WO1985002554A1

WO1985002554A1 - Controlling transmembrane pressure in membrane plasma filtration

Info

Publication number: WO1985002554A1
Application number: PCT/US1984/001800
Authority: WO
Inventors: Arnold C. Bilstad; Richard I. Brown
Original assignee: Baxter Travenol Laboratories, Inc.
Priority date: 1983-12-09
Filing date: 1984-11-05
Publication date: 1985-06-20
Also published as: IT1178737B; IT8423952A0; JPS61500590A; EP0168407A4; EP0168407A1

Abstract

Method and apparatus for controlling the pressure differential across the filter membrane (14) in membrane plasma filtration apparatus (12). Control means (26) in fluid communication with a plasma-containing fluid flow path (30) up-stream of the filter membrane (14) and cooperatively associated with the plasma filtrate flow path (32), is operable to vary the size of the plasma filtrate flow path (32) inversely with respect to changes in the pressure in the plasma-containing fluid, thereby maintaining the differential pressure substantially constant. The control means includes a movable surface (34) disposed for contact with fluid in the fluid flow path (30) upstream of the membrane (14), the surface (34) being movable upon pressure changes in the blood flow path (30) to vary the size of the plasma filtrate flow path (32). The movable surface (34) is biased to a normally open plasma filtrate flow path condition by a force of selected amount corresponding to the desired pressure differential.

Description

-1- COWΓROLLING TRANSMEMBRANE PRESSURE IN MEMBRANE PLASMA FILTRATION.

The present invention relates, in general, 5 to plasma filtration of the type in which a filter membrane is employed for the separation of plasma or plasma proteins from a plasma-containing fluid. More particularly, the present invention relates to method and apparatus for controlling the differential pres-

10 sure across the filter membrane to optimize the sepa¬ ration characteristics of the membrane.

One form of membrane plasma filtration is the separation of plasma from the cellular components of whole blood for collection or replacement. This

15 process is commonly called membrane plasmapheresis. Another form of membrane plasma filtration is the separation of one or more plasma proteins from the remaining plasma constituents for therapeutic or other purposes. In both types of plasma filtration,

20 it is desirable to optimize the separation character¬ istics of the filter membrane by controlling the dif¬ ferential pressure across the membrane, commonly known as the transme brane pressure.

In membrane plasmapheresis, for example,

25 plasma is separated from the whole blood by passing the blood along the surface of a filter membrane which has a very small pore size that permits passage of plasma, while retaining the cellular components, i.e., red cells, white cells and platelets. In a

30 continuous plasmapheresis system, the cellular compo¬ nents are returned to the donor, and the plasma fil¬ trate is collected.

■ . —OMPI H $&_. WZϊPO₀* The amount of plasma separated from the cellular components of whole blood is related in sub¬ stantial part to the driving force or differential pressure between the whole blood side of the membrane and the plasma side of the membrane, i.e., the trans- membrane pressure. The transmembrane pressure actu¬ ally preferred for plasmapheresis, however, is sub¬ ject to differing views. It has generally been be¬ lieved that higher transmembrane pressures will re- suit in a greater amount of plasma being collected from a given quantity of whole blood. See, e.g., U.S. Patents Nos. 4,191,182 to Popovich et al. and 3,705,100 to Blatt et al. In accordance with this understanding, it is desirable to operate, at as high a transmembrane pressure as possible without causing hemolysis (destruction of red blood cells) .

Others, however, have concluded that a sub¬ stantially lower transmembrane pressure will result in more efficient plasma collection. See, e.g., U.S. Patent No. 4,381,775 to Nose et al. Under this view, it may be desirable to maintain maximum blood flow rates at relatively low transmembrane pres¬ sures. Under either view, however, it is desirable to control the transmembrane pressure so as to limit it from exceeding an optimal or preferred maximum.

Numerous factors can affect the transmem¬ brane pressure. Obviously, and most importantly, the speed of the blood pump which causes the blood to flow across the membrane will directly affect the blood pressure, and thus the transmembrane pressure. The pressure on the plasma side of the membrane also will obviously affect the transmembrane pressure. In routine plasmapheresis processes, the plasma is typi¬ cally maintained at atmospheric pressure. Raising or lowering the plasma collection container relative to the filter membrane will, however, cause the plasma pressure, and thus the transmembrane pressure, to vary.

