rge co~ t.
Alternatively, the collection cont~n~r may be c~r~hle of rotating along its horizontal axis in order to change the relative position of the ~i~rh~rge CO~All ~ t.
An exemplary pressure differential y~-lelator may include a housing defining a chamber suitable for positioning a container therein. The housing or chamber may be in fluid communication with a ~-es~le regulating merh~nism suitable for varying the fluid pressure applied to the outside of the ~ 1 ~ n 1 A1 PCT/US93/~ ~7 ~ W094~01193 ~l~ul~l container positioned in the chamber. In a preferred emhoAiment~ the pressure differential operator includes an enclosed housing defining a chamber such that the ~_s~re within the chamber may be increased or decreased substantially evenly over the entire outside of the container.
The pressure differential generator may also be arranged to resist distortion of the container ~nd to promote uniform and complete e~ on of fluid from the cont~in~r~ The ~ r-~re differential generator may also be arranged to ~ix the contents of the cont~ r, e.g., the PRC and an additive or ~_Lv~tive solution.
The biological fluid ~vce~sing assembly may include any number and combinations of assemblies, ~GrVUD media, flow ~onLLol devices, gas ~Gl.L~ol elements, cont~in~rS, and cQnA~lits interconnecting them. One skilled in the art will r~co~ni~ that the invention as described here may be le~o,.rigured into different combinations. Exemplary biological fluid ~.ooe-~ing assemblies are disclosed in U.S.
Patent 5,lOO,564 and International Publication No.
WO 92/07656.
In accordance with the invention, the conduits, assemblies, porous media, gas col.L,ol elements, containers, and flow cvn~ ol devices which constitute a biological fluid ~rvce_sing assembly may be arranged to define different flow paths for biological fluid and/or gas. For example, when whole blood is p~v~ e~, the PRP may flow along a first flow path, e.g., t~ouyl. a red cell barrier assembly (if p e_ent), a PRP leukocyte depletion assembly, and into a satellite bag (e.g., a -econ~
con~ier). Similarly, the PRC may flow along a ~?~Qn~ flow path, e.g., tl~vu~ll the PRC leukocyte 21~U~ 1 PCT/US93/~ ~7 _ WO94/01193 depletion assembly, and into a satellite bag (e.g., a third container). Since independent flow paths may be present, included within the scope of the present invention is the rono ~e..L or sequential passage of separate biological fluidg (e.g., PRP and PRC) t~v~h the biological fluid ~o~essing assembly.
The cont~in-rs and ron~its which are used in the biological fluid ~oce~it~ a~sembly may be ~o..~Llucted of any material compatible with a biological f luid and gas, ~uch as whole blood or a blood com~vl.e~.L. Preferred emh~iments may be cap_ble of withs~An~; ng a ~-L,ifugation and sterilization environment. A wide variety of these containers are already known in the art. For example, blood collection and satellite bags are typically made from plasticized polyvinyl chloride, e.g. PVC plasticized with dioctylphthalate, diethylhexylphthalate, or trioctyltrimellitate. The bags may also be formed from polyolefin, polyurethane, polyester, and polycarbonate.
The con~7t~it may be any tubing or means which provides fluid communication between the cont~n~rs, and is typically made from the same flexible 2S material as is used for the cont~it7ers, preferably plasticized PVC. The co~ t may be compatible with an automatic ~e~lin~ system. It is intended that the present invention is not limited by the type of material used to ~on---LLuct the containers or the co~t7-ts which co, .~L the cont~i~7~rs The cont~jners and/or CQ~7llitS may be modified according to an in~enr7e~ use. For example, the con~ rs may include at least one internal passageway to allow fluid to flow to or from a particular portion of the cont~in~r located near the ~l~Ul~l PCT/US93/~ ~7 passageway. The container and/or CQ~tl; t may be segmented, compa~tmentalized and/or enlarged, typically to provide for isolation of a portion of the biological fluid, e.g., for sampling.
s The cQ~t~it may extend into the interior of the container. There may be a number of tubes providing fluid communication to any individual container, and the tubes may be located in a number of wayg. For example, there may be at leagt two tubes located at the top of the collection bag, or at the bottom of the bag, or a tube ~t each end of the bag, or a tube exten~itt~ from an intermediate portion of the bag.
Included within the sc~r~ of the p~e-e~t invention are single inlet and/or ~ ge tube containers 5 (U~PL and lower); two inlet and/or ~ h-rge tubes (upper, lower, and both); three tubes tupper, lower, and/or intermediate), and variations on any of these configurations. Also included within the scope of the ~.escnt invention is the use of at least one clamp A~sociAted with a contAinDr for phy~i~A11y separating a layer within the container from another layer.
A flow ~o-.L ol device, such as a seal, valve, clamp, pinch cl Q , roller, transfer leg closure, or the like is typically located in or on the ro~ its and/or contAiners~ In accorAAn~e with the invention, a flow con~ol device may be positioned on or in any or all of the conduits and/or containers in order to facilitate a desired function, i.e., establi~hing a desired flow path for biological fluid or gas. Preferably, the flow COll~ ol device may be collL,olled, e.g., o~rlP-7 and closed, in rel~ to the automated oon~ol arrangement. It is int~n~ that the ~e~
invention should not be limited by the number, - 2 1 g O 1 4 1 Pcr/vs93/o6~7 placement, or use of such flow co-, LL ol devices.
The porous media for removing leukocytes from a biological fluid may be any media which effectively removes leukocytes without having a deleterious effect on the biological fluid passing theret~ohy~.
In an emhc~ment of the invention, a porous medium for use with a biological fluid such as a non-red cell contA~n;n~ layer (e.g., PRP) may comprise a medium disclosed in U.S. Patent 4,880,548. In a preferred emhcAiment of the invention, a ,0l0~8 medium for use with a biological fluid such as a red cell cont~ n~ layer (e.g., PRC), may comprise the type of media disclosed in U.S. Patent 4,925,572 and ~.S. Patent 4,923,620, as well as ~.K. Patent Application No. GB 2,231,282A.
In a~cordance with the invention, the conduits, filter assemblies, porous media and contAiners may - be positioned according to an in~n~e~ use. For example, as shown in Figure 17, ~atellite bags 18, 41 and 42 may rest on a flow meter 72. In other embodiments (not shown) at least one r ~ ~ L means including but not limited to a tray, a scale, a bracket, a hook and a chamber may be used to ~u~G~
or hold at least one container bag in a desired position and/or at a desired location. For example, the s 1~0'L means may hold the satellite bag in an inverted or an upright position and/or at a different level than the collection bag ll. The ~U~Ol~ means may also be suitable for weighing at least one contAin~.
A red cell barrier medium, in accordance with the present invention, comprises a porous medium that allows the separation of a non-red cell contAi~;nq biological fluid, such as a suspension of platelets and plasma, from a red cell cont~;n;~g ` - 21gOl~l .
WO94/01193 PCT/US93/~ ~7 biological fluid. The red cell barrier medium prevents the red cell con~i n; ng biological fluid from entering a cont~in~r such as a satellite bag or a receiving cont~in~r ~; ~L~-am of the barrier S medium. The red cell barrier medium allows the non-red cell con~Ain;ng fluid to pass theretL~~l. but ~iqn;fican:tly 810ws or effectively stops the flow of h;~lo~ical fluid ~s the red cell conta~ning fluid approaches the barrier medium. Accordingly, a 10 ~ r ~Atant non-red cell cont~in;ng fluid such as a platelet ~V~rencion may be separated from a _ediment red cell cont~ining fluid by rA~^;ng the platelet ~ ion t~a~ a red-cell barrier medium.
Accordingly, a ~u~ L no.l ~ed cell contA;n;ng fluid such as a platelet ~ ion may be separated from a ~-~;ment red cell contAi~ing fluid by passing the platelet ~--sreneion t~ouyh the red cell barrier medium. For example, the red cell barrier medium may allow a platelet-cont~ining fluid to pass theret~ouy~, abruptly ~topping flow when red blood cells blocX the medium.

By clowing the flow of the biological fluid, the barrier medium allows the ~e~aLor or the automated co..L ol arrangement to manually stop the flow to ~ ~v~llL the red cell cont~;n;ng biological fluid from entering a con~ er such as a satellite - -bag or a receiving container do~ L eam of the barrier medium. This embodiment of the invention allows the operator or the automated ~o--L ol arrangement more time to intervene and stop the flow. For example, a ~u~e~..atant platelet-con~;n;ng fluid may flow thlo~yh the red cell karrier medium at an initial rate of about 15 ml/min, but the flow may decrease to about 5 ml/min 2 1 4 0 1~1 PCT/US93/~ ~7 as a sediment red cell con~Ai~;ng fluid approaches the medium. A reduction in flow, e.g., a 33%
reduction, may provide the operator sufficient time to stop the flow at the a~,o~iate time. In some circums~Anc~s, for example, when platelet ~o~,~Aininq fluid is ex~le--~ed from a plurality of separate bags at ~ro~imately the same time, this reduction in flow allows the o~cu~or to ~ a greater number of containers more efficiently.
A prinCir~l function of the red cell barrier medium i~ to ~eparate a red cell cont~i n; ng fraction of a biological fluid from a non-red cell con~ining fraction. The red cell barrier medium may act as an automatic "valve" by slowing or even stopping the flow of a red cell-cont~ining biological fluid. In some embodiments, the automatic valve function may quickly or instantly stop the flow of the red cell-cont~;ning biological fluid, thereby obviating the need for the O~L a~or to monitor this step.

The valve-like action is not well understood, but it is believed that flow is slowed or storre~
due to ay~.eyation in or on the medium of one or more constituents in the biological fluid. For example, at the ~es^nt time, it is believed that as the non-red cell cont~in;n~ biological fluid pACces through the medium, leukocytes are depleted from this fluid. These leukocytes appear to accumulate in or on the medium, but the remainder of the non-red cell cont~ining fluid typically flows through the medium. Hc~_~e~, on¢e red cells directly or indirectly contact the medium, e.g., directly contact the medium or contact the leukocytes which, in turn, may directly contact the medium, flow through the medium slows significantly, even stops.

' ' 21gU141 ~ WO 94tO1193 PCT/US93~06~7 Without inten~; ng to be limited to any particular explanation for the mech~n;sm of this valve-like - action, it is ~,fscntly believed that the slowing or - storp~ge of flow may reflect ay~.ey~tion of the red cells alone and/or in combination with leukocytes, forming a barrier which ~vel.Ls or blocks further flow tLrouyL the ~o~v~s medium. It may be that other factors, such a~ the zeta potential, the CWST, and/or other characteristics of the fibers or the porous medium may ~o,.-Libute to the valve-like action.
In one embodiment of the invention, the leukocyte depletion efficiency of the red cell barrier medium is incr~ , and ~o the red cell barrier medium may also r~-~Lion as a leukocyte depletion medium. Exemplary red cell barrier media and red cell barrier/leukocyte depletion media are disclosed in U. S. Patent Nos. 5,100,564 and 5,152,905; ~.S. Serial Nos. 07/846,587 and - 20 07/896,580; and International Publication No. W0 91/04088.
--In another exemplary configuration, the biological fluid ~G~essing assembly may inc~ Ae a separation assembly 81, preferably a ..on _~.LLifugal separation assembly, as shown in Figures 3 and 31.
This embodiment of the present invention involves the separation of one or more COm~G~ LS
from a biolog;c-~l fluid without subjecting the biological fluid to centrifugation. In another aspect, one or more com~ol-~ts may be separated without subjecting the biological fluid to hand spin - centrifugation. In accor~n~ with the ~~ent invention, a biological fluid, particularly whole - blood or P~P, may be ex~o_^A to a separation-medium suitable for passing at least one component of the ~ W094/01193 ~ 4 ~ PCT/US93/~ ~7 biological fluid, particularly plasma, therethrough, but not other components of the biological fluid, particularly platelets and/or red cells. Clogging of the separation medium by these other components is min;m;zed or ~ ev~.Led. Prefer_bly platelet A~heciOn to the separation medium is minimized.
An embodiment of a ~eparation assembly which includes a separation medium may be considered a ..o,. c~.LLifugal separation assembly. A biological fluid may be pAC-^~ th~Gu~h the ,.o.. _~.L~ifugal separation aæsembly where it may be separated into components which may be ~eparately collected in contA i n~æ .
In accordance with the invention, a biolo~icA-fluid may be ~o~c--^~ to form a Du~eL..atant layer and a sediment layer, and the ~u~l..atant layer (e.g., PRP) may be rAC-e~ t~lvuyL at least one filter assembly such as a leukocyte depletion filter ass~mhly, a red cell barri OE filter assembly, or a red cell barrier/l~kocyte depletion filter assembly, and then pAC-^~ t~vu~ a nv.. _~--Lifugal separation assembly where it may be ~ oco-~e~ and separated into components, which may be separately collected in container 41 and container 42. In a preferred emhoA;ment, if the ~ .,atant fluid is PRP, it may be r~c~^~ t~ a red cell barrier filter assembly 12 or a red cell barrier filter/leukocyte depletion filter assembly, and then r~S~^~ t~v~g1. a no~ ..L~ifugal separation assembly it may be separated into a plasma rich fluid, e.g., plasma, and a plasma-depleted fluid, e.g., a platelet cont~;n;ng fluid as platelet conc ..L aLe, as the PRP p~55^C through the ~Gn _entrifugal separation device. The sizes, nature, and configuration of the ~-esent inventive device can be - WO94/01193 ~lgO1~1 PCT/US93/~ ~7 adjusted to vary the capacity of the device to suit its intenAe~ environment, and may be suitable for - recirculating biological fluid th~ v~yh the separation assembly. Addi~ionA11y, multiple separation medium assemh1i~ may be uced. Exemplary separation media and assemblies inCll~e but are not limited to those ~c~r~ in International ~s~tion Nos. W0 92/07656 and WO 93/08904. -In a preferred emh~Alment, the ~ nt invention may u~ cross or tangential flow tothe separation medium. For example, a differential pressure generator sUch as a peristaltic pump 300 may be used to direct a biological fluid such as PRP
tangentially to the surface of the separation medium such that the plasma-rich fluid, e.g., plasma, ~ Lh~vuyh the separation medium, and the plasma-depleted fluid, e.g., a platelet-contA;ning fluid, pAr~?fi ta--y~.~ially across the separation medium.
The placma depleted fluid passing t~-y~.Lially across the separation medium may be repeatedly recirculated through the s~a~Lion assembly.
TYP;~A11Y~ recirculation is repeated until the plasma depleted fluid in the satellite bag contains a pre-determined amount or cr.ce,.L~aLion of the desired component, e.g., platelets.
In a more preferred embodiment, passing biological fluid L~vuyh the separation assembly may also include providing a ~ e ~e~ e differential across the ~eparation medium, e.g., by creating a backflow across the medium. Without - inten~i~g to be limited to any explanation of the me~h~nism, it is presently believed that a ~ ae - ~le_~u~- differential may provide for minimizing platelet adhesion to, or contact with, the WO94/01193 2 1 4 0 1 4 1 PCT/US93/~ ~7 separation medium. The L e~e~e pressure differential may also provide for minimizing clogging of the separation medium by blood components such as platelets and/or red cells.
S Typical devices for creating a rev~se pressure differential include, but are not limited to at least one of a pump such as a perictaltic pump, a -valve such as a check valve and the like.
The nu~ber, type and location of the devices which create the ~ev~L~e ~~ u~e differential as - well as the manner of creating the pressure differential may be varied ac~o~ing to an intDn~
use. In one embodiment of the i~,v~,Lion, as exemplified in Figure 31, at least one ~e~ e differential pressure generator such as a peristaltic pump 400, may be located between the separation assembly 81 and a con~; n-r such as a satellite cont~;ner 42, to provide for backflow across the separation medium. As shown in Figure 3, the biological fluid ~.v~ ng assembly may al~o include ron~ ts 301, 303, and 304, as well as flow co..~ ol devices 65, 66, and 67.
In a preferred embodiment, the ~ L~e differential pressure creating device provides for p~ e~ backflow across the separation medium in the separation device 81 while there is cont~n~o~C
transverse or cross flow across the separation medium. As used hereinafter, the term np~ n refers to -G-- _o1.~inuous, periodic, or intermittent backflow across the separation medium.
In the embodiment illustrated in Figure 31, r~1~e~ backflow may be provided by a ~el~e e differential generator 400, while transverse flow may be provided by a ~e~ule differential generator 300.

