WO1994006535A1 - Appareil et procede de fractionnement d'un melange liquide - Google Patents

Appareil et procede de fractionnement d'un melange liquide Download PDF

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Publication number
WO1994006535A1
WO1994006535A1 PCT/US1993/008523 US9308523W WO9406535A1 WO 1994006535 A1 WO1994006535 A1 WO 1994006535A1 US 9308523 W US9308523 W US 9308523W WO 9406535 A1 WO9406535 A1 WO 9406535A1
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WIPO (PCT)
Prior art keywords
εaid
gap
fraction
flow
mixture
Prior art date
Application number
PCT/US1993/008523
Other languages
English (en)
Inventor
Halbert Fischel
Richard J. Fischel
Original Assignee
Halbert Fischel
Fischel Richard J
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Halbert Fischel, Fischel Richard J filed Critical Halbert Fischel
Priority to AU51266/93A priority Critical patent/AU5126693A/en
Publication of WO1994006535A1 publication Critical patent/WO1994006535A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B04B5/04—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers
    • B04B5/0442—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/26—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes and internal elements which are moving
    • A61M1/262—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes and internal elements which are moving rotating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3692—Washing or rinsing blood or blood constituents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3693—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3693—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging
    • A61M1/3696—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
    • B01D63/16—Rotary, reciprocated or vibrated modules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0413—Blood
    • A61M2202/0415—Plasma
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B04B5/04—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers
    • B04B5/0442—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation
    • B04B2005/0464—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation with hollow or massive core in centrifuge bowl
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B04B5/04—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers
    • B04B5/0442—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation
    • B04B2005/0478—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers with means for adding or withdrawing liquid substances during the centrifugation, e.g. continuous centrifugation with filters in the separation chamber

Definitions

  • the present invention relates to centrifugation apparatus and methods for separating liquid mixture components, as for example, blood, having different sedimentation rates.
  • Prior centrifugal separation systems either continuous or batch, generally form layers of substantial thickness.
  • the spin axis defines the rotation that produces the centrifugal force, which force causes the eventual separation of components according to differing densities. Greater densities occupy comparatively greater depths when sufficient time is allowed to permit the effective completion of the sedimentation process.
  • the depth of a layer refers to its distance from the spin axis.
  • separation of such components by this means is necessarily incomplete. Even with no overlap of component density distributions, separation may not be complete or as perfect as desired due to instabilities in the suspending media under rotation making it particularly difficult to extract material from thin intermediate layers. Such instabilities tend to increase as total liquid thickness increases, especially when the material is caused to flow for the purpose of decanting various components.
  • Parameters such as the time required to produce useful separation by density layering, rotation rates, layer thickness, decanting geometry, volume processing capacity, and component purity have, heretofore, required undesirable trade-offs in which one was compelled to compromise purity as against separation time or volume processing capacity.
  • limitations are imposed by the decanting geometry, method and rate which may introduce disturbances in the formed layers especially when the latter are very thin as in the case of "white” cells of blood, i.e., the "buffy coat".
  • centrifugal separators for dealing with the various problems just described, they all require the separated material to form layers which closely approximate the end point of the sedimentation process.
  • the loci of separation as between the several layers can be used to define a surface normal vector that would be substantially perpendicular to the spin axis at all points of the layer.
  • the decantation of any particular layer requires at least some component of flow transverse to the layer's "surface normal" vector. See, for example, U.S. Patent No. 4,086,924. It is easily seen that one layer is required, at least in part, to "flow" in a shearing fashion over other layers in order to be decanted.
  • Efforts to prevent clogging of the membrane have included increasing the membrane area (see B.A. Solomon, et al, U.S. Patent No. 4,212,742), the shear rate of the flowing blood so as to delay the clogging effect (see R.J. Fischel, et al, U.S. Patent No. 4,755,300), or the pressure differential across the membrane (see F. Castino, et al. The Filtration of Plasma from whole Blood: A Novel Approach to Clinical Detoxification. In: Chang, T.M., et al., Artificial Kidnev. Artificial Liver, and Artificial Cells. New York: Plenum Press, 1978, pp. 259-266) .
  • centrifugal elutriation Another technique that has long been used for cell separation is usually referred to as centrifugal elutriation or CE (see M.L. Meistrich. Experimental Factors Involved in Separation by Centrifugal Elutriation. Cell Separation Methods and Selected Applications, Ed: Pretlow, T.G., Academic Press, New York, V.2, PP: 33-61 (1983)).
  • the basic principle involved in various embodiments of this technique is separation by differences in particle settling rates.
  • a counter-flowing fluid is introduced against the centrifugal force field (see R.L. Berkow et al Purification and Functional Evaluation of Human Polymorphonuclear Leukocytes.
  • FIG. 1 is a schematic central vertical section of a apparatus embodying the present invention showing the basic method of operation thereof;
  • FIG. IA is broken, fragmentary, schematic and enlarged view of the right-hand portion of FIG. 1 demonstrating the behavior of fluid components relative to the porous element;
  • FIG. 2 is a horizontal sectional view taken along line 2-2 of FIG 1;
  • FIG. 3 is a broken foreshortened central, vertical sectional view showing the major components of the form of apparatus of FIG. 1 embodying the present invention
  • FIGS. 4 and 5 are horizontal sectional views taken along lines 4-4, and 5-5, of FIG.3;
  • FIG. 6 is a foreshortened central vertical sectional view showing major components of a second form of apparatus embodying the present invention.
  • FIG 6A is a fragmentary central vertical sectional view of the apparatus of FIG. 6 showing the parts thereof arranged for a washing function;
  • FIG. 7 is a horizontal sectional view taken along line 7-7 of FIG. 6.
  • FIG. 8 is a central vertical sectional view showing major components of a third form of apparatus embodying the present invention.
  • FIG. 9 is a horizontal sectional view taken along line 9-9 of FIG. 8.
  • FIG. 10 is a graph demonstrating one principle of the invention relating to the separation of the components into separate fractions
  • FIGS. 11 and 12 are schematic views demonstrating the relationship between rotational speed of the centrifugation unit and movement of the liquid components during operation of the apparatus embodying the present invention
  • FIGS. 13, 14 and 15 are plots of diameter, density and settling rate, respectively, of various blood components in terms of population distribution, with FIG. 15 referring to Stokes settling velocity per unit of centrifugal force;
  • FIG. 16 is a schematic illustration showing how two devices embodying the present invention can be operated as two simultaneous stages for collection of platelet concentrate
  • FIGS. 17-20 are schematic illustrations showing various functions which may be obtained employing the method and apparatus of the present invention.
  • the apparatus includes a cylindrical assembly A adapted for rotation about a central vertical axis 20 and having inner and outer generally cylindrical shells I and O, respectively, defining therebetween an axially extending tubular gap G.
  • the inner shell includes a porous cylindrical structure 21 for at least a part of its axial extension for a purpose to be described hereinafter.
  • the cylindrical assembly A is shown disposed within a fixed housing H, for rotation relative to the housing about axis 20.
  • the boundaries 32 and 34 are shown as concentric tubular boundaries extending about the axis of rotation 20 of the cylindrical assembly A, and may either be cylindrical or variously, somewhat differently tapered, i.e., inclined to the rotational axis of the assembly at particular axial locations, as described hereinafter.
  • the direction of rotation of the cylindrical assembly is indicated by arrow 36, and the liquid mixture, or fractions, in various states of localized concentration of particular components flow generally downwardly, i.e., axially from the top of gap G to the bottom of gap G between the vertically orientated boundary surfaces 32 and 34.
  • a vertical support tube 41 rigidly interconnects and carries the inner and outer shells I and 0 at 42 and 44.
  • Power operated means (not shown in FIGS. 1 and 2) are interposed between housing H and the cylindrical assembly A to spin the inner and outer shells and their confronting surfaces 32 and 34 about the common axis of rotation 20 at the same angular velocity.
  • the liquid mixture to be fractionated M may be fed into the axial portion of gap G above an imaginary reference horizontal plane 81 and also pressurized by means not shown in FIGS. 1 and 2 , as via a feed stream indicated by flow path 46.
  • Boundary 48 is an imaginary cylindrical surface essentially parallel to the vertical axis of rotation 20 having a radius which can be controlled by mass balance of the liquid mixture and fraction flows into and out of the apparatus as described more fully hereinafter.