More subtly, but still significantly, blood pressure and transmembrane pressure are affected by other factors associated with the blood flow stream. For example, the size of the needle returning the cellular components (commonly referred to as plasma- poor blood) to the patient can affect transmembrane pressure. A smaller bore needle will increase the pressure on the blood side of the membrane thereby raising the transmembrane pressure. 'Similarly, the use of auxiliary equipment in the plasma poor blood return line, such as blood warmers, may also increase the transmembrane pressure. Yet a further factor is donor movement. For example, raising or lowering the arm of the donor will cause the transmembrane pres¬ sure to vary. Also, intentional or unintentional occlusions of the blood flow line, both upstream and downstream of the membrane (e.g., patient resting on supply or return tubing), can affect the blood pres¬ sure and thus cause the transmembrane pressure to vary.

It should be appreciated that the transmem¬ brane pressure is not the same at different locations along the filter membrane. Because the pressure of plasma separated from the whole blood is typically static, variations in the transmembrane pressure are essentially a function of variations in the pressure of the whole blood. As in any other flowing stream, a natural pressure drop occurs in the whole blood stream as it flows over the membrane. The transmem¬ brane pressure is thus greatest at the upstream or inlet end of the membrane, hereinafter referred to as the maximum transmembrane pressure, and continuously decreases as blood flows along the membrane. One device and method for isolating the transmembrane pressure from the effects of downstream occlusions or pressure variations is described in the U.S. Patent No. 4,412,553 to Kopp et al. The method and apparatμs disclosed there meter the flow of plas- a filtrate in response to pressure differentials be¬ tween the plasma-poor blood return line and the plas¬ ma filtrate to establish and thereafter maintain sub¬ stantial equilibrium between the two pressures. Thus, variations in the downstream pressure of the plasma-poor blood line result in a further metering of the flow of plasma from the plasmapheresis appara¬ tus. If the back pressure increases, for example, by the patient resting on the return tubing, the flow of plasma from the filter membrane is reduced according- ly, thereby increasing the pressure on the plasma side of the membrane to prevent an accompanying in¬ crease in transmembrane pressure.

Such apparatus, however, functions essen¬ tially to isolate the membrane from downstream blood flow disturbances, and will not control the transmem¬ brane pressure in the event of upstream fluctuations, -5-

for example, variations in the pump flow rate, acci¬ dental or partial occlusion of the upstream whole blood flow line. Thus, the method and apparatus dis¬ closed in the Kopp et al. patent will not totally control the maximum transmembrane pressure, either .for the purpose of preventing hemolysis or for the purpose of providing a more limited and more effici¬ ent transmembrane pressure. Accordingly, while the aforedescribed method and apparatus of U.S. Patent No. 4,412,553 to Kopp et al. functions in a highly satisfactory manner, efforts continue to be exerted for apparatus which will more completely control the maximum transmembrane pressure.

Other apparatus and/or methods for control¬ ling transmembrane pressure in plasmapheresis appara¬ tus are described in U.S. Patent No. 4,191,182 and German Offenlegungsschrift 30 43 682. The systems described in these references, however, do not fully achieve the above-identified objectives and, more¬ over, are relatively complicated, requiring addition¬ al apparatus and/or electrical systems and devices which are not conducive to an environment where the technical skills of the operator may be limited, or where a high degree of reliability is important. Moreover, these system do not lend themselves to dis- posability or high speed manufacturing practices re¬ quired for low product cost.

Accordingly, it is a general object of the present invention to provide method and apparatus which does not suffer from the above-described short¬ comings. More particularly, it is a principal object of the present invention to provide method and appa¬ ratus for controlling the optimal maximum transmem¬ brane pressure in membrane plasma filtration appara- tus under substantially all flow conditions and inlet pressures.

It is a further object of the present in¬ vention to provide method and apparatus for control¬ ling the maximum transmembrane pressure in plasma- pheresis apparatus at a relatively high level with¬ out causing hemolysis.

It is a further object of the present in¬ vention to provide method and apparatus for control¬ ling the maximum transmembrane pressure in plasma- pheresis apparatus at.a relatively low level without sacrificing high blood flow rates.