` ~ 1 4 0 1 4 1 PCT/US93/~ ~7 WO g4/01193 With respect to the reverse differential pressure generator 400, a peristaltic pump providing less than a 100% duty cycle may be utilized to - provide for r~lre~ backflow. Typically, a duty cycle of less than about 75%, more preferably, less than about 50%, may be utilized. A~s shown in Figure 32, a peristaltic pump 400 including a rotor 320 utilizing a single roller 321 may be used. Multi-roller peristaltic pumps ~ay also be used, preferably after removing at least one roller.
In ~n~alistinction, differential ~ re ye.._l~Lor 300 r~o~ preferably provide continuous, rather than r~l~eA, flow. ~cQrdingly, if differential ~ ~e ~le~ator 300 is a peristaltic pump, the duty cycle f~ be greater than about 75%. Thus, while differential ~.es~le generators 300 and 400 may both comprise peristaltic pumps, in a preferred embodiment, 300 may be a multi-roller peristaltic pump, while 400 may be a single roller peristaltic pump as described above.
~n accordance with the i~vel~ion~ the - biological fluid ~c~-~sing system may in~ Ae at least one gas ~G~.LLol element to allow gas, such as air, to be moved or displaced as desired during ~ocessing. For example, a gas ~o..~lol element may be used to remove gas from the system, to separate or displace gas from one part of the system to another part, to i~ d~ce gas into a biological fluid ~lo~ ;ng system or to separate gas from the biological fluid being ~ re~. Exemplary gas co,.Llol elem-ents include, but are not limited to, at least one of a gas inlet, a gas outlet, a gas collection and displ~cement loop, a gas container, a bypass conA~t and a conduit which extends into the biological fluid in the container, or combinations ~ A~ PCT/US93/~ ~7 _ W094/01193 ~14Ul~l of any of these. Gs control elements may be used together or separately. For example, vents such as a gas inlet and a gas outlet may be used together in connection with at least one assembly, porous medium, or contA~in~r in the system, or they may be used separately.
As used herein, gas refers to any ~? 1~
fluid, such as air, ~teri1;~e~ air, o~y~ carbon ~i9Yi~, and the like; it is in~ that the invention is not to be limited to the type of gas used.
It may be desirable to displace or remove gas, since, for example, gas ~h~-~ of a column of biological fluid may clog or impair the function of a porous medium such as a leukocyte depletion ~o~o~
medium used to treat the biological fluid. Also, gas in the receiving con~Ain~ may affect the ~lo~e~ed biological fluid stored in that cont~iner.
Accordingly, an ~fipCt of the instant invention provides means and methods for minimizing the volume of gases that remain in, or in contact with, a biological fluid during storage.
It may be desirable to displace, i~.L~G~uce and/or remove gas to maximize the 1e_V~ of a biological fluid retained or e~LL~ e~1 in various elements of the biological fluid ~Lo~er-sing system as this valuable fluid would otherwise be lost. For example, under typical conditions, using a typical device, the biological fluid will drain t~lv~1- the system until the fIow is ~orp~, leaving some of the fluid in the system. In one embodiment of the invention, the retAin~ fluid may be re~v~e~e~ by using at least one gas ~o..Llol element, for example, a gas collection and displacement loop, a g~s container, at least one gas inlet and/or at least ~140141 - WO94/01193 PCT/US93/~ ~7 one gas outlet.
For example,-with respect to the emhoAiments illustrated in Figures l and 4, a gas inlet 99 or 7 may allow gas into a biological fluid ~G~e_sing system, e.g., to increase the rec~v~ of biological fluid that may otherwise be retained in various - components of the system during ~o~ s~-ing. With respect to Fi~ules 1, 3 and 4, a gas outlet 98, 73, or 75 may allow gas that is ~r-~~t in the biological flu~d ~~ ing sygtem to be separated from the biological fluid being ~oc~e~, e.g., by separating gas-from the system or by displacing gas to another part of the system. In a preferred emkodiment of the invention, either or both of the gas inlet and the gas outlet may be selectively operable between an open and closed position by the co.,LIol arrangement.
In other emho~iments, at least one of a gas collection and displacement loop and a gas con~in~r (not shown) may be used to move gas, more preferably to ~e~aI~e gas from the biological fluid and/or from the cont~iner of biological fluid; or to ~ o~e biological fluid retained in various components of the system. For example, biological 2S fluid may be p~r^~ th~ouy}, a filter assembly 12, 13 and/or 17, and the fluid r~ssing thereth~ou~}., along with the gas displaced by the fluid, may be collected in a satellite cont~iner. Gas may be separated by passing it into a gas collection and displacement loop. In some embodiments, the separated gas may be used to purge the ~on~l~its and assemblies, e.g., ~y passing the gas into the inlet of the assembly, thus ~chasing" L.-~ed fluid into - the do~ ~ eam cont~iner. In another aspect, gas may be stored or collected in a gas container, and WO94/01193 21 4 O 1~1 PCT/US93/~547 this gas may be fed through at least one of a ro~ltit, a porous medium and a filter assembly, to purge the biological fluid, thereby facilitating the leoo~ely of the biological fluid trApre~ during ~LoccOsing.
An exemplary gas inlet and gas outlet may be described by ref~ e to Figures 3 and 4, both of which illuD~ ~Le optional flow paths which may be added to a biological fluid ~,o~e~sing assembly l0.
When such a flow path is inserted into an assembly, it may be desirable to remove gas from the flow path. In Figure 3, this may be aCcompl;ch^~ by activating or open~ gas outlet 73. In Figure 4, gas outlet 75 may be opened or activated to remove air from the flow path, and gas inlet 74 may be Gle~ or activated to allow additional ~e~ovely of biological fluid from the filter assembly 17. In a preferred emhoAiment~ both gas outlet 73 and gas outlet 75 are automatic outlets, i.e., contact with biological fluid closes the outlet automatically.
Other exemplary gas inlets and gas outlets are also ~clo--~ in International ~hli~Ation No. WO
9l/17809 and ~.S. Patent No. 5,126,054.
The gas inlet and gas outlet are rhoc~n so that the sterility of the system is not compromised. The gas inlet and the gas outlet are particularly suited for use in closed systems, or may be used later, for example, within about 24 hours of a syOtem being opened.
The gas inlet and the gas outlet each comprise at least one porous medium designed to allow gas to pass therethrough. A variety of materials may be - -used, provided the requisite properties of the particular porous medium are achieved. These include the neC~c~ry Otlelly~h to h~Al e the ` 2 1 ~ O 1 4 1 - PCr/US93/~ ~7 differential pressures encountered in use and the ability to provide the desired permeability without the application of excessive pressure. In a-sterile system, the porous medium should also preferably ~ 5 have a pore rating of about 0.2 micrometer or lecs to preclude bacteria r~CAge.
~ o that end, a gas inlet or gas outlet may be -included in any of the various elements of the biological fluid ~loce~sing system. By way of illustration, a gas inlet or gas outlet may be included in at least one of the conduits which connect the different containers, in a wall of the ~ contAin~rs that receive the ~a~csed biological fluid (i.e., the receiving con~ainers~, or in a port on or in one of those containers. The gas inlet or gas outlet may also be included on or in a combination of the elements mentioned above. Also, an assembly or porous medium may include one or more gas lnlets or gas outlets. Generally, however, it is preferred to include a gas inlet or gas outlet in the conduits which connect the cont~in~rs or in a filter assembly. Included within the scope of the invention is the use of more than one gas inlet or gas outlet in any conduit, receiving COntA i n~r, assembly, or porous medium.
It will be apparent to one cki11ed in the art that the placement of at least one gas ~o~ ol element such as a gas inlet or a gas outlet may be selected to achieve a desired result. For example, it may be desirable to locate the gas inlet u~_~ ~am of a porous medium and in or as close to the source contA i ~er of biological fluid as is practical in order to maximize the recovery of biological fluid.
Also, it may be desirable to locate the gas outlet do~l.~lleam of the porous medium and as close to the _ WO94/01193 ~ 1 4 0 1 4 1 PCT/US93/~547 receiving container as is possible in order to maximize the volume of gas that is removed from the system.
In an emho~iment of the invention, air or gas may be stored and/or collected in at least one contA;n~r such as gas contAin~r; upon o~ing of a flow c~n~Lol device, gas can be fed t~yh them to purge the con~nits and assemhlies, thereby facilitating the ~e_~V~eLY of biological fluid that may have been trApre~ during ~G~er~sing.
Preferably, the purge air or gas is fed to the CQ~ tS at a point as close as ic reA-QnAhly poscihle to a source con~Ain~r to maximize the volume of biological fluid ~VV~L~ The gas cont~in~r is preferably flexible so that the gas therein may be fed to the system merely by simple compression.
In accordance with the invention, Le~oveL~ from the various elements of the biological fluid ~L._~-cing system may be maximized. For example, biological fluid may be ~c~ and ~ to a receiving con~A i n~ through the a~L~.iate co~ tS
and porous media, if any. Biological fluid that has become entrArreA in these elements during ~LGc~F-~;ng may be ~e~overed either by passing purge gas through the co~ ts and ~o~us media, or by creating at least a partial vacuum in the system to draw out the retAin~ biological fluid and to permit it to drain into the a~lu~Liate receiving contA;n~r or assembly.
The purge gas may be from any of a number of sU~Yc~. For example, the biological fluid ocessing system may be provided with a storage contA i n~r for the storage of the purge gas, the purge gas may be the gas that was removed from the _ WOg4/01193 ~1~01~1 PCT/US93/~ ~7 system or displaced from one part of the system to another part of the system during ~Gcessing, or the purge gas may be injected aseptically into the system from an outside source (e.g., tl.~v~ a syringe). For example, it may be desirable to use sterile purge gas that has been sterilized in a separate container apart from the biological fluid pi.~ ing system.
The gases separated by at least one gas co.-LLol element, e.g., by the gas outlet, may be vented from the system, or they may be collected in a gas con~Ain~r (not shown) and ~eLul~led to the system as a purge gas to fAcilitate the lecov~L~ of biological fluid that becomes trApre~ in the various components of the system.
In accor~n~ with an emh~Ai~ent~ a gas collection and displacement loop may be in fluid communication with a selected conAllit of the biological fluid ~v~ -cing assembly 10. For example, one end of the loop may be in fluid communication with the ~_Lleam end of a filter assembly, e.g., with conduit 25 and the other end of the loop may be in fluid communication with the do~ Lleam end of a filter assembly, e.g., with co~A~it 26. In a preferred emhoAiment~ the gas collection and displacement loop includes at least one flow ~v..~ ol device.
In accorA~nae with the invention, the gas collection and displacement loop-provides a flow path for separating gas from the biological fluid flow path, and, optionally, using that collected gas to le_v~-~ additional biological fluid. The loop may also include a cont~ine~ such as a gas cont~in~r interposed in the loop for collecting and storing the displaced gas, and for collecting and isolating 2 1 4 0 1 4 1 Pcr/usg3/06547 processed (e.g., leukocyte depleted) biological fluid. For example, leukocyte depleted biological fluid may be collected in a gas collection and displacement loop for sampling. In a more preferred emhodiment, the container may be a flexible bag which can be squeezed in order to transfer gas.
Included within the scope of the ~e ent invention are other stru~L~es ~-hi~h ~-~Lion as descri~ed - above, such as a syringe, or the like, which could draw gas from the ~G~e_~ing assembly into the loop, and could transfer the collected gas in the syringe into another container and/or conduit. It is - intended that the gas collection and displacement loop functions so that leukocyte-laden fluid is isolated from the l~lkoçyte depleted fluid.
In an alternative embodiment, the gas collection and displacement loop may include a liquid barrier medium through which gas passes. The liquid barrier medium may be any of a variety of means and devices which are c~p~hle of separating gas that may be present in the blood ~ocecsing system from the biological fluid that is proceCc~A
in the system. The liquid barrier medium may be included in a housing to form a liquid barrier assembly. Suitable liquid barrier media and barrier assemblies include those disclosed in International Publication No. W0 9l/17809. In a more preferred embodiment, the gas collection loop includes at least one co~ ;t, a gas collection cont~j~er, preferably a flexible gas container, and a liquid barrier medium u~Lleam of the gas cont~ r. In this embodiment, pro~Cce~ biological fluid (e.g., leukocyte depleted biological fluid passing through a filter assembly) may be collected in a ~atellite bag, and gas in the satellite bag may be displaced ~ wo g4/0ll93 2 1 4 0 1 4 1 PCT/US93/~ ~7 through the gas collection and displacement loop into the gas collection container. If desired, pro~ecr^~ biological fluid may also be displaced from the satellite bag into the gas collection S container. In this emhoAiment~ contaminated (leukocyte cG~.lAining) biological fluid is unable to pass thL~yh the liquid barrier medium, thus isolating contaminated biological fluid from the .,vn c~nLaminated biological fluid.
A number of additional containers may be in communication with the biological fluid ~oo~ ng system, and can be~utilized to define different flow pathfi. For example, an additional satellite bag contAining phy iological solution may be placed in communication wi-th the biological fluid ~ ing system ~ Leam of the let~kocyte depletion assembly, or do~l~ ~eam of the ~ oçyte depletion assembly and the solution may be p~c~-~ thlouyh the leukocyte depletion assembly so that the biological fluid that was held up in the assembly can be collected.
It will be ~eciated that when the biological fluid from the collection bag 11 is e~ eA toward one or more satellite bags, some of the biological fluid may be LL~ in the ro~Al~its and/or a porous medium.
In accordance with the invention, an automated ~v,.L~ol arrangement 50, in ~ 4"-~ to predetermined conditions, sends and receives signals, and co..LLols the overall sequence and flow of biological fluid from a first contAin~r such as the collection contAin~r 11 to any of the receiving or satellite cont~inDrs. For example, the automated col.LLol arrangement may include one or more devices, switches, and/or indicators, c~ncors or monitors to achieve a desired ~UL~V_C, including, but not 2 1 4 0 1~1 Pcr/Us93/~ ~7 llmited to: a power switch; a start switch; a stop switch; a sequence selection switch; weight sensor devices, switches, and/or indicators; time sensor devices, switches, andlor indicators; optical fi~ncQr S devices, switches, and/or ;n~ tors; and fluid flow c~ncnr devices, switches, and/or indicators temperature devices, switches and/or i~icAtor~; and at least one interface monitor for sensing the point of separation between the first portion or component of the biological fluid and a ~con~ portion or component. As used herein, monitoring the interface includes a monitor associated with a porous medium such as a red cell barrier medium, for monitoring the flow rate of the first portion or the back pressure u~L~eam of the ~v~s medium ~uch as a red cell barrier medium; an optical sensing device, for monitoring the transition between the first and second portions of the biological fluid; a weight sensing device or a total f low monitor, for ~ensing a predetermined weight or amount of biological fluid which defines the separation point between the first and second portions or components of the biological fluid; and any other mech~ni~m for sensing the separation of one portion or component of the biological fluid from another portion or comronent.
It is intended that each of these sensors monitor a predetermined ron~ition~ and react or provide feedback according to a predetermined or pre-set array of variables. Accordingly, ~ny ~tep and/or sequence (e.g., including two or more ~tep~
for ~loc~sing a ~iological fluid may be carried out according to the invention. Thus, the biological fluid may typically separated into fractions, components and/or constituents; p~F~-~ from one location to another, which may include isolation of ~190141 WO94/Ollg3 PCT/US93J~ ~7 a portion of the biological fluid for sampling, passage through at least one ~o~ous medium, passage across at least one separation medium, combining or pooling the biological fluid, administering a biological fluid to a patient, and/or chasing the biological fluid with gas. The biological fluid may, for example, be heated, cooled, diluted, fractionated, lyor~ 7~ wAr~, oYpore~ to a viricidal agent, and/or any combination of the above. At least one fluid including, but not limited to an additive, an~i~c-gulant, ~.e3crvative, viricidal agent, and a gas may be ~ to the biological fluid or separated from the biological fluid.
For example, in one ~equence, involving directing biological fluid tangentially from a source contAi~or to a separation medium such that plasma r~ thu~h the separation medium to a satellite container, and red cells and/or platelets pass across the separation medium to the ~OU~02 contAin~r and back to the separation medium, a weight s~n-Qr receiving a signal from at least one of the contAinors may trigger a predetermined command in the automated CO1~LLO1 a~ y~ment which stops the sequence.
In an emho~iment according to the invention involving passing biological fluid tl~ouyh a porous medium such as a red cell barrier medium or a red cell barrierlleukocyte depletion medium, as flow th~ouyh the medium slows or stops, a flow ~ell~Or may trigger a predetermined command in the automated -CG~ ol arrangement which stops sequence 1 and initiates sequence 2 and/or sequence 3 as shown in the Figures.
The automated ~o~ ol arrangement 50 may be - WO94/01193 2 1 1 0 1 l 1 PCT/US93/~ ~7 connected to the various elements of the system, and may include one or more connections to the biological fluid ~LG~essing assembly, including a container, or a flow co"L~ol device, a gas ~v..Llol element, a ron~l~;t, to a rpecific element in the biological fluid ~v~eæsing assembly or the ~ re differential generator.
The ~eL~Lion of an automated biological fluid yLoce-sing system in accor~anc~ with one ~pect of the invention may be illustrated by refe~e~,~e to the automated ~.c~e_~ing system shown in Figure l and the~flow charts ~hown in Figures 5-ll.
In ~tep l (hereinafter, Sl, S2, S3, etc.), Sequence 1 is st~rted. The initial se~ e may include collecting the biological fluid directly into the collection bag ll, selecting the first sequence selection, placing the collection cont~i n-r ll in differential pressure ~el,e~Lor 51, and connecting the collection container to any satellite con~in-rs~ if ..,c~ ry. In a preferred emhoAiment of the invention, the collection cont~i n~r 11 contains a biological fluid, typically whole blood, which has been ~eparated into a ~u~_~..atant layer 31 and a ~^~iment layer 32 before placing the collection container ll in the differential pressure y~._~Lor and selecting the first sequence. If whole blood is used, the ~u~cLl.atant layer may be prim~arily PRP, and the re~iment layer may be primarily PRC. In an em~bodiment of the invention, the biological fluid can be separated under conditions in which a transition layer or interm~ediate layer (typically buffy coat) spans the interface between the ~u~e~llatant layer and the ~iment layer. In another em~ho~iment of the invention, the ~u~eLl.atant layer may be primarily 2 1 4 0 1~1 PCT/US93/~ ~