  • Controlled radially inward flow from gap zone 49 i.e., the axial portion of gap G below horizontal plane 81 of the second liquid fraction consisting of at least the continuous liquid phase of mixture M or a continuous phase including one or more discontinuous components in that zone is enabled in a pressure-drop direction operating to compel flow out of the gap zone 49 and through the porous surface 34 and the porous element 21 of the inner shell I into an inner region R defined between the inner surface of inner shell I and a cylindrical barrel element 50 coaxial with tube 41.
  • Such enable ent is effected as a function of the static pressure difference between gap G and interior region R, the effect of angular velocity of rotation ⁇ of the zones defining boundaries, subjecting the liquid to centrifugation pressure opposing inward radial flow, and the porosity of porous structure 21 which resists flow.
  • the thickness of the gap G will vary depending upon the nature of the liquid mixture being fractionated. In the case of blood, the preferred gap thickness is between about 5 to 150 mm.
  • the fluid mixture progresses axially and downwardly as it encounters the porous structure 21 of the inner shell, the primary purpose of which is to act as a flow distributor. In order to serve this function, the porous structure must have certain properties.
  • the pores must be large enough to freely pass without sensible restriction, the discontinuous or formed constituents to be decanted.
  • the pores may offer no restriction to constituents or particles that are intended to remain behind in the gap with the original medium because "filtration", understood as a sieving effect, plays no part in the operation of the method and apparatus of the present invention.
  • the porous structure must offer flow resistance to that portion of the suspending medium carrying the decanted constituent in the sense of creating a "pressure gradient".
  • the preferred operative requirement is that the Trans Porous Pressure (TPP) drop substantially exceed the pressure loss required to move fluid from its entrance to the spinning film (mixture M) to its exit from the film (first liquid fraction M.,) . Consequently, the porous structure means can act as a largely "uniform" flow distributor in accordance with the invention. In practice, this is not a serious restriction in, for example, generally useful blood flow rates, given that the thin film flow cross-sections possible in accordance with the invention, do not lead to significant axial blood flow pressure losses.
  • the uniform decanting velocity referred to here is defined by dividing the volumetric decanting rate, of second liquid fraction, M 2 (ml/sec) by the porous area (cm 2 ) .
  • the uniform decanting rate is adjusted by controlling input and output volumetric pumping rates of incompressible fluids.
  • Centrifugation of the axially (here downwardly) flowing liquid mixtures in gap G tends to move discontinuous components throughout the mixture and separating fractions, which are more dense than the suspending continuous medium, in an outward radial direction generally opposite the inward radial flux through porous surface 34 and away from axis 20.
  • Components which are less dense than the suspending continuous medium i.e., buoyant particles
  • V s settling velocity
  • D square of particle diameter
  • ⁇ inversely proportional to suspending medium viscosity
  • centrifugation may be controlled, as for example by control of angular velocity, given radial dimensions of boundaries 32 and 34, to allow permeation of any component or components having radially outward characteristic settling velocities below a selected value, in the inward radial direction, along with the liquid, i.e., controlled permeation through the porous boundary 34 and porous cylindrical structure 21, the porosity of the latter in general allowing such components in the mix to pass through unobstructed.
  • the porosity may be such as to allow all components (of different sizes and settling rates) to pass, i.e., including those of a relatively greater settling rate, but which are not allowed to permeate, due to the angular rate ⁇ of centrifugation tending to retain them in the gap zone 49.
  • Flow path 54 in FIG. 1 indicates removal from gap G of modified mixture M,, in the form of, or consisting of, the initial liquid mixture M less any liquid which has flowed radially inwardly through porous structure 21, and less any particle component or components carried with the liquid permeating porous structure 21.
  • the difference between the rate or amount of feed of mixture M into the gap along path 54 at the top and the rate or amount of removal of M 1 from the gap along path 54 at the bottom is necessarily the net rate or amount of permeation, i.e., decantation for an incompressible liquid such as blood along flow path 46.
  • static pressure is actually controlled by controlling the feed flow and removal flow rates using positive displacement pumps (not shown in FIGS. 1 and 2).
  • 11 and 12 illustrate vectorally the forces on the particles due to centrifugation and decantation.
  • the upper portion of the inner shell is formed with a impervious inverted cup-shaped entrance member 66, the sides 68 of which are tapered downwardly and inwardly away from boundary 48 towards the center of the cylindrical assembly A.
  • the lower end of entrance member 66 abuts the top of porous element 21 at horizontal plane 81.
  • Outer surface, 34 of porous element 21 forming the interior surface of the gap G is either parallel to or preferably tapered outward from axis 20 relative to boundary 48.
  • the outer cylinder 0 also preferably tapers outward from axis 20 at an angle usually similar to that of surface 34, for reasons more fully explained below.
  • Surface 68 is seen to resemble an inverted frusto-conical surface while surfaces 32 and 34 are seen to resemble upright frusto-conical surfaces, respectively.
  • the angle of taper and special shaping, if any, of surfaces 68, 32 and 34 may best be understood by treating boundary 48 as a downward axially moving surface which matches the velocities at boundary 48 associated with the axial flow of liquid in gap regions 82 and 83, respectively.
  • Gap regions 82 and 83 are radially inward and outward of cylindrical boundary 48, respectively.
  • the purpose is to minimize shear, i.e., axial velocity gradient, as between regions 82 and 83 at boundary 48.
  • shear i.e., axial velocity gradient
  • the portion of total centrifugal force assignable to the outward axial component is the sine of the angle surface 32 makes with rotational axis 20. Even at one part in one hundred the axial component of force which must be added to one gravity in vertically oriented apparatus can be considerable and always advantageous to the movement of thickened viscous material.
  • boundary 48 The radial position of boundary 48, to the extent it actually forms, is best understood in relation to the lower extremity of surface 34. If most of the continuous phase contained in the original mixture M i ⁇ decanted as suspending medium for the second fraction M2 or is itself M2 then boundary 48 will closely approach the lowest extremity of interior surface 34 because very little axial flow cross- section is required for the remainder of M2 to enter zone 62 where it re-mixes with the concentrated material leaving the lower end of gap G to become the final formulation of Ml. In the limit where all available M2 is decanted and concentrated material is well formed, that is, boundary 48 is well defined, the latter will just intersect the extreme lower corner of surface 34.
  • Boundary 48 is merely a convenient reference for purposes of illustrating the process, however, the permeation of what is, at first, a very minuscule amount of concentrated material into M2 can be used as an observable indicator of conditions within the apparatus in most cases.
  • Nephelometry or hemoglobin detection means placed at the output 86 of M2 will detect the very first permeation of cells or RBC, respectively, in the case of blood, whereby decantation flows may be adjusted at will. Similar techniques are available for most mixtures having concentrated separable components.
  • Zone RA is the space radially inward of boundary 48 radially outwardly of the cup-shaped entrance member 66.
  • Zone RB is the space radially outwardly of boundary 48 adjacent zone RA toward which all of the mixture components (more dense than the suspending liquid medium and thus subject to centrifugal force) move.
  • Zone RC is disposed below the imaginary horizontal plane 81 adjacent the outer surface 34 of porous element 21 within boundary 48.
  • Zone RD is disposed adjacent zone RC, but radially outwardly thereof and the porous element surface 34.
  • zones RA and RB all of the said more dense components that are subject to centrifugal force move radially outwardly, and there is no opportunity for radially inward flow.
  • the purpose of including these zones is to provide an opportunity for the concentration of otherwise concentrated particles nearest the spinning outer surface of the cup-shaped element 66 to be lowered so as to create dilution of such particles radially inwardly of boundary 48.
  • zone RB increasing concentration of particles is taking place which tends to make boundary 48 more visible.
  • Zone RC is the zone which is most proximate to the outer surface 34 of the porous element wherein the separation of component M2 i ⁇ occurring. Within zone RC, a predictable or characteristic radially outward settling of particles takes place, since zone RC now contains a diluted mixture of particles.
  • zone RB the liquid is becoming more concentrated, and accordingly, becomes more viscous.
  • zone RC the liquid is less viscous, as in zone RA, but is also being removed radially inwardly through the porous element, and is accordingly, losing volume as the volume increases in zone RA.
  • zone RD the liquid is becoming thicker and is substantially increased in viscosity so as to require more space within which to flow.
  • the aforedescribed tapering of the outer and inner facing surfaces of the outer and inner cylinders is designed to take into account the fundamental physical fact that the division between the liquid portion and the concentrated portion follows a surface that is essentially parallel to the axis of rotation 20, and it should be understood that such cylinder is indicated by boundary 48.
  • Boundary 48 is located radially within the gap depending upon the volumes that are flowing in and out of the cylindrical assembly. Because of the axial downwardly flow of the liquid, in combination with the radially inward flow of liquid component M2, the axial flow and the radial flow are vectorially independent as noted hereinabove.