These objects are fully met by the present invention, which is embodied in or employed in con¬ nection with membrane plasma filtration apparatus of the type having a filter membrane, one side of which forms a portion of a flow path between a plasma-con¬ taining fluid inlet and a fluid outlet, and having a plasma filtrate outlet communicating with the other side of the membrane. In plasmapheresis applica- tions, the plasma-containing fluid is whole blood and the plasma filtrate is plasma. In other plasma fil¬ tration applications, the plasma-containing fluid may be plasma itself, and the plasma filtrate may be one or more plasma proteins. In accordance with the present invention, the maximum transmembrane pressure which may occur is limited to a selected value by control means which is in fluid communication with the plasma-containing fluid flow path at a location upstream of the mem¬ brane, and which is cooperatively associated with the plasma filtrate flow path. The control means is dis¬ posed or biased by a force of selected amount (cor¬ responding to a fluid pressure which will result in the desired maximum transmembrane pressure) to main¬ tain the filtrate flow path in a normally open condi¬ tion, and is operable when plasma-containing fluid pressure exceeds the desired value to vary the size of the filtrate flow path inversely with respect to the pressure changes in the fluid flow path, so that the maximum differential pressure across the membrane is maintained substantially at the selected value re¬ gardless of upstream or downstream changes or fluctu¬ ations in the pressure of the fluid flow path.

In the preferred embodiment of the present invention, the control means includes a movable sur¬ face in fluid contact with the fluid flow path and operable to vary the size of the plasma filtrate flow path movement in response to pressure changes in the plasma-containing fluid flow path. A force exerted on the surface biases the surface to a normally open filtrate flow path position. As pressure in the plasma-containing fluid flow path upstream of the membrane increases, and the force exerted by the fluid on the surface exceeds the biasing force, the control means reduces the size of the filtrate flow path, resulting in an increase in filtrate pressure, which keeps the maximum transmembrane pressure con-

O PI stant. If the force exerted by the plasma-containing fluid decreases to a level below the biasing force, the size of the filtrate flow path increases, result¬ ing in a drop in the filtrate pressure to offset the drop in fluid flow pressure.

For plasmapheresis applications, the bias¬ ing force may be selected to correspond to a fluid pressure which will provide a maximum transmembrane pressure at or slightly below that at which he olysis begins, or to provide a substantially lower maximum transmembrane pressure at which it is believed that more efficient plasma collection occurs. In either situation, the preferred embodiment of the present invention operates to restrict plasma flow only when the upstream blood flow pressure exceeds a desired level represented by the biasing force. So long as the upstream fluid pressure (and thus the transmem¬ brane pressure) is less than the selected maximum level, the preferred embodiment of the present inven- tion is quiescent and does not affect the plasma fil¬ tration operation. In other words, the preferred em¬ bodiment of the present invention operates to limit the maximum transmembrane pressure which may occur in the plasma filtration process, and does not preclude operating at a transmembrane pressure lower than the desired maximum.

A further alternative embodiment of the present invention includes means for selecting the amount of force biasing the movable surface, thus providing the user with a capability for selecting and changing the desired maximum transmembrane pres¬ sure. These and other aspects of the present in¬ vention are depicted in the attached drawings, which show preferred and alternative embodiments of the present invention in a plasmapheresis application for purposes of ^' illustration and not limitation, and of which:

Figure 1 is a schematic representation of plasmapheresis apparatus and the flow system associ¬ ated with a continuous donor procedure, embodying the present invention to control the maximum transmem¬ brane pressure.

Figure 2 is a schematic representation of a ^"portion of the system shown in Figure 1, depicting an alternative embodiment of the apparatus for control- ling the maximum transmembrane pressure.

Figure 3 is a top view of the apparatus of Figure 5.

Figure 4 is a bottom view of the apparatus of Figure 5. Figure 5 is a sectional view taken along line 5-5 of Figure 3, depicting apparatus embodying the present invention for use in controlling the max¬ imum transmembrane pressure in plasma filtration pro¬ cesses. Figure 6 is a sectional view of alternative apparatus embodying the present invention for controlling the maximum transmembrane pressure in plasma filtration processes.

Figure 7 is a partial top view of apparatus of Figure 8.

Figure 8 is a sectional view of apparatus embodying the present invention for use in control¬ ling maximum transmembrane pressure in plasmapheresis apparatus, and including means for selecting such transmembrane pressure. Figure 9 is a sectional view of apparatus embodying the present invention for controlling maxi¬ mum transmembrane pressure in plasmapheresis appara¬ tus including means for preventing plasma flow when upstream whole blood pressure is below a selected amount.

Figure 10 is a cross-sectional view of yet another alternative embodiment of the present inven¬ tion for controlling maximum transmembrane pressure in plasma filtration processes. ^* While illustrated in connection with mem¬ brane plasmapheresis, it should be appreciated that the present invention, as defined in the appended claims, is also useful in other plasma filtration ap¬ plications where it is desirable to limit the maximum transmembrane pressure.