PPP and the sediment layer may be primarily red cells with an intermediate layer of buffy coat between them. The biological fluid may be expr~s~e~
from the collection bag as separate supernatant, intermediate, and sediment layers, .e_~e_Lively.
These layers can be ex~ e_sed in any order.
In S2, valves 61 and 62 are closed.
Alternatively, the valves may be closed in the first step in the init~ 7Ation of the seguence. In S3, a differential ~e~u~e may be ye..~ated between collection container ll and satellite bag 41.
In S4, valve or clamp 61 is opened, and the pressure differential between the collection container and first satellite bag 41 causes the Du~e~..atant layer to flow in the direction of satellite bag 41. As the ~u~-~..atant layer r~cres from the collection bag to the first satellite bag, it may pass t~o~}- at least one porous medium, such a leukocyte-depletion medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium. In another e~bodi~ent (not shown), the ~u~e-l.atant fluid may be rAsre~ tl~ou~h a separation assembly 81, inte~p~ between a container s~ch as a collection cont~ r 11 and a contAin~r such as a satellite contAir-r 41.
In S5 and S6, the initial flow rate of the ~u~c~llatant is monitored. If the flow rate is too high or too low, a signal may be generated whereby the differential pressure is decreased or increased.
Alternatively, if the flow rate is typically stable at a constant pressure, adjusting the pressure may be ~nn~cDsc~ry After a suitable initial flow is achieved in S6, the flow con~ es to be monitored in S7 until a 3~ predetermined value is reached, at which point, a _ 39 -- WOg4/01193 PCT/US93/~ ~7 signal is produced to indicate that flow should cease. In accordance with the invention, the nature of the signal will ~p~nA upon the type of monitor - used to distinguish one layer of biological fluid from another. For example, in a preferred embodiment of the i..~e-,Lion, a red cell barrier or a combined ~ ocyte depletion red cell barrier ~G~U_ medium is used, and the monitor pro~n:eF a ~ignal when the flow rate significantly 810w8, for example stops. In an emho~liment of the invention which includes a weighing de~ice, the monitor may ~ ~llce a signal when a predetermined amount of ~u~_~..atant layers has ~ into the satellite bag 41. In an embodiment of the i~ Lion which includes a optical reader, the monitor may produce a signal when the fluid passing the optical reader r~A~hes a predetermined density. It is int~n~ that the invention should not be limited by the type of flow detection and monitoring system employed.
In S8, the signal ~ c~ in S6 and S7 closes valve or clamp 61 is closed in ~ e to the signal which indicates flow ~o~ cease. In S9, the ~lG~e~S may be storr~ completely, or one or more additional seqll~ceC~ such as Sequence 2, 3 or 4, may be selected man~ ly or automatically.
In Sequence 1, the Du~eL..atant layer was the first layer to be eA~e~sed from the collection bag.
In alternative emho~iments, the initial sequence may include first e~e-~sing a layer other than the ~u~eL~latant layer. For example, the red cell sediment layer or buffy coat may be e~e_sed first.
If Sequence 2 is selected, the ~lO~eSS, typically the ~o~essing of the sediment layer, is started in S10.
In accordance with the invention, it may be 21QOl~l .
~ WOg4/01193 PCTrUS93/~ ~7 desirable to remove gas or air from the system or to separate or move gas/air from one part of the system to another part. In accordance with the ~e~cnt invention, any arrangement or method which effects removal or displacement of gas/air in the system may be used.
In aCcorA-n~ with the invention, it may be decirable to mix the contents of a container such as a collection bag and/or a satellite bag, e.g., to mix a biological fluid with an additive ~olution or the like, and/or to mix blood components.
In an embodiment of the invention, the ~o~ess may incl~ S11 in which the collection contA~r i8 inverted or ro~ d, either by rotating the collection bag within the ~ e differential generator, or by ~La~ing the ~ re differential generator itself. Inversion of the bag and/or pressure differential generator may be a desirable ~ e~~ step to achieve a variety of results, inCll-~ing but not limited to displacing gas within the collection bag and mixing a biological fluid with an additive solution, diluent, or the like, to orient the bag in a desired position, or to invert a bag which contains air. At the completion of the inversion step, cr~ t 62 may be oriented in a desired position, typically ~ o~imately 180 from its position at the begi nn i ng of S11.
In S12, a positive ~s~e is generated, valve 62 is ~e..ed (S13), and sediment layer 32 in-collection bag 11 may be r~C~e~ thlo~yh a leukocytedepletion assembly 17 and into a contA~er, such as the 8~0~ satellite bag 18. S14 and S15 may co~ o.l to S5 and S6, ~e~ Lively, to assure that the desired initial flow rate is maintained.
After a suitable initial flow is achieved, the flow ~1~01~ ' - W094~01193 PCT/US93/~ ~7 continues to be monitored in Sl6. When the flow rate slows or stops (Sl6), preferably when cubstantially all of the s^~iment layer has been e~Lssed from the collection bag, valve 62 is closed (Sl7), a stop switch may be activated (Sl8~, and the pressure differential is preferably r~ ce~
to ZOEO (Sl9).
If seguence 3 ic selected to follow ~equence l, an anti _oL~lant solution or an additive solution or the like in ~r~ satellite bag 18 may be from the ~?conA-satellite bag 18 into collection cont~Ai~-r ll. In S30, valve 62 is ~ by the ..LLol unit 50. In S3l, the collection containOE
ll is invOEted eith OE by rotating the collection bag within the ~Le_~Le differential gen OEator, or by rotating the ~Le_~uLe differential ~e..e~aLor. The sediment layer 32 then moves to the end of the collection contA;~er ll which c~ lunicates with the con~ t 25 while any air moves to the opposite end of the collection cont~in~r l~. In S32, a ~e~De or negative pressure is generated between the collection contAi~er ll and the ~econ~ satellite bag 18, drawing the solution in the ~econ~ satellite bag 18 into the collection contAin~r ll. Alternatively, the negative ~Le_~uLe differential may be generated first and the valve 62 may then be ~el.ed, or the ~?cQn~ satellite bag 18 may be contained in another pressure differential ye..~L~Lor 5lB which forces the additive into the collection bag ll. In S33-S35, the flow is monitored until the flow falls to a value, such as zero, which in~icAtes a sufficient amount of the solution has been drawn into the collection con~ r ll. In S36, mixing of the solution and the s~iment layer 12 is initiated.
The solution and the sediment layer 32 may be mixed ~ W0 ~01193 ~1~01 4 1 PCT/US93/~ ~7 in a variety of ways, for example, by rotating or rocking the collection cont~ r 11 and/or the differential pressure generator 51 or by providing a mech~ni6m in the differential yL~ re generator 51 which ma~ir~l~tes the collection container 11.
After valve 62 is closed (S45), the y~P~ re in the differential generator 51 i8 reduced to zero and gequence two may be initiated ag described above.
- Seqv~ ce~ 1, 2 and 3 can thug be implemented in the automated fluid y~v~sDing sy6tem shown in Figure 1. With the physiologically a~ e~Lable eolution initially ~tored in the second satellite bag 18, the CO~LLV1 unit 50 may step first LL~ou~L
Sequence 1 to e~-^ the Du~cl,.a~,L layer in the collection bag 11 into the fir6t 6atellite bag 41, then thLvuy}l Sequence 3 including steps S30 and S37 to add the solution in the ~e~-Q~A satellite bag 18 to the sediment layer in the collection bag 11, and then thLv~y}~ Sequence 2 ex~e~L for the inversion step Sll to e~y~e_s the ~^Ai~ent layer in the collection bag 11 into the ^QcQ~A 6atellite bag 18.
The inversion 6tep Sll in Sequence 2 is unn~ y because the collection cont~ 11 has already been inverted in S31 of Sequence 3.