  • the aforedescribed tapered surfaces insures approximately the same axial velocity for the concentrated and non-concentrated liquid components at boundary 48. If such approximately matched axial velocity is not obtained, there would be a tendency for one or the other liquid component to have a shearing effect that would tend to create vortices in the high energy rotational field generated by rotation of the cylindrical assembly A.
  • the basic concept provided by the present invention is to immerse the entire rotating cylindrical assembly A in a bath of sterile solution, compatible with blood, e.g., saline, or anticoagulant, indicated by flow arrows 90, which is contained within the stationary housing H. Access to the interior of the housing H is made through upper and lower conduits 91 and 92, to be described fully hereinafter, which lead into and out of the housing from or to sterile containers respectively.
  • the entire sterile path, including the rotating cylindrical assembly, and the several sterile containers which may be permanently attached to the assembly housing prior to sterilization comprise a closed sterile system. Conventional peristaltic pumps, not shown in FIG.
  • engaging conduits in communication with the interior of the assembly can be used to move fluids to and from the containers and the assembly without invading the sterile environment which includes, in part, the extracorporeal blood path and the vessels in which the separated concentrated blood components are stored. See FIG. 18.
  • flow path 90 which begins at the upper portion of the rotating assembly and its stationary housing H, a sterile or wash solution is urged downwardly between the space 93 separating the exterior surface of the outer cylinder O and the inner surface of the stationary housing H.
  • Such sterile or wash solution is discharged at the bottom of the rotating assembly and housing combination.
  • Fluid seals (not shown in FIGS. 1 and 2) are interposed between the upper and lower elements of the rotating assembly and its stationary housing H. A portion of the sterile solution flows through these seals.
  • the sterile bath is maintained at a higher static pressure than the fluid flowing through paths within the rotating assembly.
  • the entire rotating assembly is surrounded by the sterile bath and the seals which need not function as bearings, are provided to operate between that bath and the fluid flow paths of the rotating assembly.
  • the criteria governing the design of the seals are less critical than the criteria normally required for sterility barriers.
  • these rotating seals can be impervious to fluids without detracting from the operation of the apparatus and method of the present invention
  • the sterile bath is maintained at a higher static pressure than the blood, or, in the alternative view, caused to flow at a pre ⁇ determined rate across the seal by means of positive displacement into the blood, as long as the leakage rate is small, the dissolution effect is harmless, and the direction of flow operates to protect the fragile components of the mixture by preventing them from entering the seals.
  • the sterile bath may also be the wash solution and a high leakage rate is intended.
  • the advantages of such a rotating seal concept are significant in connection with high spin rates.
  • the same concept may be employed in separate load bearing bearings between the housing H and cylindrical assembly A, except that flow through the bearings is much higher and does not represent a "leak" from one fluid into another.
  • the cooling effect of the sterile bath can be enhanced by maintaining a circulation of this bath around the rotating mechanism and through the rotating bearings and seals exposed to the circulating bath.
  • the same sterile bath can be continuously recirculated by providing fluid entrance and exit routes on the stationary containment vessel, as shown in FIG. 1 for that purpose.
  • the power-operated means for rotating the cylindrical assembly A within housing H may take the form of a conventional electro-magnetic armature drive utilizing a stator 100 affixed to the upper part of housing H which cooperates with an armature assembly 102 which is keyed to an upper coaxial drive tube 104 that extends downwardly with its lower end affixed to the upper portion of the support tube 41.
  • An upper bearing member 115 is interposed between the upper portion of drive tube 104 and a drive support member 105 that extends upwardly from a neck 107 formed on housing H.
  • the upper end of drive support member 106 is provided with an inlet fitting 110 which is connected with the upper end of drive tube 104 to conduct the liquid M downwardly therethrough.
  • An upper combination bearing and O-ring assembly 112 is interposed between the upper portion of drive tube 104 and the drive support member 106.
  • a sterile solution conduit 91 is affixed to the neck 107 of the stationary housing H to conduct sterile solution upwardly through a first sleeve 113 formed on the neck along the inner surface thereof, radially inwardly and downwardly through vertical passages 114 of upper bearing 115, then radially outwardly below bearing 115 and downwardly along the inner surface of a second sleeve 116 below drive support member 105 and exterior of armature assembly 102. From the space below the armature assembly 102, the sterile solution flows downwardly through a main bearing assembly 118 through vertical passages 119 formed through the intermediate bearing assembly. Main bearing 118 is carried by neck 107.
  • the sterile solution flows downwardly into space 93 between the interior of the housing H and the exterior of the outer shell O.
  • the sterile solution flows downwardly through the lower confines of the space 93 underneath the outer shell O to flow downwardly out of a discharge conduit 92.
  • additional sterile solution is introduced into the base portion 120 of the housing H through a conduit 130, such sterile solution being indicated by flow arrows 132.
  • the sterile solution entering through conduit 130 flows upwardly through vertical passages 133 formed in a lower bearing assembly 142 to mix with the sterile solution entering through the upper conduit 91, and then flows outwardly through discharge conduit 92.
  • This second flow of sterile solution also moves downwardly through a lower top combination bearing and O-ring seal assembly 140 and upwardly through a lower combination bearing and O-ring seal assembly 142.
  • the sterile solution may serve as a coolant for the bearings and seal assemblies.
  • the liquid component M designated by flow arrows 54 is moved downwardly through drive tube 104 and radially oriented in passages 141 formed in the common top wall of the inner and outer cylinder, then into the upper portion of gap G to flow downwardly therethrough to be separated as described herebefore into the first liquid component Ml.
  • liquid Ml flows radially inwardly through passages 145 formed in the common bottom wall of the inner and outer shells, and then downwardly through lower tube 150 to be finally discharged through discharge conduit 86 which is coaxial with the tubes and the cylindrical assembly.
  • the lower tube 150 extends through bearing O-ring seal assemblies 140 and 142 and a bottom combination bearing O-ring assembly 154.
  • the sterile solution entering through lower conduit 130 cools the lower bearing and combination bearing and O-ring seal assemblies.
  • liquid component M2 which flows through the porous cylinder 21, as indicated by flow arrows 46, moves radially inwardly from the bottom of inner region R through passages 160 formed in the lower portion of the inner and outer cylinders I and O to be collected in chamber 164 formed between the lower portion of the vertical support tube 41 and the lower drive tube 150 for ultimate discharge through fitting 87.
  • Shock absorbing pads 156 may be interposed between the horizontally facing surfaces of housing H and outer cylinder 0.
  • the sterile solution entering through the respective upper and lower conduits 91 and 130 follows a sterile path which includes the exterior of the rotating cylindrical assembly A and is maintained at a higher static pressure than the fluids M, Ml, and M2 so as to protect the fragile components of these fluids by preventing them from entering the seals as described in detail hereinbefore. It should also be understood that it is possible to force a saline solution into the gap G, as hereinbefore described, should it be necessary to re-liquify or otherwise render fluid any packed cells of the liquid component Ml within the lower portion of gap G.
  • the housing A4 of the separator apparatus receives blood from a donor at its upper end.
  • the concentrated blood cells of the donor are returned to the donor, as indicated by the directional arrows.
  • Plasma is transferred to a suitable receptacle from the lower right side of the housing as shown by the directional arrows.
  • the volumetric pumping rate of the blood- handling upper pump Pll is greater than that of the lower pump P12 so as to provide the pressure differential required to effect permeation of the plasma through the walls of the porous cylinder element 21.
  • Saline sterile solution forced by pump P13 enters the upper and lower left-hand portions of the housing A4 and such saline solution is metered out of the lower portion of the housing by pump P14 as shown by the directional arrows.
  • Saline pumps P13 and P14 maintain the saline solution at a higher pressure than the pressure maintained in the separator apparatus and the conduits leading to and from such separator for the reasons set forth hereinbefore.
  • This form of the invention is similar to the form of the invention shown in FIGS. 3, 4, and 5, with the exception that the inner shell I' is formed at its lower portion with a second porous structure in the form of a porous ring 170 disposed below the main porous cylinder 21'.
  • the upper part of the apparatus of this second form of the invention is also provided with a electro-magnetic armature drive (not shown) disposed within a drive support member 106' of the type utilized in the apparatus of FIG. 3 for rotating the cylindrical assembly A as a liquid M to be fractionated is caused to flow downwardly within drive tube 104'.
  • a third liquid fraction M3 is harvested from the lower portion of the fluid within the radially inner lower zone E portion of the boundary 48'.