As set forth in more detail below, the pre¬ sent invention may be generally embodied or employed in connection with plasmapheresis apparatus 12 of the type having at least one filter membrane 14 of suit- able pore size for separating plasma from whole blood as the whole blood flows along the surface thereof. As shown schematically in Figure 1, which depicts a continuous plasmapheresis apparatus and system, whole blood from a patient/donor is introduced into an in- let 16 of a filter module or housing 18 containing the filter membrane. In the illustrated embodiment.

-li¬

the membrane 14 is in the form of a hollow fiber through which the blood flows, and a bundle of such fibers extend between the inlet 16 and a housing outlet 20, from which the plasma-poor blood exits. The membranes, of course, could be of other suitable shape or configuration without departing from this invention. Plasma removed from the whole blood is collected from a plasma outlet 22 and stored in a suitable container 24. As noted earlier, the amount of plasma col¬ lected or harvested from the whole blood depends in significant part upon the pressure differential be¬ tween the blood side of the filter membrane and the plasma, side of the filter membrane, i.e., the trans- membrane pressure, although there are different views as to which transmembrane pressure is most desirable. In accordance with the present invention, the transmembrane pressure, and in particular, the maximum transmembrane pressure, is limited to a se- lected vaiue by control means, generally at 26. The control means 26 is in fluid communication, via con¬ duit 28, with whole blood flow path 30 upstream of the membrane 14, and is cooperatively associated with the plasma flow path 32 which extends between the plasma outlet 22 and the container 24. The control means 26 is operable to vary the size of the plasma flow path inversely with respect to changes in the whole blood pressure in flow path 30, and is biased toward a normally open flow path position by a force of selected amount representative of the desired blood flow pressure or transmembrane pressure. Preferably, the control means 26 for vary¬ ing the size of the plasma flow path, includes means defining a movable surface 34 exposed to contact with the blood flow stream. In Figures 1 and 2, this is conceptually illustrated as the surface of a movable piston 36. In the preferred embodiments depicted in Figures 3-8, the blood and plasma flow path are sepa¬ rated by a membrane 38 which coacts with a spring- biased plunger 40 that varies the size of an orifice through which plasma flows. Biasing means in the form of a compressed spring 42 exerts a biasing force against the plunger 40, which force may be fixed as depicted in the embodiment shown in Figures 5 and 6, or adjustable, as depicted in Figures 7 and 8, to permit operator selection of the maximum transmem- brane pressure by the simple rotation of a dial which varies the compression of the spring. In accordance with yet a further embodiment of the present inven¬ tion, as depicted in Figure 9, backflow prevention means, such as the sealing sleeve 44 carried on the plunger 40, is provided to close the plasma flow path completely, in the event that the plasma pressure ex¬ ceeds the blood inlet pressure. Depending on the nature of biasing force selected, the sealing sleeve may also operate to block the plasma flow path in the event that the whole blood inlet pressure falls below the selected value corresponding to the maximum transmembrane pressure. In that mode, this embodi¬ ment, unlike the other embodiments, would require that the plasmapheresis be conducted at the maximum selected transmembrane pressure. p And in accordance with yet a further em¬ bodiment of the present invention, the biasing force, as shown in Figure 10, need not be an inwardly direc¬ ted force as shown in Figures 1-9, but may be an out- wardly directed.

Turning now to a more detailed description of the attached drawings, which depict the present invention in its preferred and alternative embodi¬ ments. Figure 1 shows a plasmapheresis apparatus and system embodying the present invention for use in continuously collecting or harvesting plasma from the whole blood of a patient or donor. Blood is taken from the patient/donor through a phlebotomy needle or the like, and collected temporarily in a reservoir or chamber (not shown) which communicates with pump 46. The pump is typically a peristaltic type pump which operates by massaging the walls of the flexible plas¬ tic tubing through which the blood flows, either by rollers or a series of contacting fingers. In any event, peristalic pumps are well known in the medical field and the present invention is not directed or limited to the use any particular type of pump in the plasmapheresis system.

From the pump, the whole blood flows along conduit 30, which is typically a plastic tube, and into the inlet 16 of the filter module or housing 18. The particular filter module shown is generally representative of a plasmapheresis filter commercial¬ ly available from the Fenwal Laboratories Division of Travenol Laboratories, Inc. as the Model CPS-10, al¬ though other plasmapheresis filter modules could readily be used with the present invention.