As noted in S9 above, the ~uy-l,laLallL layer may be subjected to additional ~o~ g, if desired, preferably downstream of the porous medium 12 and/or 13, either conn~cted to the system or after being separated from the system. For example, when a desired amount of the ~u~eLIlatant fluid has been collected in fir6t satellite bag 41 it may be r~
from satellite bag 41 to a 6eparation medium, e.g., - to separate the plasma from the platelets.
Alternatively, the ~u~eLnatant fluid may be _ WO94/01193 2 1 ~ O 1 4 1 PCT/US93/~ ~7 separated into a second supernatant layer, and a second sediment layer. Typically, if the supernatant fluid is PRP, it may be separated into a -se~QnA ~u~e~..atant layer including plasma and a SCCQn~ sediment layer including platelets, which may - be ~Gee~S~ to form PC.
For example, if Se~en~e 4 is selected after Se~uence 1, the automated ~v~e C~nq system may be used to separate plasma from platelets. In S21, valves or clamps 63 and 64 are closed.
Alternatively, the valves may be closed as the first step in the ini~iAli7~tion of Sequence 3. In step 22, a positive ~l~3~e differential is ~.eLated between satellite bag 41 and satellite bag 42. The differential ~le_~u -~ may be generated by substituting the seconA satellite bag 41 for the collection bag 11 in the differential pressure trAnCAl~c~r 51 or by providing another differential - pressure trAnCAl~c~r 51B for the ~conA satellite bag 41. Once a desired pressure is r~A~heA~, valve 64 may be olC~A tS23), allowing the ~econA Du~_~..atant layer to flow t~lv~l. CQ~Al~it 28 into satellite bag 42.
In S24 and S25, flow con~;n~eC until a predetermined value or ronAition is r~AçheA, e.g., a sufficient amount of s?CQnA ~el~,atant layer has pAC~e~ into satellite bag 42. In accordance with the invention, the amount of ~u~e.,.atant layer passing into satellite bag 41 may be predetermined, e.g., based on time, weight or density, but it is int~n~ that the i.lvenLion-should not be limited thereby.
In S26, after the predetermined amount of C~o~A ~u~ell.atant layer has been collected, valve 64 closes, a stop switch may be activated (S27~, and WO94/01193 21 4 O 1 4 1 PCT~US93/~ ~7 the pressure differential may be reduced to zero (S28).
The operation of the automated biological fluid ~lG~_sing syctem in accor~ e with another aspect of the p~ nt i..ve..~ion may be illustrated by ref~ e to the automated ~ ing syctem shown in Figure 2 and the flow chart æhown in Figure 9.
In this exemplary emhcA;ment, collection container 11, which includes biological fluid which has been separated into a Du~e~l,atant layer 31 And a ~ediment layer 32, may be positioned in a differential re generator 51. In this exemplary e~od$ment, it is preferred that the differential ~ re y~ or 51 iS a combined ~ re and vacuum e~e or. Collection container 11 may be in fluid communication with a fir_t satellite bag 41 suitable for receiving the -u~_L.,atant layer 31, a ~o".l satellite bag 18 suitable for receiving a sediment layer 32, and a fourth satellite bag 71 suitable for storing physiologically acceptable solution, such as a nutrient solution or a ~L~ vative ~olution. The fluid flow path between the collection con~ainer ll and the firct satellite bag 41 preferably includes a red cell barrier porous medium or a combined leukocyte depletion red cell barrier porous medium and the fluid flow path between the collection container 11 and the ~e~onA
satellite bag 18 preferably includes a leukocyte depletion porous medium.
The three satellite bags may be positioned in or on a flow monitor 72 suitable for monitoring flow by weighing the amount of fluid in the Le-~e~ive satellite bags. Flow monitor 72 may be co~n~ted to ~v,.~ol unit 50, preferably a mi~lv~.ooes~or ~u~.~oller. Co..~ol unit 50 may be ro~nected to the 2 1 ~ O I ~ 1 PCr/US93/06547 pressure differential generator 51 through pump 73 and valve 74, preferably a two-way valve, suitable for inducing pressure or a vacuum on collection container ll. In a preferred embodiment, pump 73 S can create positive pressure on collection bag ll through line 75 and can create a ~e~e~e or negative pressure, i.e., a vacuum in collection bag ll tL~o~h line 76.
As this sequence is initiated, the flow paths 10 1~A~;n~ from the collection bag ll to all of the satellite bags are closed tS4l). In S42, steps Sl through S8 of Sequence l may be conducted, whereby a differential pressure between collection bag ll and satellite bag 41 is established and the ~u~natant layer is e~Lessed into satellite bag 41. Valve 61 may then be closed (S8) and ~alve 65 opened (S43).
In S44, steps S31 through S36 of Sequence 3 are conducted, whereby an anti-coagulant solution or an additive solution or the like in fourth satellite bag 71 is ~Asce~ from fourth satellite bag 71 into collection COntA; n~r 11. In S3l the collection container ll is inverted, e.g., as described with respect to Sll. The sediment layer 32 then moves to the end of the collection contA; n~r 11 which communicates with the conAn;t 90 while any air moves~
to the opposite end of the collection con~i n-r 11.
In S32, a reverse or negative pressure is generated between the collection con~; n~r 11 and the fourth satellite bag 71, drawing the solution in the fourth satellite bag 71 into the collection con~;n~r ll.
Alternatively, the negative pressure dif$erential ea~le may be generated first and the valve 65 may then be opened. In S33-35, solution flow is monitored until if falls to a value, such as zero, which indicates a sufficient amount of the solution WO94/01193 PCT/US93/~ ~7 has been drawn into the collection container 11.
M; Yi ~g of the solution and the sedim~ent layer 32 is then initiated in S36. The solution and the r^~iment layer 32 may be mixed in a variety of ways, - 5 - for example, by rotating or rock;~g the collection contAi~er 11 and/or the differential ~ re genOEator 51 or by providing a mech-~igm in the d$fferential ~,~ re generator 51 which manir~lAtes the collection container 11. After valve 65 is closed (S45), sediment layer 32 may then be e~er~sed into ~ e~l satellite bag 18 (S46) by following cteps S12 U~o~h Sl9 of Sequence 2.
In awv~&nce with an additional embodiment of the invention, a method is provided whereby the lecv~e~ of various biological fluids ~a~el or retAinoA in various elements of the system is maximized, either by causing a volume of gas hoh i n~
the ~ ~ed or re~Ai~o~ biological fluid to push the fluid t~ h those elements and into the designated contAinor, or by drawing the ~L-llJ~-l or retained fluid into the ~^si~n~ted container, by y..e~ re differential (e.g., gravity head, ~ re cuff, suction, and the like~. This provides for a more complete emptying of the container, assembly, or ~Ol~ medium. Once the contAinor~ assembly or porous medium is emptied completely, the flow may be s~orre~ automatically.
Figure 10 includes an exemplary flow chart for an embodiment of the invention which includes separating gac in the sygtem from the biological fluid to be ~oo~ . In a preferred embodiment, - gas in the system may be displaced to a part of the system separate from the biological fluid; in a more preferred embodiment, gas in the system may be expelled from the system.