  • Such liquid component fraction M3 is forced through the lower porous ring 170 by the excess of fluid pressure within the gap G over that maintained in an inner region RR interior of porous ring 170.
  • Such liquid after passing through the lower porous ring 170 continues to move radially inwardly through the lower region RR which is defined by passages 174 formed in the lower walls of the inner and outer shells.
  • This M3 liquid fraction is collected within a space 176 disposed outwardly of lower tube 150' to be ultimately discharged through an outlet conduit 178 formed in the lower right-hand portion of the stationary housing base 120'.
  • the lower portion of the outer shell 0' is formed with a cylindrical opening 180 over which is disposed a vertically movable cylindrical valve ring 182.
  • Such valve ring 182 is seated on a pair of O-ring seals 183 mounted in the outer portion of opening 180.
  • the lower portion of the valve ring is formed with a plurality of circumferentially spaced holes 186.
  • a porous diffusion ring 184 is disposed within the reduced diameter opening 185 inwardly of and aligned with opening 180.
  • Valve ring is normally arranged in its lowered position of FIG. 6, however, such valve ring may be moved upwardly into its raised position of FIG.
  • Steps 188 limit movement of the valve ring.
  • the holes 186 of the valve ring are disposed radially outwardly of the openings 180 and porous diffusion ring 184.
  • valve ring 182 When the valve ring 182 is moved to its raised position of FIG. 6A, however, saline wash solution is introduced radially inwardly through valve ring holes 186, as indicated by flow arrows 194, whereby such saline solution will flow radially inwardly from space 93' through the porous rings 184 and then ring 170 at a rate of flow effective to enable an inward radial velocity of controllable and uniform value within the gap G'.
  • Diffusion ring 184 may be somewhat displaced axially upward (i.e., toward the entrance zone of the gap) relative to porous ring 170 in order to accommodate downward axial displacement of wash solution in the time required for the latter to cross the gap.
  • the saline wash solution After the saline wash solution enters and crosses porous outer ring 184 and gap G', it enters and crosses porous ring 170, and enters inner region R' , as noted above.
  • the inward radial convective velocity associated with wash solution flow should be higher than that of prior flow across surface 34' of porous element 21' in order to take full advantage of a sequential concentrating followed by a washing step intended to remove contaminants not otherwise permitted to follow with flow across surface 34'. Forced inward convection of wash solution into and across the concentrated cell mass tends to displace the cellular material radially inward away from the interior surface of porous outer ring 184, i.e., floated or "levitated" off the surface.
  • Each cell that remains with the first fraction finds a new point of equilibrium (at some radial position within the gap) where convective drag on the cell (a force which is controlled by wash solution flux) is in balance with centrifugal force on the cell. Any particle which cannot find new equilibrium, e.g., broken cell stroma, will be washed out. It should be understood that the portion of boundary 48' between the facing porous surfaces of rings 170 and 184 will become somewhat displaced radially inward from its position as shown in FIG. 6A and less clearly defined because the population of cells has a distribution of settling velocities. Some perturbation of reference boundary 48' must occur in zone E due to the change in equilibrium conditions previously established in zones RC and RD'.
  • Liquid component M2 which flows through the porous cylinder 21', as indicated by flow arrows 46', moves radially inwardly into inner region R' and then upwardly through such region and into passages 199 formed in the upper common walls 198 (Fig. 6) of the inner and outer shells and then upwardly through a space 201 between the outer surface of drive tube 104' and the inner surface of support tube 41' into a collection chamber 202 between combination bearing and O-ring seals 203 and 204 to be discharged through a conduit 205.
  • sterile solution is forced through conduit 91' into the housing neck 107' so as to cool the bearings and seals disposed in the drive support member 106' and the housing neck in the same manner described hereinbefore with respect to the apparatus of FIG. 3.
  • the sterile solution entering through conduits 91' and 130' follows a sterile path which includes the interior of the housing H' and the exterior of the rotating cylindrical assembly A, and is maintained at a higher static pressure than the fluids M, Ml, M2, and M3 so as to protect the fragile components of these fluids by preventing them from entering the seals as described in detail hereinbefore.
  • the introduction of sterile solution through porous element 184 makes it possible to re-liquify or otherwise render axially flowable any packed cells of the liquid component Ml within the lower portion of gap G'.
  • FIGS. 13 - 15 for a description of the general mode of operation of the present invention as applied to previously described separator apparatus. It is important to note: a) the separation of particles is occurring as a result of differences or changes in "settling rate", see FIG. 15, i.e., a dynamic condition; and not due to separation after the particles have arrived at their static bands, as shown in the classical separation bands of FIG. 14. b) Settling rate in a given medium is a function of particle size, shape, concentration, and density.
  • FIG. 15 is a plot of the population distribution for several formed elements of blood with respect to their settling rates divided by the multiplier r ⁇ 2 . Dilute concentrations are assumed and the Stokes approximation is used for these plots. There is good agreement with observation for all blood particles except concentrated red blood corpuscles (RBC) .
  • RBC red blood corpuscles
  • FIG. 15 is a plot of the population distribution as in FIG. 15 but, in this case, with respect to particle density only, wherein the platelet band overlaps (i.e., is not spaced from) the lymphocyte particle band.
  • the density bands of FIG. 14 illustrate the end point distribution of essentially fully settled particles. c) In accordance with the present invention, decanting occurs while particulate is settling out, and not after settling is completed into bands as shown in FIG. 14.
  • decanting can occur after some particles have settled out according to density to form distinct bands, however prior art centrifugal separators employ means to extract material from these formed "layers", which is radically different from and inferior to that which is used in the present invention partly due to the fact that in the present invention, decanting occurs in a direction parallel to the force field (i.e., in the direction of vector 300 in FIG. 11) , and not at an angle to the force field, thereby eliminating otherwise obligatory and destabilizing shear to achieve decanting. The latter effect reduces the effectiveness of all known prior art devices; and e) particles separate even while they are still physically mixed in suspension not otherwise possible when separating particles from "formed" layers.
  • FIGS. 13, and 14 show a summary of published data on the population distribution of effective diameters and densities, respectively, of four important classes of human blood components, namely, red blood corpuscles (RBC), platelets, lymphocytes, and granulocytes. Except in regions of high concentration of components, the settling rate of that component in human plasma may be computed or at least characterized from these data using the Stokes drag equation:
  • V s D 2 ⁇ P r ⁇ 2 18 ⁇
  • Equivalent particle diameter refers to that diameter that gives the experimentally observed or "correct” settling velocity according to the Stokes equation which is more useful to show how settling velocity varies with design and operating parameters r and ⁇ , respectively.
  • Stokes equation calculates based on the Stokes equation as velocity per unit of centrifugal acceleration. Note that granulocytes, due to size as well as density, settle much faster than other particles, and the lot settles at least eight times faster than platelets.
  • liquid mixture M is blood which enters the upper portion of the rotating cylindrical assembly A through drive tube 104 and enters gap G.
  • This form of the apparatus is particularly adapted for use as a collector of cell free or platelet rich plasma.
  • a typical donor can be "bled" at a rate of about 100 ml/min.
  • Hct hematocrit
  • the suspending medium which, incidentally, is over 90% water, the rest being dissolved complex organic molecules, lipids, and salts.
  • the inward radial convective decanting velocity is 1.0 cm/min or
  • red blood corpuscles For operating and design purposes, one might pick a settling rate for red blood corpuscles to be 0.02 cm/sec which exceeds the convective velocity by enough to prevent red blood corpuscles from approaching the porous surface. Referring to FIG. 15, one has
  • the blood film thickness is nominally 0.1 cm, which, as will be shown herein, is well within the allowable range.
  • the red blood corpuscles and lymphocytes travel about 0.05 cm, they are nearly fully settled out as together they comprise nearly half the volume of the initially whole blood. They travel nearly this entire distance, or about 0.04 cm in 2 seconds, in the absence of a radial convective velocity such as obtains over the initial impregnable zone.
  • a hold-up volume of 3-1/3 ml of blood film over this zone (which may, for example, be obtained by using a gap G thickness of 0.1 cm and a first encountered impregnable surface area of 33-1/3 cm 2 ) will cause the blood to have a residence time of 2 seconds over the impregnable area and 6 seconds over the 50 cm 2 of porous surface 21.
  • the latter value is due to the fact that half of the 100 ml/min is withdrawn resulting in an effective axial flow of 50 ml/min through a hold-up volume of 5.0 ml over 50 cm 2 of porous surface.
  • the total residence time is 8 seconds in the operative blood film.