In the depicted filter module 18, the fil¬ ter membranes 14 are in the form of hollow polypropy¬ lene fibers through which the blood flows. The bore of such fibers is typically about 300 microns in dia¬ meter, and the walls of the fibers have an average pore size of about 0.3 microns, which permits the passage of plasma through the walls while retaining the cellular components of the blood within the bore of the hollow fiber. To achieve high flow rates and satisfactory plasma collection capacity, a bundle of many hollow fibers is positioned within the housing 18, extending between the inlet 16 and the plasma- poor blood outlet 20. Each end of the bundle of hollow fiber mem¬ branes 14 is encapsulated in a liquid-tight polyure- thane potting seal 48. The end seals 48 are spaced slightly from the respective inlet and outlet ends of the module or housing 18 to provide manifold spaces 50 which permit blood to flow into and from all of the fibers in the bundle. As the blood flows through the fibers, plasma filters through the porous walls of the membranes, and collects in chamber 52 within the module between the potted seals 48. Plasma-poor blood exiting from the hollow fibers is removed through the plasma-poor blood outlet 20 of the module. Plasma collected in the chamber 52 between the potted seals 48 may be drained or removed through the plasma outlet 22. After the whole blood passes through the hollow fibers, and plasma is removed through the membrane walls, the plasma-poor blood is returned to the pati¬ ent/donor through conduit 54 and a needle (not shown). Typically there may be auxilary equipment, such as blood warmers or the like associated with the 5 plasma-poor blood flow line and there will, of course, be a bubble trap through which the plasma- poor blood must flow before return to the patient.

Although the present invention is described in terms of a hollow fiber plasmapheresis module, 10 other membrane configurations, e.g. planar, may be used without departing from the present invention.

For purposes of this description, the pres¬ sure of the whole blood at the upstream end or inlet of the filter membrane is generally designated as BPi 15 and the pressure of the the plasma-poor blood at the downstream or outlet end of the membrane is desig¬ nated as BPg. The plasma collected between the pot¬ ted seals 48 has a sufficiently low flow rate that it is essentially static, and thus substantially the 20 same pressure is present throughout the collection chamber 52 and plasma flow path 32. This plasma pressure is referred to, for convenience, as PP.

As the blood flows through the hollow fibers, there is a substantial pressure drop (BP**_- 25. BPg), due to normal frictional forces retarding flow between the inlet and outlet of the membranes. Ac¬ cordingly, the transmembrane pressure (BP-PP) varies along the length of the membrane, being highest at the upstream end of the filter membrane (BPi-PP) and 30 lowest at the downstream end (BPn-PP) . Thus, to maintain the maximum transmembrane pressure below a selected level requires maintaining the transmembrane pressure at the inlet end of the membrane below that level. For example, hemolysis typically begins to occur when the transmembrane pressure exceeds about 120 mmHg, although the precise point at which hemoly¬ sis occurs may vary with different filter modules and different blood flow rates. Thus, if it desired that the filter be operated at as high a transmembrane pressure as possible without hemolysis, the transmem- brane pressure at the upstream end of the membrane (BPi-PP) should not exceed 120 mmHg.

In accordance with the present invention, as discussed briefly earlier, the maximum transmem¬ brane pressure is controlled at a selected level, which may be the* highest possible pressure without hemolysis or- an optimal pressure for more efficient plasma collection, by providing control means 26 which is in fluid communication with the whole blood flow path 30 upstream of the filter membrane, and is cooperatively associated with the plasma flow path 32. The operation of the control means 26 is figura¬ tively illustrated in Figures 1 and 2. As shown in Figure 1, the piston 36 is slidably mounted in the chamber of a housing 56, and divides that chamber in- to two subchambers 58 and 60, respectively below and above the piston.

Chamber 58 receives whole blood through conduit 28 which communicates with the whole blood flow path 30 at a location upstream of the filter membrane. Plasma from outlet 22 flows through the other chamber 60 of housing 56, and through an aper- ture 62 defined in top wall 64 of the chamber. From the housing, the plasma flow line connects with an appropriate collection container 24. To control the flow of plasma, the piston 36 mounts a tapered stem 66 which extends upwardly through the outlet aperture 62, with the space between the stem and the edge of the aperture defining the opening through which plas¬ ma must pass. Movement of the piston upwardly re¬ duces the size of the opening, and movement downward- ly increases the size of the opening.

Biasing means, generally designated 41, such as the compressed spring 42 or other suitable force generating means is provided for exerting a biasing force of selected amount downwardly on the plunger to maintain the plasma flow path between the stem and the edge of the aperture in a normally open position. The biasing force is preferably pre-selec- ted to provide the desired maximum transmembrane pressure. Thus, so long as the blood inlet pressure BPi is below an amount BPi_max which will provide the maximum transmembrane pressure, the piston remains in a downward position and the plasma flow path open.