2 1 9 0 1 ~ 1 PCr/US93/06547 ~ .
In an exemplary embodiment, in which a gas outlet and additive/prLming solution is used to prime a leukocyte depletion filter assembly 1~, a - gas outlet 98 and a gas inlet 99 may be positioned as shown in Figure 1 and con~ e~ 18 includes an additive/priming solution. In S50, clamp 62 is closed. In S51, gas outlet 98 is activated or opened, and a differential ~e_~u~e is generated between con~i n~r 18 ana the ambient environment of the gas outlet 98 so that a column of additive solution flows through con~ t 26, through leukocyte depletion filter assembly 17, and into conduit 25.
In some embodiments, the pressure differential may be generated by gravity head, and container 18 may be inverted. In the ill~DLLaLed e_ho~iment~ the pressure differential is generated by pressure differential generator 51A. As the solution advances, it pushes gas in the conduit ahead of it until the gas reaches gas outlet 98. Gas ahead of the column of additive solution passes through the o~tlet and out of the system.
In S52, before the ~olution reaches a predetermined position u~-LLeam of the gas outlet, the column of additive solution triggers a monitor which closes a valve in the fluid-flow path leading to the gas outlet or depressurizes the pressure differential generator 51B, if the gas outlet is a non-automatic gas outlet. Optionally, if the gas outlet is an automatic outlet, no monitor is required, or a monitor may signal the location of the additive solution. In S53, clamp 62 opens, and additive solution flows into container 11. In S54, - the f low of additive/priming solution is stopped or completed. The flow path between container 11 and container 18 is now prepared for use in accordance 21401~1 WO94/01193 ~ PCT/US93rO6~7 with the invention, for example, by the initiation of Seguence 2.
After passing a biological fluid tl~ouy11 the system, for example, in Sequence 2, ambient air or a S sterile gas may enter the ~ystem t~v~h gas inlet 99 in order to ~eco~.~ the biological fluid retained in the system. If gas inlet 99 is a manual inlet, the ~nlet is opened and/or a clamp i8 released, if the gas inlet 99 is automatic, the ~ re differential between the gas inlet and satellite bag 18 will cause the gas to flow ~lo~yL con~ t 25, t~ouy~ leukocyte filter assembly 17, and toward ~atellite bag 18. In ~ome embodiments, the container 18 and the ~ o~yte 17 may be positioned at a point below that of container ll, preferably with cont~;n~r 18 in an upright position, before activating gas inlet 99. In the ~e-s, retained biological fluid that is trapped in those elements during ~ cing are ~e_~v~ from those elements and collected in satellite bag 18.
Figure ll illustrates ~nother exemplary flow chart for an embodiment of the invention as ~hown in Figure l. Initially a collection bag ll cont~ini~g a ~ ..atant lay OE 31 and a sediment layer 32 is placed in the diff OE ential ~e_DuLe generator 51.
The system is then started and allowed to stabilize in S60 and the valves 61 and 62 are closed in S61.
Alt OE natively, the valves 61 and 62 may be closed before the system is started.
A positive ~ re is generated in S62 and valve 61 is opened in S63 and flow begins. The flow - of the ~el-latant layer is monitored in S64, to ess an amount of the ~e-.,atant layer which is less than the total amount of the ~u~ atant layer.
For example, the fluid monitor may monitor the _ WO94J01193 PCT/US93/~ ~7 21~0141 weight of collection bag 11 and/or satellite bag 41.
Alternatively, the flow rate over time may be monitored. After a predetermined amount of the ~u~e~..atant layer has been e~~ , valve 61 is closed in S65, leaving a desired amount of Du~e~-atant layer 31 with the ediment layer 32 in the collection bag 11.
The desired amount of Du~ ant fluid from ~u~el~tant layer 31 to be left in collection bag 11 will vary ~p~nAing on the in~en~e~ use of the re~ining contents of the bag, e.g., the ~e~iment layer 32 and/or the intermediate layer between the ~u~e~atant and ~e~iment layers.
For example, if the sediment layer is PRC, and the ~ .atant layer i5 PRP, and the PRC is -int~n~ to be used for transfusion, a sufficient amount of PRP may be left in the collection bag 11 to produce a hematocrit of about 52% or greater, more preferably a hem~atocrit of about 70% to about 80%, or more.
Alternatively, if the ~u~eLl.atant layer is PPP, with an intermediate layer of buffy coat between the PPP and the ~^~;ment layer of PRC, an amount of PPP
may be left in the collection bag 11 to be ~o~s~-~
with the buffy coat.
After valve 61 is closed in S65, the positivepressure is decreased to 0 in S66. Optionally, the contents of the collection bag 11, i.e., the rem~in;ng ~u~e~..atant layer and the sediment layer, may be mixed in S67. Suitable techniques for mixing include those as described in Sequence 4. The collection bag 11 may be inverted and/or ~n~e~ -during mixing, and may be left in the inverted position at the end of the mixing step in S68. A
positive ~e~ e is generated in S69, and then ~ WO94/01193 2 1 ~ O I ~ 1 PCT/US93/~ ~7 valve 62 opens in S70, expressing the remaining fluid from the collection bag ll to the second satellite bag 18. The flow of the fluid from the collection bag is monitored in S71 to determine when - 5 flow ceA~ .
Valve 62 then c1O~ in S72. ~he pump is shut off in S73, and the ~ re r~h-~ zero in S74, thus completing the sequence.
In other embodiments, e.g., involving the L~rry coat, other se~ may be ut;1i7~. For example, buffy coat may be isolated by any known ~echni~ue, including separating whole blood into a ~u~e~natant layer of PPP, an intermediate buffy coat layer, and a sediment layer of PRC and ~eparating the layers as noted above. After the unit of buffy coat is separated, it may be pooled with other units of buffy coat. Pooled or ~ll~ooled buffy coat may be separated, typically by centrifugation, to form a ~u~eL..atant platelet contAining layer and a sediment red cell contAining layer in a satellite bag.
The satellite bag (which is connected to an additional empty satellite bag) may be placed in the pressure differential generator, and the empty satellite bag may be placed in or on the flow meter.
The ~u~cl..atant layer may be separated from the sediment layer as described in the se~Ges above.
For example, the ~u~clnatant platelet contA~n~
layer may be pA~e~ t~v~g}. a red cell barrier medium or a combined red cell barrier leukocyte depletion barrier until the flow rate nears or reaches zero.
~ A Preferred Differential ~ re Generator Co..ve,.Lional ex~e~sors have many drawbacks.
For example, they apply an uneven pressure to the fluid collection bag and may create wrinkles and - WO94/01193 2 1 1 0 1 4 1 PCT~US93/~ ~7 folds in the bags. Biological fluids can become trapped in these wrinkles and folds, preventing lO0 of the biological fluid from being expressed.
~..e~e.. pressure also tends to agitate the fluid within the container, and may, for example, disturb the interface between components, for example, between the supernstant layer and the sediment layer, e.g., the L~r~ coat, and thus reA~- e the amount of ~u~el"atant layer which can be reliAhly collected. Additionally, h~C~ ? the collection bag may be distorted and because the stru~L~le of cul.v~lLion ~x~ sors can h~nA~r o~e~v~tion of the container, it may be difficult for an operator to determine ~o. ~_L ~e~Lion of the apparatus by watching an interface layer between a sediment and a ~e.l.atant layer. Further, in ~ome applications, it is desirable to draw fluid into a cont~i~er.
Ho~e~el, convel.Lional e~Les~ors are merely capable of squeezing a container. So while they can force fluid out of the contAin~r~ they are unable to draw fluid into the container.
Embodiments of the ~ nt invention vvt~ome these disadvantages. In accor~nçe with the ~ a-~nt invention, an c~L._-?r for varying the amount of fluid in a variable-volume container c~ Led to at least one ~on~it may comprise a ho-cin~ defining an enclosed chamber for accommodating the con~in the housing having at least one oroning t~uyh which the conAl~it can extend; a ~ re regulating me~h~nism coupled to the housing to vary the pres-sure of fluid in the chamber and thereby vary the volume of the cont~in~r; and an arrangement for moving fluid within the cont~;n~r, the arrangement including at least one of a) a drive mech~nism for moving the housing and b) apparatus for pressing - wO 94/OIlg3 2 1 4 0 1 q 1 PCT/US93/0~7 against a first portion of the con~i n~r A method for exylessing a biological fluid from a cont~;~er in an enclosed chamber may comprise varying the y .~~-ure within the chamber; and moving - 5 fluid within the container by at least one of a) moving the chamber in an o-cillAtory fashion or b) pre~e~n~ against a fir~t portion of the container.
A~ shown in Figure 12, a fir~t exemplary e~yl~æDo~ for use in the y~-ent invention comprises a housing 110 which defines an enclosed chamher 111 and a prescure regulating meçh^nism 130 pneuma~;c~lly coupled to the housing 110 by a fl~Yihl~ hose 131 or other ron~t~;t to vary the ~ e within the cha~ber 111. A variable volume fluid container, such ~s the collection bag 11 contA;n~ng a biological fluid, may be placed in the chamber 111 with one or more ~ections of fleY;hle tubing 20, 2S eYten~;~7 from the collection bag 11 th~yh an or~;ng 117 in the ho~lC;ng 110 to the exterior of the housing 110. The collection bag 11 need not be fl~Yihle, but it preferably is ~4.._L,~Led so that its internal ~olume can be varied by ~Gn~Lolling the fluid ~ re applied to the outside surface of the collection bag 11. The ~ re regulating mech-nism 130 supplies and/or witl,d,a~_ a fluid (i.e., eit~er a gas or a liguid) to and/or from the chamber 111 in order to vary the ._s~re exerted on the collection bag 11 within the chamber 111. This, in turn, varies the volume of the collection bag 11 and thereby forces fluid (i.e., either a liquid or a gas) out of or into the collection bag 11 thlv~h the flexible tubing 20, 25.
Preferably, the pressure regulating meçh~nism 130 includes a valve arrangement such as a four way -- W094/01193 ~1~O1~1 PCT/US93/~ ~7 pneumatic valve capable of connecting flexible hose 131 to the input or to the output of a stAnA~rd piston pump. The fou~ way pneumatic valve is electron;c~lly ~ul.LLolled by the ~Gl,L~ol unit 50 (Figure 18). Additionally, there may be a plurality of relief valves and a prescure sensor ele_LL~ lly ~o.~LLolled and monitored by the cGl.LLol unit 50. In thiC manner, the ~ol,L~ol unit 50 may coll~ol and monitor the ~Le_~UL2 or vacuum exerted on the collection bag 11. The f~ul ~ray pneumatic valve, the plurality of relief valves, and the pressure s~n-~r may be, for example, ~i~por^~ in the ~l-~ol unit 50, the ~e_~u~e regulating meçh-n;sm 130, and/or the housing 110.
The housing 110 may be formed from any suitable material which has sufficient structural integrity to withstand the differences in pressure between the chamber 111 and the exterior of the housing 110.
The housing 110 may have a variety of configurations. For example, in the ~Le~sor shown in Figure 12, the housing 110 comprises a base 112 and a cover 113 which may be rele~c~hly mounted to the base 112 in any suitable manner to form the chamber 111 and envelop the collection bag 11. In the exemplary ex~.~ sor~ the cover 113 is releasably mounted to the base 112 by means of hinges 114 on one side of the base 112 and cover 113 and at least one and preferably two latches 115 on the other side.
The housing also preferably includes a transparent portion positioned to permit observation of the fluid container. For example, the transparent portion may be a window 119 in the cover 113. Alternatively, the entire housing by be formed from a tr~ncp~rent material such as a tr~Cp~rent ` ~140141 W094/Ollg3 PCT/US93/~ ~7 plastic.
One or more hooks 121 may be mounted inside the - chamber 11 at the same end as the flexible t~hi~g 20, 25 and/or at the end ~rroe;te from the flexible S tubing 20, 25. It was found that utili~ing a single hook on the end of the collection bag 11 opposite to the fl~Yihle ~-hin~ 20, 2S and using one and preferable two hooks on the end of the collection bag nearest the flexible tubing 20, 25 better ~e~ed the collection bag 11 within the housing and facilitated t~er-ion of fluid from the collection bag 11. Further, if the ~hg~-e; ng 110 is inverted so that the end orrQeite the flexible t~h~ng 20, 25 is facing up, the collection bag 11 will not become dislodged and pinch off the fluid flow. Thus, it is preferred to secure the collection bag at both ends.
Al~holgh the use of ho~ 121 to secure the collection bag 11 within the housing 110 is preferred, other securing mech~ni~ms such as, for example, a clamping mer~-n~sm can also be utilized.
Figure 13 discloses the housing 110-movably mounted to a ~ rL 133 using, for example, a gearing arrangement 266, a motor 132 and a shaft 134. The shaft 134 may be hollow so that pneumatic, l.ydlaulic, or electric supply or col.L~ol signals may be provided to the ho~ ng 110 tl~yh the shaft.
The motor may be variously configured, for example, as a pulse modulated printed circuit motor, and is preferably coupled to the ~ L 133. The motor 132 may drive the shaft 134 directly, or the motor may be coupled to the shaft 134 using the gearing - arrangement 166. Although the illustrated gearing arrangement is external to the motor, it may be ~ o~o-~Led within the motor. The motor and/or gearing arrangement may be configured to oscillate - WO94/01193 ~1gO1~1 PCT/US93/~ ~7 the housing lO axially along or circumferentially about the shaft 134, or to oscillate the shaft back and forth along an X, Y, and/or Z axis to thereby agitate the fluid in the collection bag ll by ror~i~g~ rotating, o-cil1Ating, r~k~ng, and/or vibrating the housing. Of cource the apparatus is not limited to a ~ingle shaft, gearing arrangement and/or motor arrangement, but may have two or more shaft, gearing, and/or motor arrangements coupled to the ho~C~ng llO at, for example, op~osite ends.
- In a preferred embodiment, the housing llO is rotated th~o~yh an angle of about 180 dey~ee3 so that the housing llO may be i,.ve.Led. ~he direction of the motor can be ~C~ ~DCd ~0 that the housing is rotated back th~ the same 180 degree rotation.
In this manner, the orientation of the housing can be ~eL~llled to the original position, with the flexible tubing 20, 25 exiting from the ~æl most portion of the ho~-cing 110. By rotating the hou~ing back and forth t~ yh the same 180 degree angle, the flexible tubing is ~.e~ ed from becoming tangled. ~o~e~cl, a rotation of less than or greater than 180 dcylee_ is within the ~cOre of the invention. In preferred embodiment, the velocity of the ~-~illAting housing llO is slowed grA~ lly at either end of the o~c;ll~tory movement. ~his re~nces the force acting on the meçh-n~sm which se~u~es the collection bag ll within the housing llO. The motor 132 is electrically coupled to and c~,.L-olled by the cGnL ol unit 50. Additionally, the meçh~ni~m for effecting the rotation may be any suitable movement meçh~nism such as pneumatic, elecLr-omay--_-ic, and/or hydraulic meçh~n;cm. The gearing arrangement 266 may contain a suitable gear configuration, e.g., a double heliY configuration, ~140191 WO94/01193 PCT/US93/~ ~7 so that the housing 110 is rotated back and forth through the same angle. The ~vl.Llol unit 50 may receive a feedback signal from the gearing arrangement 266 or motor 134 80 that the housing 110 may be storre~ in one or more positions along its rotation. Addi~io~ y, the gearing arrangement 266 may contain one or more lo~ing me~h-ni8ms~
electloni~lly which may be ~o..~Lolled by the ~v,.~.ol unit 50, for lo~k;ng the housing 110 in one or more positions.
In a preferred mode of an e~ ing operation, the collection bag 11, such ac a fl~Y;~l~ bag cont~i~;ng a biological fluid, i~ mounted to the base 112 of the ho~ci~g 110 with the fl~Yihle tubing lS 20, 25 exten~ tl~vu~ the ~ren; ng 117. The collection bag 11 is preferably fixed at both the top and bottom using book~ 121. The cover 113 is then sealed to the base 112 80 that the collection bag 11 is completely enclosed within the ch~mber 111 and envelore~ by the housing 110. The housing 110 is then oriented in a desired direction by the ~o.lLLol unit 50 using, for example, the motor 132.
If the collection bag 11 contains whole blood which has been ~e,.~ ifuged to form ~;ment and ~u~l,.atant layers, the housing 110 is preferably oriented vertically with the ~u~eLnatant layer between the sediment layer and the flexible t~hinq 20, 25. The housing may be oriented 80 that the flexible t~hin~ 20, 25 extends through the portion of the housing llO, where the flexible tubing 20, 25 communicates directly with any air in -- the collection bag 11 or with the ~u~el~.atant layer or the housing may be oriented so that the flexible tubing 20, 25 extends through the lower portion of the housing 110, where the flexible tubing 20, 25 ~1401~1 WO94/01193 PCT/US93/~ ~7 communicates directly with the sediment layer.
With the housing llO suitably oriented, fluid may be forced from or into the collection bag ll by supplying or withdrawing fluid from the chamber lll of the housing llO by means of the pressure regulating mech~nism 130. For example, the pressure regulating mech~ni~m 130 may supply air into the chamber lll, incr~sin~ the ~ re on the collection bag ll. If the flexible ~l-hing 20, 25 extends from the u~e~ portion of the housing llO, - the increase in ~ - r~re within the chamber lll will first force any air and then the ~u~el..atant layer from the collection bag ll via the flexible tubing 20, 25. The interface between the D~c~l.atant layer and the sediment layer may be observed tk~v~h the window ll9 and it will rise as the ~u~l..atant layer is ~e~ed from the collection bag ll.
The fluid pressure inside the chamber lll will be substantially uniform L~o~Jl~t the chamber lll, so the outer surface of the collection bag ll will be ~o ~-1 to substantially uniform ~2~ re. As a ~ lt, the collection bag ll will be subjected to much less wrinkling~ folding, or other forms of distortion than in co,.~.Lional mech-nical ex~ ---ors or p~e~ e cuffs. Because the collection bag develops fewer wrinkles or folds and ~ c~ -e fluid ~ re is applied to the entire external surface of the collection bag ll, substantially all of the fluid in the collection bag ll can be ~es~ed from the collection bag ll rather than trapped in the folds and wrinkles. In addition, when the collection bag ll contains ~,.LLifuged blood, the uniform external pressure applied to the collection bag ll tends not to disturb the buffy coat interface.