  • red blood corpuscles are nearly settled out before they even get to the porous surface 21 and settle even further thereafter. It is therefore reasonable to conclude that throughout the proximity of the porous surface, the concentration of red blood corpuscles is low and the Stokes settling rate is obeyed.
  • the platelets move away from the surface by, at most, 0.005 cm or barely 1/lOth of the distance they would otherwise travel to their settled position absent convective decanting. They retrace this entire displacement in less than l/3rd second after encountering radial inward convective flow upon first reaching the porous surface 21 and continue to be drawn through the porous flow distributing surface for the remaining 5.67 seconds of residence time over that surface.
  • FIG. 16 illustrates the manner in which two separator apparatus A-l and A-2 of the type shown in FIG. 3 may be operated simultaneously to produce platelet concentrate (PC) using positive displacement peristaltic roller pumps commonly available for the pumping of blood or other sterile fluids.
  • PC platelet concentrate
  • liquid M would be blood which enters the upper portion of the rotating cylindrical assembly A through drive tube 104' and enters gap G'.
  • This form of the apparatus i ⁇ particularly adapted for use as a rapid PC collector in certain surgical settings where high platelet loss is expected. If a fully therapeutic dose of platelets could be obtained from the surgical patient in the O.R. during surgical preparation and returned to that patient following surgery, significant clinical benefits (related to control of bleeding, i.e. clotting mechanisms) would be expected.
  • H a v i n g reference to FIGS. 6, 6A, and 7, such a procedure can be carried out in one step in the apparatus shown.
  • the plasma remaining in zone E after decantation of cell free plasma from zone RC contains PC which can, in sequential decantation acros ⁇ the outer surface of porous element 21' be largely removed from z ⁇ ne E through porous ring 170 as third liquid fraction M 3 , the remainder rejoining the concentrated material from zone 83' at pas ⁇ age 144' where the recombined material, now first fraction M.., is led away at conduit 86'.
  • PC in sequential decantation acros ⁇ the outer surface of porous element 21' be largely removed from z ⁇ ne E through porous ring 170 as third liquid fraction M 3 , the remainder rejoining the concentrated material from zone 83' at pas ⁇ age 144' where the recombined material, now first fraction M.., is led away at conduit 86'.
  • In order to prevent RBC or lymphocytes from being decanted along with the platelets it i ⁇ necessary to choo ⁇ e a convective radial velocity which exceed ⁇ the ⁇ e
  • FIGs 6, 6A, and 7, yet another application of the invention has great utility in the washing and concentrating of red blood corpuscle ⁇ either in connection with frozen blood storage or, perhaps more importantly, for application to blood cell salvage in what is termed auto-transfu ⁇ ion of the surgical patient's own blood during surgery. In the latter instance, it is the removal of excess heparin and return of concentrated protein and clotting factors for the purpo ⁇ e of clotting function regulation that ha ⁇ the greate ⁇ t clinical importance.
  • the proce ⁇ ing of high volumetric rate ⁇ can be u ⁇ eful.
  • Cell wa ⁇ hing should involve a concentration step followed by the simultaneous addition, separation and removal of wash solution, usually saline. If concentration precedes washing, the amount of wash solution required to displace cell stroma dispersed in the original suspending medium is minimized.
  • a saline wash solution indicated by flow arrows 189 from space 93' flows radially inwardly through porous rings 184 and 170, respectively, at a rate of flow effective to enable an inward radial velocity of controllable and uniform value acros ⁇ the gap and into pa ⁇ sages 174, space 176, and through discharge conduit 178 (see FIG 6) .
  • the inward radial convective velocity associated with wash solution flow should be higher than that of prior flow acros ⁇ surface 34' of porous element 21' in order to take full advantage of a sequential concentrating followed by a washing step intended to remove contaminants not otherwi ⁇ e permitted to follow with flow acro ⁇ s such surface.
  • the apparatus of the present invention is capable of removing 200 ml/min from a blood flow that would be typically 300 to 400 ml/min.
  • surface 34' has an area of 200 cm 2 so that the inward radial convective velocity i ⁇ 0.0166 cm/sec.
  • the operative parameter is about 10 ml/min of wash ⁇ olution for each 1.0 cm 2 of exterior and interior porous surface of porous elements 170 and 184, respectively, in order to maximize the washing effect (i.e. displacement of cell stroma) while still retaining all RBC in the first fraction.
  • washing process operative in the example herein described displace ⁇ rather than mixe ⁇ with the original suspending medium as in prior art cell washing method ⁇ . Con ⁇ equently, washing is more thorough per unit volume of wash solution because, as in the compari ⁇ on between a ⁇ hower and a bath, the wa ⁇ h solution is not substantially diluted. It is further noted that the crystalloid portion of the first separated protein containing liquid (i.e. plasma) can be removed as by ultra filtration in separate apparatus so that protein concentrate can also be returned to the patient. See FIG. 17.
  • FIG 17 is a schematic illustration of the operation of separator apparatus embodying the present invention which is convertible from a platelet concentrator to a cell washer/concentrator in accordance with principles of the invention.
  • Whole blood or a solution containing blood components is delivered by pump P6.
  • pump P7 removes concentrated blood while pump P8 remove ⁇ cell-free and stro a-free liquid.
  • the difference, that is, the volumetric pumping rate of P6 les ⁇ the ⁇ um of rate ⁇ of P7 and P8 is a net flow which is PC or contaminated wash solution in the cases of platelet collector and cell washing/concentrating, respectively.
  • cell-free plasma is recombined with concentrated blood to form reconstituted blood for return to the patient.
  • cell-free liquid containing plasma proteins and crystalloid material including water
  • a separate device incorporating membrane filtration to remove a large part of the water and crystalloid to form concentrated pla ⁇ ma protein.
  • the latter i ⁇ recombined with concentrated blood for return to the patient.
  • Saline circulation i ⁇ handled in each ca ⁇ e a ⁇ follows: Pump P9 delivers saline to each end of the apparatus while pump P10 removes saline from the central port 190 simultaneously, and at a slightly slower volumetric rate, in the case of platelet collection, in order to force some saline acros ⁇ the seals.
  • pump P10 For cell washing, pump P10 is slowed further. Pump P10 removes saline from the apparatus A at a volumetric rate which is les ⁇ than the volumetric rate of pump P9. The difference i ⁇ the volumetric rate at which ⁇ aline wa ⁇ h ⁇ olution i ⁇ delivered acro ⁇ the gap. It i ⁇ understood that fluids other than saline may be used for the purpose described above.
  • the cylindrical valve ring 182 (FIG.6) is raised, ⁇ aline solution enters the porou ⁇ ring 170 and outlet conduit 178 to wa ⁇ h contaminants picked up by the saline solution for dispo ⁇ al, a ⁇ indicated by the dotted lines at the right portion of FIG. 17.
  • FIGS. 3, 4, and 5 there is ⁇ hown the major components of a third form of apparatus embodying the present invention.
  • This form of the invention is similar to the form of the invention ⁇ hown in FIGS. 3, 4, and 5, with the exception that the outer cylinder O i ⁇ provided with a porou ⁇ element 193 over a portion of it ⁇ axial exten ⁇ ion. Like part ⁇ bear double primed reference numerals.
  • the upper part of the apparatu ⁇ of the third form of the invention is provided with an electro-magnetic armature drive, like that shown in FIG. 3 arranged to effect rotation of the inner and outer cylinders I'' and O'' within stationary housing H''.
  • a sterile solution is introduced into the conduit 91'' at top of drive support member 104'', and is discharged through an outlet conduit 92'' at the lower right-hand portion of housing H''.
  • the liquid component M to be fractionated enters through the upper end of drive tube 104' ' and flows downwardly through the lower end of the drive tube into the entrances of radially outwardly extending pas ⁇ age ⁇ 196 formed between the upper walls of the inner and outer cylinder members.
  • the radially outer ends of the ⁇ e pa ⁇ sages empty into the upper end of gap G''.
  • a circular baffle 210 is arranged coaxially between support tube 41'' and inner cylinder I'' to define inner region R' ' .
  • Inner region R" receives liquid fraction M2 which permeate ⁇ through porou ⁇ element 21'' of the inner cylinder I'' by a pre ⁇ ure differential created between the gap G ' ' and inner region R' ' , as fully described hereinbefore.
  • Passages 211 formed in the lower portion of the cylindrical a ⁇ embly A' ' transfer liquid component M2 into a space 212 from which the liquid is discharged through the lower portion of housing H''.