But, when the whole blood flow pressure BP-j_ increases above BPi_max, the force exerted on the piston 36 is greater than the biasing force, the piston is forced upwardly, constricting the plasma flow path through the housing 56 and causing a resultant increase in the plasma pressure PP which maintains the maximum transmembrane pressure substantially constant. A subsequent decrease in the whole blood pressure in conduit 30 permits the biasing force to move the piston 36 downwardly, opening the plasma flow path, thereby reducing the plasma pressure and maintaining the transmembrane pressure at or below the desired maximum. The biasing force is thus predetermined so as to correspond to the net force exerted on piston 36 by the blood inlet pressure (BPi) when it reaches the level BPi_max at which the desired maximum transmembrane pressure exists. For the piston 36 depicted in Figure 1, which has the plasma pressure (PP) acting on the top surface and the inlet blood pressure (BP^) acting on the bottom surface, the net force pushing the piston upwardly is simply the quantity (BP^-PP), which is also the transmembrane pressure, multiplied by the surface .area, of the piston. Thus, for example, to maintain a transmembrane pressure of about 120 mmHg., the biasing force needed may be calculated by multiplying 120 mmHg. by the surface area of the piston 36. It should be noted from this calculation, that for the piston operated control means 26, the pre-selected biasing force remains unchanged regardless of the amount of the plasma pressure (PP) . Thus, the present invention operates to limit the maximum transmembrane pressure to that selected regardless of the height of the plasma collection container 24 relative to the filter membrane, thereby eliminating operator error or variance in the positioning of the collection container as a factor affecting the maximum transmembrane pressure which may occur. -19-

As noted earlier the whole blood pressure may vary for different reasons. Variation in the up¬ stream pump speed will result in different whole blood pressures. Also, upstream or downstream con- strictions to the flow of plasma-poor blood flow path, for example, blood warmers, needles or other auxilary equipment, may also cause a change in the blood flow pressure. Regardless of the reasons for the change in blood flow pressure, and regardless of whether the result of upstream or downstream con¬ striction, the control means 26 of the present inven¬ tion operates to limit the maximum transmembrane pressure to the selected value represented by the biasing force. For this reason, the . present invention finds particular application in connection with plas¬ mapheresis processes which are preferably operated at an optimum transmembrane pressure substantially less than the transmembrane pressure at which hemolysis occurs. As noted in the introduction, it is desir¬ able in connection with such a process to maximize the blood flow rate along the membrane. However, as blood flow rate increases so does the blood inlet pressure BP-, which is likely exceed BPi_max before the highest possible blood flow rates are attained. Therefore, without the present invention, flow rates would have to be maintained at less than the prefer¬ red highest rate so that the optimal transmembrane pressure (BPi_max-PP) is not exceeded. In accordance with the present invention, the blood pump speed may be increased to provide as large a blood flow as practical through the module, while apparatus of the present invention limits the maximum transmembrane pressure to that pre-selected value at which most ef¬ ficient plasma collection is believed to occur, even though the blood inlet pressure exceedsBPi_max.

The means 26 for controlling transmembrane pressure in Figure 1 is remote from the whole blood flow path 30, requiring the conduit 28 to communicate between the whole blood line and the subchamber 58 of housing 56. Figure 2 is an alternative schematic presentation of the present invention, in which the blood flows directly through the subchamber 58 up¬ stream of the filter membrane. This embodiment re¬ duces the potential for stagnant blood which is pos- sible in the remote embodiment depicted in Figure 1. Otherwise, the operation of the control means 26 depicted in Figure 2 is the same as that shown in Figure 1, employing the piston 36 which is movable in the same manner as described earlier to constrict or open the plasma flow path between plasma outlet 22 and the plasma collection container 24.

Figures 3-5 depict a preferred embodiment of the means 26 of the present invention for control¬ ling the transmembrane pressure in membrane plasma- pheresis apparatus. In the embodiment depicted in Figure 5, the housing 56 is made of two-piece rigid plastic construction, with a bottom portion 68 and a top portion 70 which are preferably joined by solvent or sonic bonding or the like. As shown in Figures 3 and 4, the housing is generally circular in plan view, although other shapes suitable for high speed plastic molding operations may also be used. The top and bottom portions are appropriately shaped to de¬ fine, when joined, a hollow interior chamber, which is divided into two separate subchambers 72 and 74 by the flexible diaphragm 38. The subchamber 72, lo¬ cated below the diaphragm, is intended for remote communication with the blood flow path 30 upstream of the filter membrane in the same manner described -lier in connection with Figure 1. As shown in ires 4 and 5 a channel 76 is formed diametrically "he bottom portion 68, and has an end aperture 78 communication with the conduit 28 extending between the blood flow path 30 and the housing 56.