WO94/01193 PCT/US93/~ ~7 When an even pressure is applied to the exterior of the collection bag ll, a problem may - arise in that as fluid i~ e~ r^~ from an outlet portion 147 of the collection bag ll adjacent to the - - 5 flexible t~hing 20, 25, the opposing sides of the outlet portion 147 of the collection bag ll may tend to coll~p^? toward one another. This interferes -with the flow of fluid from the collection bag ll L~ou~h the flexible CQ~ t 20, 25 and extends the time e ~C~ry to aompletely e~e_ the fluid-It was found that by positioning or ~le__ing anobject and/or directing a force against a portion of the collection bag ll, preferably a portion located sub~La,lLially away from the outlet portion l47 of the collection bag, the fluid in the collection bag ll is moved within the collection bag ll and urged towards the outlet portion 147 of the collection bag ll, maint~;n;~g the opposing sides of the collection bag ll spaced from one another. The object and/or force provides a means to move the fluid within the collection bag ll and urge the fluid toward the outlet portion 147 of the collection bag ll. Urging the fluid towards the outlet portion 147 of the collection bag ll ~...Ls the uniform external ~e_~u~e exerted on the collection bag ll from collapsing the outlet portion 147 of the collection bag ll. A plurality of arrangements are suitable for applying an object and/or a force to the collection bag ll, including a bl~d~er, a spring, a rigid or resilient foam block, and/or a pneumatic, hydraulic, or ele~LLomagnetic arrangem~ent.
Referring to Figure 28-30, a preferred emho~iment of an e~e_~or cont~in;~g an arrangement for moving fluid within the collection bag ll to resist collapse of the outlet portion 147 of the _ 59 _ ~ wog4/ollg3 ~ 1 4 0 111 PCT/US93/~ ~7 collection bag 11 during expression is shown. At least one bladder 239 is disposed within the enclosed chamber 111, preferably at a location substantially away from the outlet portion 147.
5 Additionally, the blAAA~r 239 is preferably ~;~ros~ -adjacent to only a portion of the collection bag 11, e.g., the portion, ~uch as the lower portion, which i away from the outlet portion 147. The hl~A~r 239 may be attached to the hou~ing 110 using ~ny suitable mechAni~m, ~uch as an -~hP~ive or a co~ctor. The hlA~APr 239 may be pneumatically coupled to a ~ re regulating mech~nism 130 via a flexible hose 131 which extends tL~y~ the chaft -134 or ~t~G~y~ a ~eparate ~r~ing in the ho-cing 110. Figure 30 ~i~^loses a ~e__~Le regulating me~hA~ism 130 contAining a first section 130A for regulating the ~_s~re of the enclosed chamber 111 and a secon~ section 130B for regulating the ~ re of the b~ ^r 239. The first pressure reguiating section 130A is coupled to the enclosed chamber 111 via a first flexible hose 131A and the ~econ~ pressure regulating section 13OB is coupled - to the blA~Pr 239 via a ~econ~ flexible hose 13IB.
The first and ~ecQn~ re regulating sections 130A, 130B are preferably in~ppe~d~ntly ~o~.LLolled by the ~o,.L~ol unit 50.
In operation, the ~lF_-~Le regulation me~h niFm 130 supplies air to the hlA~Aor 239, preferably under c~..~ ol of the ~o..L}ol unit 50. As the hl~ r 239 eY~n~c~ it contacts the portion of the collection bag 11 away from the outlet portion 147 and applies a force against the collection bag 11.
This force causes fluid within the collection bag 11 to move within the collection bag 11 toward the outlet portion 147, and thereby maintains the W094/01193 ~101 4 1 PCT/US93/~ ~7 opposing sides of the collection bag ll spaced from one another as described above. The cv~.LLol unit 50 - may ~ol.LLol the operation of the b~ r 239 so that the hl~A-er 239 oYp~nAc to any suitahle dimension or - 5 cize at any suitable time in a ~equence. The cv..L~ol unit 50 may al~o cvl.LLol the deflation of the hladder, for example, by opening a relief valvé
coupled to the bladder 239 and all~:wing the ~.~-r-~re within the enclosed cha~ber lll or the weight of the collection bag ll to deflate the blr~r 239.
Alternatively, the ~o~L~ol unit may draw a vacuum on the inflated hlr~-r and maintain the vacuum even ~fter the bladder 239 deflates, ensuring that the hlA~Aer 239 remains flat. The ~ re within the 15 hl~A~r 239 may be incre~r-~/decrea~ed with ~e_~e_L
to the ~e_~u~e in the enclosed chamber lll so that the hl~ r inflates/deflates ~ro~e~ly. Also, the volume of air in the housing may be adjusted to maintain a constant ~ ~e on the bag ll as the h~ or 239 inflates or deflntes.
In alternative embodiments, the bladder may include more than one section and/or compartment, and individual sections and/or compartments may be ;n~e~o~A~tly ~e~&~ed (e.g., inflated and deflated) 25 in a s;m~lar manner. Multiple hl~ rs spaced within the enclosed chamber lll, may be c~ olled by the ool.~ol unit 50 to move the fluid within the collection bag ll. The bl~d~o~ may even be used to e~e_~- fluid from the container ll, obviating pressurization of the housing llO.
In some embodiments, it may be desirable to mix the contents of the collection bag ll. In a preferred mode of the optional mixing operation, the e~le~sor is c~r~hle of moving fluid within the collection bag ll to mix a plurality of fluids - W094/01193 2 t ~ O 1 g 1 PCT/US93/~ ~7 contained in the collection bag 11. Mixing a biological fluid, particularly the mixing of, for example, a preservative solution with PRC, may be automated in accor~nae with the invention. A
plurality of tec~ni1ues have been developed in accordance with the i-~lLion which have re~l~ceA the mixing time from, for example, over ten minutes to two minutes or less. In preferred embodiments, the mixing time i8 less than about one minute and more preferably in the ~-ye of 15-30 ^eCQn~c or less.
As will be described in more detail below, the mixing G~e~aLion may compri~e ~-c~ ting, rotating, roc~i~g~ and/or inverting the collection bag 11.
The mixing v~e~Lion may also compri~e kneA~ing the collection bag using one or more hlA~rs. In a -preferred embodiment, the housing 110 con~ining the collection bag 11 is oscillated, rotated, rocked and/or inverted about the shaft 134 to mix the fluid in the collection bag. For example, rotating or ro~ing the collection bag about the shaft 134 at a rate of about once e~y 1-2 ~con~c may be suitable.
Figures 14-16 ~i~Clo-e a ~eco~ exemplary embodiment of an arrangement for moving fluid within 25 the con~; n~ 11 to resist coll~rc~ of the outlet portion 147 of the collection bag 11 during ~ sion and to promote complete and uniform flow of the fluid from the collection bag 11, as well as moving fluid within the collection bag 11 to mix various fluids contained in the collection bag 11.
A solenoid 144 includes a coil 136 ~u~ g and electromagnetically coupled to a plunger 135. The solenoid 144 may be electrically co~n~cted to and ool.~ olled by the CG~ ol unit 50. The pl~l 135 35 is coupled to a shaft 139 at a co~n~cting point 138.