  • the lower portion of the hou ⁇ ing H'' is provided with bearings and O-ring bearing seals (not shown) through which a sterile, cooling solution is circulated as with the apparatus of FIGS. 3 and 6.
  • Wash solution which crosses porous element 193 nearest the top of the gap enters the concentrated blood cell mixture at gap region 218 and operates to dilute the mixture (provided wash solution is miscible with carrier fluid) even a ⁇ the cells migrate radially outwardly under the influence of centrifugal force.
  • the cells form a concentrated cell mas ⁇ exterior to imaginary boundary 48''.
  • Wash solution accumulates in gap region 219 and flows axially downwardly along with the concentrated cell mass in gap region 218.
  • Gap region 219 is formed by impervious entrance element 216 which compri ⁇ es an axially extending portion of the inner shell at the latter's top, which portion i ⁇ tapered radially inwardly or away from boundary 48'' in the downward direction. Consequently, gap region 219 increase ⁇ in thickne ⁇ downwardly to accommodate the addition of wash solution to the mixture.
  • Wash solution enters gap region 220 at a flux velocity identical to that at which it enters region 218.
  • wash ⁇ olution is simultaneously cros ⁇ ing the outer surface of porous element 21'' at the same rate thus removing wash solution from gap region 221 as fast as it enters.
  • the net effect is that wash ⁇ olution cro ⁇ e ⁇ the gap in a radially inward direction with no net accumulation of wa ⁇ h ⁇ olution in the gap for the axial extent of the gap which i ⁇ defined and enclosed by the common axial overlap (i.e., axially co-exten ⁇ ive portions) of porous elements 21" and 193 acting together.
  • porou ⁇ elements 21'' and 193 where they do not face each other, serve purposes de ⁇ cribed separately herein.
  • the gap-defining surfaces of the porous elements, where they face each other, remain concentric and parallel to boundary 48'' and to each other. The latter is the principal washing region of the gap.
  • the washing method is practiced by causing the wash solution flux velocity to be greater and less than the settling velocities of particles and/or cell ⁇ to be washed out and cells to be retained in the gap, respectively.
  • continuous phase will be washed out and virtually replaced with wash solution, provided the two liquids are miscible. If they are not, it is not po ⁇ ible to predict with certainty the behavior just described.
  • Wa ⁇ h ⁇ olution that was added to gap regions 218 and 219 is an excess volume not removed from gap region 221 and must flow axially toward exit region 209.
  • the bottom portion of the outer cylinder is comprised of an impervious element 222 having an inner gap defining surface 223 for approximately the same axial extent a ⁇ the imperviou ⁇ upper element 216 of the inner shell.
  • Impervious surface 223 is a continuation of porous element 193 wherefore wash solution flows out of gap region 224 without simultaneous replenishment from gap region 225. Consequently, porous surface 226 of element 21'' is tapered outwardly and downwardly toward boundary 48'' to account for the diminishing amount of continuous phase. Cells in gap region 225 become more concentrated until they reach the level of concentration at which they entered, thus canceling the dilution introduced in gap regions 218 and 219. Surface 226 is tapered outwardly and downwardly to boundary 48'' to aid in the flow of concentrated cells toward exit region 209.
  • the described method of dilution and re- concentration has the effect of increasing the distance between imaginary boundary 48'' and the inner shell's porous outer surface 226.
  • the additional distance operates to maintain dilute concentration of cells in the mixture most proximate the porous " ⁇ eparation" ⁇ urface 226.
  • the main concentration of cell ⁇ is radially exterior of boundary 48''.
  • the "environment" in which biologically valuable cells exist in gap regions 220 and 221 is unique in the present invention and, being su ⁇ tainable indefinitely, has not been so achieved in apparatus heretofore.
  • the opposing forces on a biological cell, operative in the gap are centrifugal force urging the cell to seek the inner porous surface of the outer shell and the drag force of radially inwardly flowing media tending to carry the cell toward the outer porous surface of the inner shell.
  • Such apparatu ⁇ can ⁇ uperimpo ⁇ e a controlled axial flow or operate without axial flow by deleting gap region ⁇ 218, 219, 224, and 225 along with the associated impervious elements.
  • Wa ⁇ h solution can carry nutrients and oxygen to the cell ⁇ and ⁇ imultaneou ⁇ ly remove C0 2 and other wa ⁇ te product ⁇ . It can be u ⁇ ed to control temperature, enzymes and drug delivery to the cell. It is clearly a novel cell culturing method that does not subject the cell to the damaging effects of mechanical ⁇ hear and filtration or ⁇ ub ⁇ trate interaction as used in some prior cell culturing methods.
  • FIG. 19 illustrate ⁇ a simple pumping arrangement for washing stored blood using the ⁇ eparator apparatu ⁇ of FIGS. 8 and 9. Blood is pumped via pump P15 while washed cell concentrate is pumped via pump PI6 into a separate washed-blood bag.
  • Becau ⁇ e of the normal time delay required for some chemicals ⁇ uch as ethylene glycol (typically used to store frozen blood) to leave the red blood corpuscle ⁇ (RBC) one would allow the fir ⁇ t wa ⁇ hed blood to re-enter the original ⁇ torage bag, after all blood i ⁇ cycled through the cell wa ⁇ her, by opening a valve between the two bags. After a period of time, the cycle is repeated for as many cycles as may be required to rid the ⁇ tored blood of objectionable chemical. The la ⁇ t cycle leaves the clean blood in the washed-blood bag.
  • ethylene glycol typically used to store frozen blood
  • Pump ⁇ P18 and P19 provide circulation and po ⁇ itive pre ⁇ sure on the seals of the apparatus A5 for controlled leakage as described hereinbefore, but the difference in their volumetric rates, i.e., the pres ⁇ ure of pump P18 minu ⁇ the pre ⁇ sure of pump P19 is now also u ⁇ ed to provide the po ⁇ itive definite flow of wa ⁇ h ⁇ olution.
  • the volumetric rates of pumps P15 and P16 match at all times so that there is never any difference in blood volume. Consequently, all exce ⁇ s flow, i.e., flow from pump P18 minus flow from pump P19 must leave the separator apparatus A5 via the waste wash path.
  • FIG. 20 illustrates such general method.
  • the first stage employs a pla ⁇ ma ⁇ eparator apparatu ⁇ A6 of the type shown in FIGS. 8 and 9 yields two outlet streams, one being highly concentrated RBC bearing de-oxyhemoglobin, that is, red cells poor in oxygen and ⁇ aturated with carbon dioxide, RBC-D, the other being mo ⁇ t (90% to 95%) of the pla ⁇ ma which i ⁇ returned to the patient.
  • the concentrated RBC-D (not pumped in order to minimize hemoly ⁇ i ⁇ ) , is led to a mixing chamber 400 through conduit 402 where it is thoroughly mixed with concentrated oxygen rich artificial blood particles, AB-0.
  • the resulting mixture contains RBC bearing oxyhemoglobin, RBC-0, and spent AB saturated with C0 2 or AB-D.
  • the mixing chamber output rate of flow i ⁇ determined by the rate of pump P20 (PR1) minus the rate of pump P21 (PR2) plus the rate of pump P25 (PR6) , which flow enters the cell washer A7 through conduit 403.
  • the difference of pump rates, PR1 minus PR2 is determined by the hematocrit of the patient blood (i.e., cell volume fraction, Hct.).
  • the rate of pump P25 (PR6) will neces ⁇ arily be related to that difference which correlates with the mass flow of hemoglobin, Hb., that is:
  • PR6 f (PR1 - PR2) where f is some factor depending upon the AB product used.
  • the wa ⁇ h ⁇ olution in this example should be the patients own plasma or donated plasma. This is both pos ⁇ ible and practical because very little wash solution is required per pas ⁇ to remove AB particle ⁇ from the concentrated RBC cell mass in accordance with the method of the present invention.
  • the RBC-0 is recombined with the plasma from the plasma separator to reconstitute the blood, i.e., plasma with, now, oxygen-rich, C0 2 - regulated, RBC.
  • the reconstituted whole blood must flow into sufficient positive pres ⁇ ure ⁇ o that neither pumps P21 nor P22 apply suction to the fluid ⁇ .
  • Thi ⁇ provision is important to prevent fluid outgassing or cavitation.
  • the suction side of pump P22 is the lowe ⁇ t pressure in the sy ⁇ tem, but it need not be below atmo ⁇ pheric if there is adequate re ⁇ i ⁇ tance in the patient return line 404. Having de ⁇ cribed the ⁇ y ⁇ te , it i ⁇ important to note that there are many varietie ⁇ of artificial blood generally con ⁇ i ⁇ ting of particles of extraordinary solubility relative to gases ⁇ uch as 02 and C0 2 . Many are very compatible with blood and organ ti ⁇ ue ⁇ .