The top portion 70 of the housing is gener- ally circular for mating connection with the bottom portion 68. The top portion has a generally flat upper wall 80, with an upstanding plasma inlet port

82 and an upstanding hollow center portion 84 for r^eceiving the upper end of plunger 40. A radially • acted plasma outlet 86 communicates through the

-_^* wall of the upstanding center portion 84 at aperture 88.

The diaphragm 38 which divides the housing chamber into subchambers is preferably of flexible, resilient, medically inert material, such as silicone rubber or other suitable material. The diaphragm is generally circular, and includes a thickened rim por¬ tion 90 which is captured in an annular slot 92 in the underside of the edge of the top portion. When the top and bottom portions of the housing are assembled, the thickened rim is locked in a liquid-

O PI tight seal between the annular slot and an upwardly facing shoulder 94 on the bottom portion.

For controlling the flow of plasma in re¬ sponse to pressure in the blood flow line, the plunger 40 is mounted for reciprocal movement in the subchamber 74 of the housing. The plunger 40 is pre¬ ferably of rigid plastic construction, including a broad flat circular base portion 96, which is sub¬ stantially the diameter of the subchamber 74 and rests atop the diaphragm 38, and including an up¬ standing stem 98 which extends into the hollow of the center portion 84 of the housing. The upstanding stem 98 has a curved sidewall 100, and an upper reduced diameter portion 102. The flow of plasma through the housing is controlled by reciprocal move¬ ment of the plunger 40, which varies the space be¬ tween the curved side wall 100 of the stem and the facing inside corner surface 104 of the top portion of the housing. For example, in the lower plunger position shown in solid lines in Figure 5, the stem sidewall 100 is spaced from the corner 104 and thus open to plasma flow from the inlet 82 to plasma out¬ let aperture 86. In the upward plunger position shown in dashed lines, the sidewall 100 of the stem 98 and the corner surface 104 of the housing are in contact, completely blocking the flow of plasma through the housing. There are, of course, an infinite range of positions between the illustrated open and closed positions. Various biasing means 41 may be employed to bias the plunger 40 in a normally opened position.

"BJRE4 OMPI In the illustrated embodiment, the biasing means is a compressed spring 42 which exerts a downward force on the plunger. The spring 42 extends between a raised locating boss 106 on the top wall of the center por- tion of the housing and a shoulder 108 on the stem 98 formed by the reduced diameter portion 102. The coil spring is selected to exert the desired downward force on the plunger, to maintain the plasma flow path open when the inlet blood pressure BPi is below the amount BPi_max required for the desired transmem¬ brane pressure. The following examples illustrate biasing force selection for a desired maximum trans¬ membrane pressure. For a system where the plasma is maintained at atmospheric pressure (i.e. PP of 14.7 psi or 760 mmHg.) and where the desired maximum transmembrane pressure (BPj_-PP) is 120 mmHg., the maximum blood pressure BPi_max which will provide the maximum transmembrane pressure is 880 mmHg. The up¬ ward force exerted by this pressure on the plunger 40 is essentially the product of the pressure multipli¬ ed by the area of surface 34 of the piston or plunger •■^BPimax ^x plunger area). Assuming that the surface area 34 is ten (10) square centimeters, the force exerted by the blood flow pressure is calculated as 8800 mmHg cm². The plasma pressure PP of 760 mmHg. is exerted downwardly over essentially the entire upper surface of the plunger, with a resultant down¬ ward plasma force of 7600 mmHg. cm² (760 mmHg. X 10 cm²). The net upward force exerted on the plunger is thus 1200 mmHg. cm² (8800-7600), which, as described earlier, is simply the desired maximum transmembrane pressure multiplied by the surface area of the pis¬ ton.