WO94/01193 214 014 i PCT/USg3/~ ~7 - The shaft 139 is pivotally connected at a first end to a pivot 137 so that the shaft may rotate about - the pivot 137 as shown by dotted line 140. At a _? ^~A end, the shaft 139 is connected to a paddle ~ 5 141. The connection 145 may be a rigid connection, a r~ t connection, or a biased .G. o~Lion, e.g., where a spring h;A~ the paddle away from the shaft. The paddle 141 may have any suitable configuration, but is preferably semicircular, and it may be dimensioned so that it does not extend across the full width of the collection bag 11.
When the colenoid 144 is actuated by the col.LLol unit S0, it serves as a drive mech~ ;m, r~;rl~ the plunger 135 into the enclosed chamber 111, causing the shaft 139 to .,L~Le about the pivot 137, and moving the shaft 139 and paddle 141 into the position shown by the dotted line 140.
As shown in Figure 15, when a full collection bag 11 is placed in the enclosed chamber 111, the paddle 141 and the shaft 139 are compressed ~inct the back of the base 112 and the pl~.yel 13 5 is p~lche~ into a fully retracted position within the solenoid 144. As fluid in the collection bag 11 is e~e_~ed and flows out of the collection bag 11 thlouyll the conAllit 20, 25, the paddle 141 ~_r~c or bears against the collection bag 11.
It was found that in some embodiments, the time required to e~re_~ fluid from the collection kag 11 could be re~ e~ by the application of the solenoid 30 force, as fluid contirm~~ to be e~eed from the collection bag 11. The force of the solenoid 144 compensates for the additional fluid that has been e~ essed from the collection bag 11, without requiring a large spring that may render insertion of the collection bag 11 in the enclosed chamber 111 Z1401gl - ' WO94/01193 PCT/US93/~ ~7 difficult. As the plunger 135 is forced out of the solenoid, the action of the solenoid-driven paddle 141 upon the fluid in the collection bag 11 serves to y~e~ collApse of the outlet portion 147 of the collection bag 11, even as the ~u~E...atant layer is e~L~ from the collection bag 11. The position of the collection bag 11 relative to the housing 110 before and after the actuation of the solenQi~ 144 is shown in Figure 15. The dotted lines 140 and 148 ~e_~e~Lively ~ nt the position of the - collection bag 11 and the paddle 141 after the golenoid 144 has been actuated.
Using the ~olenoid 144 and p-~le 141 to repeatedly ~e__ against the container 11 in conjunction with orc;llAting, ~vL~Ling, rorking and/or inverting the collection bag 11 as d~_~ibed above may further facilitate mixing the fluid in the collection bag 11. For example, the solenoid may be actuated by the eol.L.oller 50 at a frequency of, for example, 1-5 cycles per second. T.he solenoid 144 is preferably actuated using a square wave pulse of a relatively short duration.
Figures 24-27 disclose a third exemplary embodiment-of an arrangement for moving fluid within . 25 the cont~;n~r to resist coll~p~? of the outlet portion 147 of the cont~ r 11 and/or to mix fluid in the cont~iner 11. The e~ es~or includes the collection bag 11, a roller or a non-rolling kneader . fist 201 located within the housing 110, and a motor 166 which serves as a drive mech~n;sm to actuate the kneader fist 201. The mech~n;sm for effecting the movement of the ~n~ r fist 201 is unimportant, and any suitable movement mech~n;sm such as pneumatic, electromagnetic, and/or hydraulic mech~nism may be utilized as a means for moving the kneader fist 201 WO94/01193 2 1 4 U 1 4 1 PCT~US93/~547 in place of the motor 166. The motor 166 or other movement mechAni-c~ may be fixed to the housing 110 using any known ~ n;~ue, e.g., a motor mount 206.
The motor mount 206 is shown in detail in Figure 26.
-- 5 A chaft 234 of the motor 166 is fixedly coupled to a cv~LDing ball ~crew 205, which i8 preferably - configured in a double helix configuration. A ball nut 204 is ~ hly coupled to the ~ ing ball ~ u 205. A kneader block 203 and the kneader fist 201 are fixedly coupled to the ball nut 204 and move with the ball nut 204 along the ~ev~L~ing ball screw 205. Tracks 211, formed in a ~e~ala~ing plate 207, extend parallel to the ball ~crew 205-and guide the kneader fist 201 nd the kneader block 203 as they move ~long the ~e~ ~ing bsll ~l.U 205. The kneader fist 201 and the kneA~r block 203 are shown in detail in Figure 27.
In G~ ~Lion, sctuation of the motor 166 causes the ~ Ding ball ~ r 205 to rotate, and .~ -^quently results in a linear back-and-forth - movement of ~he bsll nut 204, the kneader block 203, snd the kneader fist 201. The motor 166 may be coupled to and ~G..Llolled by the ~o..L.ol unit 50 and may receive p~rer and ~G--L~ol signals from the wl.Llol unit 50 tL~ou~L a hollow portion of shaft 134. The motor 166 may be operated in a con~inl~o~s f~c~ion for achieving the mixing o~-~aLion as described above, preferably as the housing 110 is ocr~ ted along the shaft 134. Alternatively, the motor 166 may be actuated so that the kneader fist 201 is moved along the lev~ing ball screw until it is bto~hL into contact with, and ~e6se6 2g~inct~
the collection bag 11 to ~V~ the outlet portion 147 of the collection bag 11 from collapsing. The co..~ol unit 50 may receive a f~h~ck signal from ~ W094/Ollg3 2 1 9 0 ~ 4 1 PCT/US93/~ ~7 the gearing arrangement 266 or motor 166, 132 so t~at the housing llo may be stopped in one or more positions along the rotation or the kneader block 203 may be storp~ at one or more locations along the ,~ ing ball screw 205. Additionally, the - gearing arrangement 266 and ~vel~ing ball screw may contain one or more lor~ing mech~ni~ms, ele_L~o~.icAlly controlled by the ~o.,L ol unit 50, for loc~:ng the housing 110 and/or kneader block 203 in one or more positions.
A preferred automated biological fluid ~r~ ing system 149 may be configured, for example, as ~hown in Figure 17. The ~G.~L~ol unit 50, may for example, inC~ a user interface, such as a keyboard 150, a display 151, a ~oy.am/data entry medium such as a magnetic storage disk 152, and/or a ~cAnn~r 170. The ~G.,L~ol unit 50 is also coupled to flow meter 72.
The flow meter 72 is preferably similar to the flow meter described in U.S. Application Serial No.
07/589,523 filed on September 28, l990 and EPO
Publication 0477973 pUbli-eh^~ on April 1, 1992. The flow meter 72 may be a differential flow meter that measures the rate of fluid flow into or out of a cont~;n~r by measuring the rate of change of the weight of the container. The flow meter typically includes a weight trAneAI~cer coupled to a differentiating mechAnism and a ~Gll~ ol unit. The weight trAn~ ce~ preferably is a structure suitable for pro~cing a signal ~ ~o~Lional to a weight placed upon the structure. The contA;~er may be placed directly on the structure or the container may be placed in the housing 110 of an expressor which, in turn, is placed on the structure. The differentiating mech~nism pro~l~ses a signal ~ W094/01193 2 1 4 O 1 4 1 PCT/US93/~ ~7 o~o.Lional to a rate of change of a weight placed on the load~cell and bearing the strain gauges. The co"~ol unit may determine the absolute weight of an object by directly sampling the ~L~L signal from - S the weight tr~nCA~c~r, or the ~l.L.ol unit may determine the rate of flow of fluid to or from the weight trAn^~c~ by ~ampling the ~ignal from the differentiating mech-nism. When such a flow meter is used in conjunction with the automated blood ~ ing system, it is possible to determine both the total quantity and the rate of flow of a fluid.
A block diagram of the preferred biological fluid ~o~_sing system 149 is shown in Figure 18.
Figure 18 is imilar to Figures 1 and 2 in ~G,.~ Lion and operation, and identical reference numerals refer to identical parts. The collection bag 11, or any other fluid cont~; n~, may be mounted within the differential ~e_~u e generator 51.
Flexible tubing 20, 25, 28 intcl~o.~.e_Ls a plurality 20 of cont~in~rS 11, 18, 41, 42. Valves 61-64 are elecLLically coupled to the col,Llol unit 50.
The o~Lion of a preferred embodiment of the automated biological fluid ~G~ ing system 149 shown in Fiyu~Le_ 17 and 18 in accordance with the invention may be illustrated by-refe~ e to the flow charts shown in Figures 19-22. Prior to initiation of a particular operation sequence, a biological fluid is typically collected into the collection bag 11, which is co~ Led ~y cQnAllits to at least one satellite container. The collection bag 11 is then centrifuged to form a ~u~e~"atant layer and a C~A iment layer. The collection bag 11 then is placed in the differential pressure generator 51, the cQnAllits A~soc;~ted with each of the satellite containers are ~o~ cted to valves 61-~1901~1 - WO94/01193 PCT/US93/~ ~7 64, and the satellite bags 18, 41, 42 are placed on the flow meter 72. In a preferred em~ho~;ment, the collection bag ll contains whole blood which has been separated into a ~u~cl..atant P~P layer 31 and a sediment PRC layer 32.
Figure l9 discloses a ~lGylammable initial sequence ~o..L~ol block. In this block, a ~vyLam in the ~o..L.ol unit 50 can s^l~ct any number and combination of se~nGes for ~Lo~essing biological fluids. The particular se~^n~ec and parameters within the seq~ ceC are ~vy.ammed to ~ ,o.
to, for example, the fluids to be ~o.n~ , the filter types and sizes in the system, the size of the fluid containers, the length of the t~h;ng, the type and quantity of ~L~-e~vative cont~in^~ in the fluid containers, and the quantity of the desired fluid to be obtained. If desired, this information, and any other selected information, e.g., donor identification information, may be collected using any suitable input, e.g., scAnne~ 170, and for inventory cG~LLol.
In some embodiments, it may be desirable to track andtor monitor the biological fluid as it is ~oc~sre~ according to the invention, e.g., to automatically provide information to the operator and/or the end user(s) of the biological fluid.
Accordingly, information relating to the source of the biological fluid, such as the donor or source batch identification, the blood type, the weight of the donated unit may be man~ ly or automatically entered into the ~o--L~ol unit using, for example, the rcAnn~ 170 and/or other portions of the user interface means. The information may be stored in the ~o..~ ol unit 50 and made avAilAh1e as desired.
Additionally, as the biological fluid is ~o~se~, W094/01193 ~1 4 01 4 1 PCT/US93/~ ~7 additional information, for example, the additive solution and/or the viricidal agent used, the level of leukocyte depletio~, the final weight of the ~G~,e--~ eA fluid, the number of units ~.oce~ by a particular v~L~Lor and the time period reguired to ~o~ a particular unit, etc., may also be by the ~o..L ol unit 50.
In an exemplary e~bodi~ent, the biological fluid may be ~ according to the invention to produce PRC, PC and plasma in separate containers, and a label including some or ~ll of the above information may be man~ y or automa~i çally generated, for example using a l~h~l printer 253, at the a~.v~.iate time to be placed on the ~.o~Liate container. In a preferred emhoA~ment, the container of donated biological fluid may include a bar code label ~co~ing the ~ o~iate source information, ~o that the use of the scanner 170 all-ws the automatic entry of the information before the biological fluid is ~.v~ according to the invention. This has the advantage of minimizing the risk of ~e.~or error in initiating the co~-e~L
~e_sing seguence for ~G~.L ol unit 50.
Among other aavantages, the information ~c~oci~ted with a particular fluid contai~D~ may be used as part of an inventory ~G~L~vl and/or tracking system. In this ~eyo~d~ a plurality of cu..L ol units 50 may be ~-o.. ~Led together with one another, and with a ~.L.~1iZ~ data base, which, may also be interfaced to one or more user locations.
Integrating an inventory ~v..L ol and tracking system into the ~ol.Llol unit 50 has many advantages, including minimizing the possibility that the wrong unit may be used during a medical ~O~ r~~
In some emho~;ments, it may be preferable to ~ WO94/01193 2 1 4 0 1 4 i PCT/US93/~547 pool a number of units from a plurality of containers. In this case, it may be desirable to identify the source of all fluids that have been pooled. When pooling is being preformed by the S cv-~ol unit 50, the c~l.Llol unit may provide a detailed label identifying the svulces of the pooled biological fluid as well as any ~o~ ing and h-nAl~ng steps that have o~L.e~-relative to the pooled or source biological fluid.
Additionally, the ~v.. L ol unit 50 may i..~v.~G~Le various fail--safe ~.Gy.~ms to e..~ule that an alarm is i nA i ~ted if a particular biological fluid is ~ A using an improper ~ocf~ ng seq~ ce. Co..L~ol unit 50 may al~o be ~.oylommed to provide a warning if an in~ e_L
amount of one or more com~o.,_nLs of the ~OC~ ~ceA
biological fluid is ~1 c~A.
In a preferred emhoAiment~ the cG..L~ol unit 50 is ~oy.ammed to ~F-rectively initiate seql~o.~s A, B, C, and D shown in Figures 19-22 for separating the components of a biological fluid such as whole blood. The operator would instruct the ~ol.L.ol unit as to the ~o~e~ sequence using a user interface means, such as display 250, disk drive 152, and/or k~yboald l50. After the collection bag ll and any satellite bags 18, 41, 42 have been ~v~.e~Lly positioned, the operator initiates the ~Ol~ ol sequence by, for example, pressing a start button.
In step lO0 (hereinafter, SlOl, Sl02, Sl03, etc.), sequence A is started. The ~vllL ol unit 50 verifies that there is a stable flow, e.g., 0 ml/minute, for a predetermined time period such as 3 S~CQ~AC. This initial check can be utilized to c~lih~ate the flow meter 72 and co,.L~ol unit 50 to a zero flow condition. The initial check for zero WO94/01193 21 4 01 41 PCT/US93/~ ~7 flow verifies that the system has st~hi 1; zed after the flexible tubing 20, 25, 28 and the satellite bags 18, 41, 42 have been placed on the flow meter 72 by the v~c~aLor. If the flow has not stAhili7ed~
the operator is notified via the user interface means, such as display 2S0. The display may be uti~ d in ~o..j~.-Lion with an a~ihle indication or othOE means of notifying the v~e~Lor of anomalous condition~.
In SlOl, valves 61 and 62 are closed.
Alternatively, the valves may be closed as the fir~t step in the initiPli7~tion of seguence A.
In Sl02, a differential ~ re is generated Le~ e~. the collection bag ll and the ~atellite bag 41 by, for example, ~c~ rizing the enclosed chamber lll of the ~e_~u~e differential generator 5l. The flow mèter 72 may be r~c~e~ to cl~Ou~e that the flexible tubing 20, 25 has been ~v.,e~ly - inserted into clamps 61 and 62, ~~F~ctively, and that clamps 61 and 62 are func~ioPing cv~.c~Lly.
Thus, the ~o..LLol unit 50 verifies that a stable flow, e.g,, 0 ml/minute, is maint~in~ even after the differential ~c_~u~c is generated. In the c~e-~ion of PRP t}~G~y~ a ~o~s medium such as a red cell barrier medium, it was found that a differential ~ ~_~u~e of a~.o~imately 2 psi provides optimum ~ ts with .e_~e~L to ~ eOsion time, effecti~ of the filter medium, and the ability to detect that the PRP layer has been completely e~ r~
In Sl03, valve or clamp 61 is o~ 1, and the pressure differential between the collection bag ll and the first satellite bag 4~ causes the Ou~ell,atant PRP layer 31 to flow in the direction of the satellite bag 41. As the ~u~eL..atant PRP layer - W094/01193 ~1 4 ~1 4 1 PCTlUS93/~ ~7 31 p~Csec from the collection bag 11 to the first satellite bag 41, it typically passes through at least one porous medium, preferably a red cell barrier medium or combined lPl~kocyte depletion and red cell barrier medium.
It is preferable to close both valves 61 and 62 prior to the initiation of the differential - pressure. It may also be preferable for the ~.. L~ol unit 50 to monitor the ~.~ re in thè pressure differential generator 51 to ~.~uLe that a sufficient pressure has been estab~ P~ prior to or~ing clamp 61 in S103. The es~Ahli~hment of a sufficient ~ Le differential, combined with the ~ APn ope~lin~ of valve 61, L~ t~ in a column of biological fluid which p-~c a column of air through the porous medium and then allows the column of biological fluid to impact the porous medium ~ e~ly. This sequence of op OE ation results in optimum performance and is particularly important for optimal operation of the ~lOUS medium. If valve 61 is left open so that the biological fluid is r~ Lt~ouyh the tubing slowly as the pl~-s~re is increased, air bubbles become trapped in the fluid, and the efficiency of the ~o~ous medium is re~ce~. Thus, in the preferred o~eL~Lion the valves 61, 62 are closed prior to establ ish;ng the differential pressure and the valve 61 is ~ P~ly opened.
In S104, an initial flow detection is performed. The flow of the ~u~cl~latant layer is monitored to ensure that the valve 61 has been properly released and that the flexible tubing 20 is not obstructed. The initial flow detection performs a check to verify that the flow eYsee~c a first predetermined level. If the initial flow rate is W094/01193 PCT/US93/~ ~7 - 2 1 ~0~ Ql too low, the operator may be notified via the user interface means, or the differential pressure may be adjusted. Once the first predetermined level of - initial flow has been detected, S105 is initiated.
In S105, the flow i~ monitored until either a predetermined quantity of fluia has been e~r~_-e~
from the collection bag or until a predetermined time period has ~l~r7-~ from when the initial flow ~o~ the predeter~ined level. In a typical application, the predetermined time period is ~et, for example, at Le.~_cll 3 to 5 minutes and the predetermined quantity may be set, for example, at between about 100 and about 120 cc.
In S106, the ~G11LLO1 unit 50 may cause a force to be aprli~-A- against the collection bag 11. As previously -A~ c-~, the force may be applied by, for example, the bla-A-A-~r 239, the paddle 141, or the kneader fist 201. In a preferred embodiment, the ~O11LLO1 unit 50 actuates the blAAA--r 239 by having the ~ section 1308 of the ~L~_~uLe regulating mech-ni~m 130 increa~e the pressure within the hl~A~-r 239 to a level which ~ e-Ac the yLe~ re of the Dno~ chamber 111. Incr~a~ing the y~ re within the bladder 239 fG~ an exterior surface of the hl AA~r 239 A~7 ~ n~t the collection bag 11. In this manner, the fluid in the collection bag 11 is ~oved so as to y e~.L the outlet portion 147 of the collection bag 11 from collap~ing as previously ~i~c~ . Ho~e~, step S106 may be omitted if desired. If this step is omitted, ~r o~e ~sing y~ c~ directly to S107.
In S107, the flow is monitored until the flow decreases below a C-CQn~ predetermined level. When the flow has fallen to the ~?con~ predetermined level, the ~G~ ol unit 50 determines that flow wo 94/01lg3 2 1 4 0 1~1 PCT/US93~06~47 should cease.
The first and cecon~ predetermined levels may be variously selected dPrPn~i ng on a particular application. For example, these levels may be a S ~e ~-Laye of a ~aximum e~e_Led flow from the container. The first predetermined level may be a~ ~imately 50%-75% of the ~aximum expected flow while the ~e~o~ predetermined level may be a~ ~imately 20%-50% of the ~ax i e~e_Led flow.
In the preferred emh~Aiment of the invention, a red cell-barrier ~G~OUS medium or a red cell barrier - leukocyte depletion ~ous medium is used, and the monitor produces a signal monitoring the flow rate thlv~yh the red cell barrier or the red cell barrier leukocyte depletion ~or~s medium. Once the ~u~e~..aLant PRP layer has been completely e~ ce~
from the collection bag 11, the red cells near or in the sediment PRC layer contact the red cell barrier medium or the red cell barrier leukocyte depletion medium. Flow tL~uyh the medium then significantly slows or stops. In one embodiment, where the maximum c~e~ed flow is about 40 cc/minute, the first predetermined level may be about 25 cc/minute while the ~ecQn~ predetermined level may be about 15-20 cc/minute. Alternatively, where the maximum ~e~Led flow is about 20-25 cc/minute, the first predetermined level may be about 10-15 cc/minute while the recQ~ predetermined level may be about 4-7 cc/minute.
In S108, the signal proA~l~e~ in S107 causes the ~Gu~.ol unit 50 to close valve or clamp 61, and eliminate any force, i.e., the blAAAPr 239, the - -paddle 141, or the kneader fist 201 from bearing against the collection bag 11. In a preferred embodiment, the clamp 61 is closed quickly and the WO g4/0ll93 2 1 4 0 1~1 PCT/US93/06~7 conduit 27 ext~nAi ng from the red cell barrier medium or the red cell barrier leukocyte depletion medium to the first satellite bag 41 is relatively ~ long. ron~^quently~ in the event that any red cells S pass thLv~yh the ~Lo~S medium, they will be eve,.Led from r~ ;ng the first satellite bag 41.
In S109, the ~o..LLol unit 50 decreases the differential ~L~ ~e to zero ~nd ~eL~..~ the ~equence co.-LLol to the ~Loy.ommable initial sequence C~LLO1 block for the initiation of, for example, seguence ~ as shown in Figure 21.
Sc~ 2 B provides, for example, a mech~n;sm to transfer an additive solution, diluent, ~ vative, or the like, from a satellite bag into the collection bag 11 and add it to the ~e~iment PRC
layer 31 remaining in the collection bag 11 after completion of sequence A. In S109 the collection container is preferably inverted by rotating the pressure differential yel.e~tor ~Loximately 180 dey~ee_.
In SllO, a L~veL~e differential pressure is created for example, by creating a vacuum in the differential pressure generator 51.bct-een the collection bag 11 and the ~ec~nA satellite bag 18 which contains the additive solution The flow meter 72 may be monitored by the ~l.L.ol unit 50 to UL-` that the flexible ~1-hing 20, 25 has been .Le_Lly inserted into clamps 61 and 62, ~e_~ectively, and that clamps 61 and 62 are functioning ~Le-tly so that a zero flow is indicated.
In the retrieval of the solution from the æ~co~A satellite bag 18 into the collection bag 11, it was found that a negative differential pressure of ~.o~imately 1 psi provides optimum results with WO94/01193 2 1 ~ O I q 1 PCT/US93/06~7 respect to retrieval time and with respect to the viscosity of the fluid.
In Slll, valve or clamp 62 is opened, and the pressure differential between the coliection bag ll and the C~conA satellite bag lB causes the solution in the ~con~ satellite bag 18 to flow in the direction of the collection bag ll. As the solution n~ from the ~econ~ satellite bag 18 to the collection bag ll, it typically r~c~c L~o~h at least one porous medium, preferably a leukocyte depletion medium.
It is preferable to close both valves 61 and 62 prior to the initiation of the differential pressure. It may also be preferable for the co..Llol unit S0 to monitor the pressure in the pressure differential generator Sl to ensure that a sufficient pressure has been established prior to opening clamp 62 in Slll. As discussed above, the establishment of a preexisting pressure differential, com~ined with the sudden opening of valve 62, provides ~nh~n~e~ flow of the solution from the second satellite bag 18 to the collection bag ll.
In Sl12, an initial flow detection is performed. The flow of the solution is monitored to ~ ule that the valve 62 has been ~ ly released and that the flexible tubing 20 is not obstructed.
The initial flow detection performs a check to verify that the flow into the collection cont~in~r ll ~Yr~e~c a predetermined level, e.g., up to 40 ml/minute or more. If the initial flow rate is too low, the operator may be notified via the usér interface means, or the differential pressure-may be adjusted. Once an initial flow of, for example, at least 40 ml/minute has been detected, Sl13 is 094/01lg3 ~1 4 0 1 4 i PCT/US93/06547 initiated.
In S113, the flow is monitored until the negative flow decreases below a predetermined minimum flow rate, for example, between about O and 7 ml/minute into the collection contAi nor 11. When the flow has fAllen to the minimum predetermined flow rate, the co..~Lol unit 50 determines that flow ~ho~ cease. The G..~.ol unit 50 may then ~ ~l---o a ~;~n-l inAi~Ating that the solution has been transferred from the satellite hag 18 into the collection bag 11. This signal may be used to generate either an A~;hle or visual indication to the op OEator, e.g., via the us_r interface means.
In S114, the signal ~L~l~e~ in S113 causes the c~l~LLol unit 50 to close valve 62, and shut off the differential pressure generated he~.rLe~. the collection bag 11 and the satellite bag 18. In S115, the solution and the PRC are mixed together by oscillating or roc~;ng the collection bag. It has been found that an occillAtion frequency of about once a ~Çcon~ is sufficient for mixing the contents of the collection bag 11. Of course, a hi~h~ or lower lo~c; 11 Ation rate co~ be u~
Optionally, the m;xing of the collection bag 11 may be fAc;litated by, for example, ~-c;ll~ting~
vibrating, and/or ~h~; ng the housing 110 and/or collection bag 11 along one or more of the three dimensional axes of movement, pulsating the collection bag 11 using, for example the paddle and/or one or more b~ ^r, and/or ~.6~ the collection bag 11 using the kneader fist 201. If one of the optional mixing mech~nisms are utilized, it may be desirable to actuate the mixing mech~nism at a relatively high freguency. The ~G~.L~ol unit 50 preferably continll~s the mixing ~ro~eFs for WO94/01193 2 1 ~ O 1 4 1 PCT/US93/~47 approximately 2 minutes or less. The mixing time is variable with the guantity of PRC and the particular solution utilized in the mixing ~L OOe3S .
In S116, the miYing ~LG~e~s is sto~A so that the differential pressure generator 51 is located in the inverted position and c~LLol is LeLuL~led to the ~LCY dmmable initial sequence CO~LU1 block for initiation of, for example, sequence C as-shown in Figure 21.
Sequence C serves to ~e_s the sediment PRC
layer 32 from the collection bag 11 into the ~e~onA
- satellite bag 18. In S117, a differential pressure is generated between the collect~on bag 11 and the ~ eOQ~ satellite bag 18 by ~Le_~uLizing the ~Le~ ~e differential generator 51. In the ex~Le_~ion of PRC
t~lvuyll a ~ s~yte depletion assembly, it was found that a differential ~e~uLe of a~oximately 1-3 psi provides optimum ~e~ ts with .e_~e~ to e~e_~ion time and effectiveness of the porous medium.
In S118, valve 62 is ~p~ and sediment PRC
layer 32 in collection bag 11 is preferably p~
L~uu~ a leukocyte depletion assembly 17 and into the ~rco.~l satellite bag 18. As with the previous inst~nceC when the valves are olC~l, it may be desirable to create a ~e_~uLe differential before s~Dning the valve 62, and for the cG,~ol unit 50 to verify that the clamp ls functioning ~o~-~ly and that a sufficient differential pressure has been g~.e~a~ed.
In Sll9, an initial flow detection is performed. The flow of the sediment layer is - -monitored to ensure that the valve 62 has been p~u~e~ly released and that the flexible tubing 25 is not obstructed. The initial flow detection performs WO ~/01193 ~1 4 0 1 ~ 1 PCT/USg3/06~7 -a check to verify that the flow ~Y5~AC a predetermined level, e.g., about 20 ml/minute or more. If the initial flow rate is too low, the ~ operator may be notified via the user interface means, or the differential ~ ~e may be adjusted.
~ Once an initial flow of, for example, at least about 20 ml/minute has been ~?tected, S120 is initiated.
In S120, the flow is monltored until the flow decreases below a predetermined minimum flow rate, for example, between 3 and 7 ml/minute. When the flow has fallen to the minimum predetermined flow rate, the ~o..L~ol unit S0 determines that flow ch~ cease.
In S121, the signal pro~ e~ in S105 c~ ^c the vullL~ol unit S0 to close valve 62.
In S122, the ~LLO1 unit decreases the differential pressure between the collection bag 11 and the satellite bags to about zero.
In S123, the ~llLLol unit resets the ho~lCi ~g 110 by rotating it LLo~yh an angle of 180 degrees in the manner ~ above to ~6LUL11 the hQ-c;~q to the normal upright or ~on;nverted position as shown in Figure 17~ ~lOyL~m co~,Llol is then l~LuL.Ied to the ~Lv~lammable initial sequence 2S cu.-LLol block for initiation of another sequence, e.g., sequence D as shown in Figure 22.
Prior to initiation of sequence D, the operator may be prompted by the user interface means of the co~l~ol unit S00 to remove the satellite bags from the flow meter 72 and to remove the empty collection bag 11 from the pressure differential generator Sl.
In one emhoA;ment, involving a collection bag 11, first satellite bag 41, ~econ~ satellite bag 18, and third satellite bag 42, the empty collection bag and the ~?.CO~ satellite bag 18 cont~;n;ng the mixture W094J01193 2 1 g O 1 4 1 PCT/USg3/~547 of PRC and additive solution are separated from each other and the remaining two satellite bags. The remaining satellite bags, i.e., first satellite bag 41 (Con~ain;ng the PRP) and the third satellite bag 42 (which is empty) remain in fluid communication.
Typically, the first and third satellite bags 41, 42 are pla~e~ in a ~.LLifuge and spun to ~c~al~Le the PRP contained in the first ~atellite bag 41 into a second D~e~..atant layer, typically plasma, and a rsco~ sediment layer, typically a platelet cont~in;ng layer which may be ~o ~ to form PC.
- After ~e.. L ifugation, the ~Lor places the first satellite bag 41 into the pressure differential ~ Lor 51 and the third satellite bag 42 onto the flow meter 72, as shown in Figure 23. The con~nits - are located with ~e_~c~L to valves 63 and 64 as shown in Figure 23. At this time, the operator instructs the c~.,Llol unit 50 to begin initiation of sequence ~.
Sequence D ~erves to separate the ~u~.. aLa,.L
plasma layOE from the -r~iment platelet con~inin~
layer. In step 124, the ~o--L.ol unit ~1~F~ ~ ~ to verify that there is a stable flow (e.g., 0 ml/minute) for a predetermined time period such as 3 ~ecQ.,l~. This initial check can be utilized to c~lih~ate the flow meter 72 and ~o-lLlol unit 50 to a zero flow condition. The initial check for zero flow verifies that the system has stabilized after the con~llits 27, 28 and the satellite bags 41, 42 have been placed on the flow meter 72 by the operator. If the flow has not stabilized, the operator is notified via the user interface means.
In steps 125, valves 63 and 64 are closed.
- In step 126, a positive pressure differential is generated between the first satellite bag 41 and WO94/01193 ~1 4 0 1 4 1 PCT/US93/~ ~7 the third satellite bag 42. The control unit 50 may monitor the flow meter 72 to verify that the valves 63, 64 are operating correctly. Once a desired pressure is reached, valve 64 may be op~n~ (5127), S allowing the ~?ao~A D~e~natant plasma layer to flow t~ conAl~it 28 into the third satellite bag 42.
In Sl28 and Sl29, flow con~ c until a predetermined value or condition is r~hs~ e.g., a sufficient amount of the feco~A Du~eLnatant plasma layer has p~c~^~ into satellite bag 42. This amount is preferably ~ufficient to collect much of the plasma without any of the platelets in the ~e~on~
sediment platelet cont~ining layer passing into the third satellite bag 42. Tn accordance with a preferred embodiment of the in~e~.~ion, the amount of Du~l..atant passing into the third satellite bag 42 is preferably predetermined h~e~ on weight or time, but it is inten~-~ that the i.-ve-,~ion should not be limited thereby.
In Sl30, after the predetermined amount of ~ecQn~ ~upcLl.atant placm~ has been collected as determined by the co..L~ol unit 50, in Sl28 and Sl29, valve 64 closes.
In Sl31, the pressure differential is shut off by the wtl~ol unit So, and the sequence is ~e~.e~
to the ~y ammable initial sequence co..~ ol.
In accordance with an additional emho~iment of the invention, e~vely of various biological fluids trapped or re~Aine~ in various elements of the system is maximized, either by causing a volume of gas heh i nd the trapped or retained biological fluid to push the fluid through those elements and into the designated container, assembly, or porous medium, or by drawing the tr~pp~ or ret~in~ fluid into the designated container, assembly, or porous WO94/01193 2 1 4 0 1 4 1 PCT/US93/~ ~7 medium by a pressure differential. This is accomplished automatically by the control unit by automatically col.L~olling the various gas inlets or outlets 73-75, 81-82, 98, and 99. This provides for a more complete emptying of the cont~i~er, assembly, or porous medium. Once the cont~in~r is emptied completely, the flow may be s~orro~ by the ~Gl.~ ol unit so ~ lly after a predetermined period of time has ~l~p~-~ since the valve has been ore~ or closed.
While the il-v~l-Lion has been described in some - detail by way of illustration and example, it should be understood that the i,lv~,-Lion is c~cc~rtible to various modifications and alternative forms, and is not ~Llicted to the specific embodiments set forth above. It ~o~l~ be understood that these specific embodiments are not intended to limit the invention but, on the co~ ary, the intention is to cover all modifications, equivalents, and alternatives f~ll;n~
within the spirit and ~csr~ of the invention.