  • a typical example is Perfluorooctyl Bromide, PFOB, sold by Nippon Mektron Ltd.
  • PFOB Perfluorooctyl Bromide
  • Nippon Mektron Ltd. The ability of the ⁇ e particles to rapidly transfer oxygen and remove C0 2 from the body ti ⁇ ue ⁇ and blood cell ⁇ , with no apparent toxicity, i ⁇ well e ⁇ tabli ⁇ hed. Consequently, direct mixing of PFOB with concentrated RBC-D converts the latter immediately to RBC-0. The problem has always been separating the spent PFOB from the blood before returning the latter to the patient. Wholesale injection of PFOB into the patient is not approved.
  • the oxygenator ⁇ ystem of the pre ⁇ ent invention a ⁇ de ⁇ cribed immediately hereinabove include ⁇ a pla ⁇ ma ⁇ eparating ⁇ tep ( ⁇ o as not to require separating PFOB particles from plasma) followed by a step which mixes RBC with AB, followed by a step which washe ⁇ AB and any other ⁇ troma out of the RBC and finally recombination of clean, oxygenated RBC with the plasma for return to the patient.
  • These steps run continuously and simultaneously in a closed extracorporeal circuit a ⁇ will be clear from FIG. 20.
  • porou ⁇ elements disposed in the inner shells I, I', and I" of FIGS, l through 9 their necessary properties may be summarized a ⁇ follows. They should have:
  • the porous flow distributors are es ⁇ entially tubular and can be comprised of multi-layers of concentric cylinders of various properties which, acting in combination, achieve the desired results. Once the outer surface i ⁇ "wetted", the interior remainder of the porou ⁇ structure need not obey this condition (i.e., hydrophobia) which is one way of significantly increasing flow resi ⁇ tance.
  • the outer diameter of the porou ⁇ cylinder have a high "open” to "solid" volume ratio or stated in other terms, a high concentration of pores per unit surface area.
  • This condition should exist for a depth of at lea ⁇ t several pore diameters in order to prevent local concentration of ⁇ upernatant flow velocity at a micro ⁇ copic level.
  • the high open to solid ratio need not be maintained. Consequently, inner layers of the continuously open porous structure can be comprised of lower open to solid ratios or lower concentration of pores. This further adds to flow resi ⁇ tance without affecting the requi ⁇ ite blood contact ⁇ urface properties of the porous flow distributor. Of course, simply adding layers, or pore structure thickness, further adds to flow resistance.
  • the fluid film, (e.g., blood) being separated must be thin enough that secondary flows which would disturb settling may not arise.
  • the only flows permitted are the bulk rotation of the fluid film trapped between two surface ⁇ rotating at the same angular velocity, the axial laminar streamline viscou ⁇ boundary layer flow within that film from top entrance to bottom exit, and the forced convective radial inward flow through one or more porous flow distributing surfaces.
  • the flow must occur in a region where vi ⁇ co ⁇ ity can up ⁇ et the geostrophic force balance to allow a fluid velocity.
  • visco ⁇ ity is important only near the walls of the rotating container and, as a result, the bulk of the flow occurs only in thin layers near the wall.
  • the layer where viscosity is important i ⁇ called the Ekman layer when the wall ⁇ urface normal vector is approximately parallel to the axi ⁇ of rotation, and the Stewartson layer when the wall surface normal vector is nearly perpendicular to the axis of rotation.
  • the Ekman number i ⁇ a ratio of the vi ⁇ cou ⁇ force to the Coriolis force in a rotating system. In sy ⁇ tem ⁇ rotating at high ⁇ peed, e k , is typically very small, suggesting that geostrophic flow dominates the character of the flow.
  • the blood film perpendicular to the rotation axis that is, blood flow along horizontal surfaces in a vertically oriented device
  • the operative separation chamber namely, the "thin" blood film flowing parallel to the vertically oriented rotation axis i ⁇ within the Stewartson boundary layer thickness provided the blood film is limited to those thicknes ⁇ es listed in Table II under t st .
  • the ⁇ e value ⁇ define maximum claimed blood film thickness, at least for the entering whole blood.
  • a blood film thickness of 0.060 inch at the whole blood entrance is adequate for the purpose of limiting axial pre ⁇ ure gradients, even for flow ⁇ on the order of 1 to 2 liter ⁇ /min.
  • in ⁇ tabilitie ⁇ which might give ri ⁇ e to inertial wave ⁇ could occur at the entrance to the proce ⁇ ing chamber but are quickly damped due to supporting vanes which separate walls defining entry to the blood film, and to the stabilizing influence of the initial impregnable zone which quickly e ⁇ tabli ⁇ hes the Stewartson viscou ⁇ boundary flow.
  • the first is ⁇ ue i ⁇ the particle Taylor number, T .
  • a ⁇ econd non-dimen ⁇ ional parameter related to the settling of a particle is the time ratio ⁇ .
  • the time ratio is the ratio of separation time for a particle to the spin-up time for that particle.
  • the spin-up time is the time for the particle to reach the sy ⁇ tem rotational speed after it enters the rotating sy ⁇ tem.
  • Table V lists the time ratios for these particles:
  • red blood corpuscle ⁇ or platelet ⁇ is a relatively fa ⁇ t proce ⁇ . In fact, it may happen so quickly that the cells are not up to the rotational speed of the device (for ⁇ ⁇ 1.0) . This would be a problem for red corpuscles at very high speed ⁇ . Potentially, red blood corpu ⁇ cle ⁇ could ⁇ ediment to the outer wall before they have reached approximately the ⁇ ame rotational ⁇ peed as the wall. This could tend to cause high shear on the red blood corpu ⁇ cles with the pos ⁇ ibility of hemoly ⁇ i ⁇ which mu ⁇ t be avoided.
  • conduit ⁇ and vanes at the blood entrance to the device serve not only to ⁇ pace and ⁇ upport the wall ⁇ defining the blood film but are indeed crucial in the de ⁇ ign to force, especially the red blood corpuscles to spin-up to match device rotational speeds.
  • Supporting vanes are both shaped and angled in such a manner as to accomplish the imparting of system rotational ⁇ peed to the red blood corpuscles with a minimum of trauma, i.e., ⁇ hearing of the red blood corpu ⁇ cles among the spin-up ⁇ urface ⁇ .
  • the time ratio for platelet ⁇ is about 10 times that for red blood corpuscles and, consequently, red blood corpu ⁇ cle ⁇ ⁇ ediment about 10 times fa ⁇ ter than platelet ⁇ as was ⁇ een in the ⁇ everal examples previously presented.
  • the appropriate blood film thickness has been computed and must be limited by vi ⁇ cou ⁇ boundary flow or the Stewart ⁇ on layer.
  • Inertial in ⁇ tabilities are small, particularly in connection with the forced convection which decants the supernatant, i.e., the Ros ⁇ by number i ⁇ very ⁇ mall.
  • the particle Taylor number indicates that, apart from concentration effects which influence only red blood corpuscles, the Stokes model for the drag on a particle i ⁇ valid.
  • the time ratio is ⁇ uch that the ⁇ ettling of particles can be relatively fast in compari ⁇ on with their ⁇ pin-up time so that entry vanes are essential to force particle spin-up and ⁇ hould be de ⁇ igned with a minimum of turbulence and ⁇ hearing of the particles.

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Abstract

Appareil et procédé de fractionnement d'un mélange liquide en un ensemble de fractions liquides dont les composants présentent des vitesses différentes. Un ensemble cylindrique rotatif (A) comporte des corps interne et externe (I, O) définissant entre eux un interstice tubulaire (G). Un corps comprend une structure poreuse (21) pouvant être traversée par une ou plusieurs fractions liquides et résistant à l'écoulement radial vers l'intérieur des autres fractions. L'ensemble cylindrique (A) tourne à une vitesse conférant une force centrifuge suffisante aux fractions liquides pour maintenir une de ces fractions dans l'interstice (G), tout en forçant l'écoulement radial de l'autre fraction liquide vers l'intérieur à travers la structure poreuse. L'invention comprend une structure poreuse (21) aussi bien dans le corps interne que dans le corps externe (I, O) afin de permettre la lévitation d'une fraction du mélange entre lesdites structures pendant qu'une solution de lavage contenant des composants réducteurs s'écoule radialement vers l'intérieur à travers les structures.
PCT/US1993/008523 1992-09-11 1993-09-09 Appareil et procede de fractionnement d'un melange liquide WO1994006535A1 (fr)

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US07/943,731 1992-09-11

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EP0784496A1 (fr) * 1995-08-09 1997-07-23 Baxter Travenol Laboratories, Inc. Systemes et procedes de separation des erythrocytes
EP1057534A1 (fr) * 1999-06-03 2000-12-06 Haemonetics Corporation Bol de centrifugation avec noyau filtrant
EP1281407A1 (fr) * 2001-07-30 2003-02-05 Jean-Denis Rochat Méthode pour la séparation continue du sang entier et appareil pour la mise en oeuvre de cette méthode
US6629919B2 (en) * 1999-06-03 2003-10-07 Haemonetics Corporation Core for blood processing apparatus
EP2049223A2 (fr) * 2006-07-31 2009-04-22 Hanuman LLC Appareil et procédé de préparation d'un plasma riche en plaquettes et concentrats de ce plasma
WO2010030406A1 (fr) * 2008-09-12 2010-03-18 Caridianbct, Inc. Appareil pour traiter le sang comprenant une chambre pour capturer les cellules pourvue d'un orifice d'admission protubérant
RU2447950C1 (ru) * 2010-08-30 2012-04-20 Государственное научное учреждение Всероссийский научно-исследовательский институт использования техники и нефтепродуктов Российской академии сельскохозяйственных наук (ГНУ ВНИИТиН Россельхозакадемии) Центрифуга для очистки масла
US8808978B2 (en) 2010-11-05 2014-08-19 Haemonetics Corporation System and method for automated platelet wash
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US8834402B2 (en) 2009-03-12 2014-09-16 Haemonetics Corporation System and method for the re-anticoagulation of platelet rich plasma
US9095665B2 (en) 2008-04-14 2015-08-04 Haemonetics Corporation Three-line apheresis system and method
US9302042B2 (en) 2010-12-30 2016-04-05 Haemonetics Corporation System and method for collecting platelets and anticipating plasma return
US9364600B2 (en) 2008-04-14 2016-06-14 Haemonetics Corporation System and method for optimized apheresis draw and return
CN107344145A (zh) * 2016-05-06 2017-11-14 七汁实业有限公司 离心过滤机及其操作方法
CN108837952A (zh) * 2018-07-07 2018-11-20 廖大萍 固液的旋液分离方法
US10562040B2 (en) 2015-07-03 2020-02-18 Seven Juice Co., Ltd. Centrifugal filtering device and method for operating the same
US10758652B2 (en) 2017-05-30 2020-09-01 Haemonetics Corporation System and method for collecting plasma
US10792416B2 (en) 2017-05-30 2020-10-06 Haemonetics Corporation System and method for collecting plasma
TWI710398B (zh) * 2017-03-31 2020-11-21 榮崑行生技股份有限公司 血液過濾裝置
TWI710397B (zh) * 2017-03-31 2020-11-21 榮崑行生技股份有限公司 血液過濾裝置
US10946131B2 (en) 2018-05-21 2021-03-16 Fenwal, Inc. Systems and methods for optimization of plasma collection volumes
US11065376B2 (en) 2018-03-26 2021-07-20 Haemonetics Corporation Plasmapheresis centrifuge bowl
US11412967B2 (en) 2018-05-21 2022-08-16 Fenwal, Inc. Systems and methods for plasma collection
US11837357B2 (en) 2011-05-18 2023-12-05 Fenwal, Inc. Plasma collection with remote programming
US12033750B2 (en) 2023-08-08 2024-07-09 Fenwal, Inc. Plasma collection

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US4871462A (en) * 1985-12-23 1989-10-03 Haemonetics Corporation Enhanced separation of blood components
US5034135A (en) * 1982-12-13 1991-07-23 William F. McLaughlin Blood fractionation system and method

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US4871462A (en) * 1985-12-23 1989-10-03 Haemonetics Corporation Enhanced separation of blood components

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EP0784496A1 (fr) * 1995-08-09 1997-07-23 Baxter Travenol Laboratories, Inc. Systemes et procedes de separation des erythrocytes
EP0784496A4 (fr) * 1995-08-09 2000-07-26 Baxter Travenol Lab Systemes et procedes de separation des erythrocytes
EP1057534A1 (fr) * 1999-06-03 2000-12-06 Haemonetics Corporation Bol de centrifugation avec noyau filtrant
US6464624B2 (en) * 1999-06-03 2002-10-15 Haemonetics Corporation Blood processing method and apparatus using a centrifugation bowl with filter core
US6629919B2 (en) * 1999-06-03 2003-10-07 Haemonetics Corporation Core for blood processing apparatus
EP1281407A1 (fr) * 2001-07-30 2003-02-05 Jean-Denis Rochat Méthode pour la séparation continue du sang entier et appareil pour la mise en oeuvre de cette méthode
WO2003011368A1 (fr) * 2001-07-30 2003-02-13 Jean-Denis Rochat Procede de separation continue du sang total et dispositif de mise en oeuvre de ce procede
EP2049223A4 (fr) * 2006-07-31 2012-10-03 Hanuman Llc Appareil et procédé de préparation d'un plasma riche en plaquettes et concentrats de ce plasma
EP2049223A2 (fr) * 2006-07-31 2009-04-22 Hanuman LLC Appareil et procédé de préparation d'un plasma riche en plaquettes et concentrats de ce plasma
US9364600B2 (en) 2008-04-14 2016-06-14 Haemonetics Corporation System and method for optimized apheresis draw and return
US8808217B2 (en) 2008-04-14 2014-08-19 Haemonetics Corporation System and method for plasma reduced platelet collection
US9095665B2 (en) 2008-04-14 2015-08-04 Haemonetics Corporation Three-line apheresis system and method
WO2010030406A1 (fr) * 2008-09-12 2010-03-18 Caridianbct, Inc. Appareil pour traiter le sang comprenant une chambre pour capturer les cellules pourvue d'un orifice d'admission protubérant
US7963901B2 (en) 2008-09-12 2011-06-21 Caridianbct, Inc. Blood processing apparatus with cell capture chamber with protruding inlet
US8226537B2 (en) 2008-09-12 2012-07-24 Terumo Bct, Inc. Blood processing apparatus with cell separation chamber with baffles
US8834402B2 (en) 2009-03-12 2014-09-16 Haemonetics Corporation System and method for the re-anticoagulation of platelet rich plasma
US9248227B2 (en) 2009-03-12 2016-02-02 Haemonetics Corporation System and method for the re-anticoagulation of platelet rich plasma
US9789243B2 (en) 2009-03-12 2017-10-17 Haemonetics Corporation System and method for the re-anticoagulation of platelet rich plasma
RU2447950C1 (ru) * 2010-08-30 2012-04-20 Государственное научное учреждение Всероссийский научно-исследовательский институт использования техники и нефтепродуктов Российской академии сельскохозяйственных наук (ГНУ ВНИИТиН Россельхозакадемии) Центрифуга для очистки масла
US9833794B2 (en) 2010-11-05 2017-12-05 Haemonetics Corporation System and method for automated platelet wash
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US10806847B2 (en) 2010-12-30 2020-10-20 Haemonetics Corporation System and method for collecting platelets and anticipating plasma return
US9302042B2 (en) 2010-12-30 2016-04-05 Haemonetics Corporation System and method for collecting platelets and anticipating plasma return
US11837357B2 (en) 2011-05-18 2023-12-05 Fenwal, Inc. Plasma collection with remote programming
US10562040B2 (en) 2015-07-03 2020-02-18 Seven Juice Co., Ltd. Centrifugal filtering device and method for operating the same
CN107344145B (zh) * 2016-05-06 2019-06-14 七汁实业有限公司 离心过滤机及其操作方法
CN107344145A (zh) * 2016-05-06 2017-11-14 七汁实业有限公司 离心过滤机及其操作方法
TWI710398B (zh) * 2017-03-31 2020-11-21 榮崑行生技股份有限公司 血液過濾裝置
TWI710397B (zh) * 2017-03-31 2020-11-21 榮崑行生技股份有限公司 血液過濾裝置
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US10946131B2 (en) 2018-05-21 2021-03-16 Fenwal, Inc. Systems and methods for optimization of plasma collection volumes
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CN108837952B (zh) * 2018-07-07 2019-12-03 廖大萍 固液的旋液分离方法
CN108837952A (zh) * 2018-07-07 2018-11-20 廖大萍 固液的旋液分离方法
US12033750B2 (en) 2023-08-08 2024-07-09 Fenwal, Inc. Plasma collection

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