Claims

WHAT IS CLAIMED IS:

1. An automated biological fluid processing system comprising:
a pressure differential generator;
a biological fluid processing assembly including:
a first container operatively associated with the pressure differential generator, a second container in fluid communication with the first container, and a porous medium interposed between the first container and the second container; and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly to control flow between the first container and the second container.

2. An automated biological fluid processing system comprising:
a pressure differential generator;
a first container, operatively associated with the pressure differential generator and a second container;
a porous medium interposed between the first container and the second container;
a valve arrangement for directing the flow of biological fluid from the first container;
at least one separation monitor for monitoring the interface between a first portion of the biological fluid and a second portion of the biological fluid;
a control unit coupled to the valve arrangement and to the separation monitor to control flow between the containers.

3. The system of claims 1 or 2 wherein the porous medium comprises at least one of a leukocyte depletion medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

4. The system of claims 1 or 2 further comprising a third container, wherein a leukocyte depletion filter is interposed between the first container and the third container.

5. The system of claim 4 wherein the automated control arrangement controls flow between the first container and the third container.

6. The system of claims 1 or 2 further comprising at least gas control element in communication with the first container.

7. The system of claims 1 or 2 wherein the pressure differential generator includes an arrangement to move fluid within the first container.

8. m e system of claims 1 or 2 wherein the pressure differential generator includes an enclosed housing in fluid communication with a pressure regulating mechanism suitable for controlling the fluid pressure applied to the outside of a container positioned in the housing.

9. The system of claim 1 further comprising at least one separation monitor for monitoring the interface between a first portion of the biological fluid and a second portion of the biological fluid.

10. A method for automatically processing a biological fluid comprising:
a) placing a container of biological fluid into an enclosed chamber of a differential pressure generator;
b) supplying a signal from an automated control arrangement to the differential pressure generator; and c) in response to the signal, varying pressure within the chamber to establish fluid flow into or out of the container;

11. A method for processing a biological fluid comprising separating a biological fluid in a container into a supernatant portion and a sediment portion; and passing at least one of the supernatant portion and the sediment portion through at least one porous medium, wherein said passing includes initiating, monitoring, and terminating flow of the portions by an automated control arrangement.

12. The method of claims 10 or 11 further comprising passing a portion of the biological fluid through at least one of a leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

13. The method of claim 12 further comprising venting gas.

14. The method of claim lo wherein the biological fluid includes first and second portions and further comprising monitoring the interface between the first portion of the biological fluid and the second portion of the biological fluid.

15. A method for automatically processing a biological fluid comprising:
at establishing flow of a first portion of a biological fluid along a first fluid flow path to at least one of a leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium;
b) generating a signal indicative of the separation of the first portion of the biological fluid and a second portion, and supplying the signal to an automated control arrangement; and c) in response to the signal, terminating flow through the first fluid flow path.

16. The method of claim 15 wherein generating the signal indicative of the separation of the first portion of the biological fluid and the second portion includes generating a signal indicative of at least one of a predetermined position of the second portion, a predetermined back pressure in the first fluid flow path, and a predetermined flow rate through the first fluid flow path.

17. The method of claim 15 further comprising establishing flow of a second portion of the biological fluid through a second fluid flow path to a leukocyte depletion porous medium.

18. The method of claim 17 wherein flow of the second portion of the biological fluid through a second fluid flow path is established in response to the signal indicative of the separation of the first portion of the biological fluid and a second portion.

19. The method of claim 15 further comprising:
a) in response to a signal from the automated control arrangement, establishing flow of a physiologically acceptable fluid through a second fluid flow path;
b) generating a termination signal for terminating the flow of the physiologically acceptable fluid, and supplying the termination signal to the automated control arrangement; and c) establishing flow of a second portion of the biological fluid through the second fluid flow path in response to the termination signal.

20. The method of claim 19 wherein establishing flow of a physiologically acceptable fluid through a second fluid flow path includes passing the physiologically acceptable fluid through at least one of a leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

21. The method of claims 17 or 19 further comprising separating gas from the second fluid flow path.

22. The method of claims 10, 11, or 15 including moving fluid within the container in response to a signal from the automated control arrangement.

23. An expressor for varying the amount of fluid in a variable-volume container connected to at AMENDED CLAIMS

least one conduit the expressor comprising:
a housing defining an enclosed chamber for accommodating the container, the housing having at least one opening through which the conduit can extend;
a pressure regulating mechanism coupled to the housing to vary the pressure of fluid in the chamber and thereby vary the volume of the container; and an arrangement for moving fluid within the container, the arrangement including at least one of a) a drive mechanism for moving the housing and b) apparatus for pressing against a first portion of the container.

24. A method for expressing a biological fluid from a container in an enclosed chamber comprising:
varying the pressure within the chamber; and moving fluid within the container by at least one of a) moving the chamber in an oscillatory fashion or b) pressing against a first portion of the container.

25. A method for automatically processing a biological fluid comprising:
a) placing a container of biological fluid into an enclosed chamber of a differential pressure generator;
b) providing a signal between an automated control arrangement and the differential pressure generator; and c) in response to the signal, varying pressure within the chamber to establish fluid flow out of the container and through a porous medium.

26. The method of claim 25 comprising establishing fluid flow through at least one of a leukocyte depletion medium and a separation medium.

27. The method of claim 26 comprising placing a container of whole blood into the enclosed chamber.

28. The method of claim 27 comprising establishing fluid flow of whole blood through the leukocyte depletion medium.

29. The method of claim 26 including ceasing fluid flow in response to a signal from an optical reader.