It is well known that the force exerted by a coil spring 42 is the spring constant (K) multipli- ed by the distance of compression. Accordingly, in the present invention, a spring 42 would be selected having the desired constant K so that when mounted in compression in the housing, it would exert a force equal to 1200 mmHg cm² on the plunger in the open plasma flow path position. In operation, when inlet blood flow pressure BPi is less than 880 mmHg., the spring will keep the plasma flow path open and the transmembrane pressure will always be less than 120 mmHg. When the blood pressure BPi exceeds 880 mmHg., the force it exerts on the- plunger 40 will overcome the spring force and move the plunger upwardly to restrict the plasma flow path and thus increase the plasma pressure PP, thereby maintaining the maximum transmembrane pressure (BPi_max-PP) substantially con- stant.

Another example shows that the elevation of the plasma collection container 24 does not affect the biasing force selection for an optimal maximum transmembrane pressure in the preferred embodiment of the present invention. For example, if the plasma collection container is elevated so that the plasma pressure PP is 18 psi or 930 mmHg., and assuming the desired maximum transmembrane pressure is still 120 mmHg., the maximum inlet blood pressure BP _max which may occur before exceeding the desired transmembrane pressure is 1050 mmHg. Applied over a plunger area

OMPI i Λm ι?o . *>y -25-

of 10 cm², the inlet blood pressure BPi_raax exerts an upward force of 10,500 mmHg cm² on the plunger. The plasma, however, exerts a downward force on the plunger of 9300 mmHg. cm² (930 x 10), leaving a net 5 upward force of 1200 mmHg. cm², the same as with the example above.

One additional example shows that the pre¬ sent invention will provide the desired maximum transmembrane pressure even when the collection con- 10 tainer is below the membrane, in a gravity-assist position. Such positioning of the plasma collection container may be helpful, for example, if patient limitations do not permit a pump speed sufficient to generate the desired blood inlet pressure. Assume, 15 for example, that the collection bag is sufficiently lower than the membrane that the static plasma pres¬ sure PP is 700 mmHg. To operate, for example, at a optimum transmembrane pressure of 120 mmHg., the in¬ let blood pressure BPi_max need only be 820 mmHg., as 20 constrasted to 880 mmHg. and 1050 mmHg. in the above examples. Applied over a plunger area of 10 cm², the inlet blood pressure BPi_max exerts an upward force of 8200 mmHg. cm² on the underside of the plunger. Because the plasma pressure PP pushes down on the 25 plunger with a force of (700 mmHg. x 10 cm²) 7000 mmHg. cm², the resultant upward force on the plunger is 1200 mmHg. cm², the same as with the other examples. Thus, the selected biasing force need not be changed, and the maximum pressure is still limited 30 to the desired value, even when the plasma collection is in a gravity-assist position. In summary, in the normal course of opera¬ tion of a preferred membrane plasmapheresis appara¬ tus, the plunger 40 is biased downwardly by the coil spring 42, maintaining the plasma flow path in a nor- mally open position. In the event that the pressure in the blood flow path increases, either intentional¬ ly or unintentionally, above the selected maximum pressure, the force exerted on the plunger from the underside of the diaphragm 38, pushes the plunger up- wardly, reducing the size of the plasma flow path between the plunger stem and the housing wall, and causing an increase in the plasma pressure to offset the increase in the blood inlet pressure. In the event that blood pressure is reduced to. below the selected maximum, the plunger moves downwardly by the spring force-, further opening the flow path and allowing a greater flow of plasma" with a resultant lower pressure of plasma.

An alternative embodiment of the transmera- brane pressure control means 26 of the present inven¬ tion is depicted in Figure 6. That apparatus is con¬ structed essentially the same as the one described in Figures 3-5, except that the subchamber 72 forms a portion of the whole blood flow path upstream of the filter membrane 14 in a manner similar to that dia- grammatically shown in Figure 2. To achieve this, the chamber 74 has a whole blood inlet 110 and an outlet 112 which permits blood flow through the cham¬ ber, instead of the remote arrangement to which Figure 5 is directed. Otherwise, the operation of the apparatus depicted in Figure 6 is identical to

OMPI sf WIPO -St_j -27-

that described for Figure 5.

Figures 7 and 8 depict another embodiment of the control apparatus shown in Figure 5, which permits the operator to adjust the biasing force and thereby select the preferred maximum transmembrane pressure. Many of the features of the apparatus de¬ picted in Figure 8 are the same as shown in Figure 5, and the description will not be repeated. Although various means may be provided to adjust the biasing force, either manually or automatically, the essen¬ tial difference between Figure 8 and Figure 5, is that the top wall of the upstanding center portion 82 in Figure 5 has been replaced by a rotary cap or dial 114 threadedly attached to the wall of the center portion. Rotation of the cap clockwise (Fig. 7) com¬ presses the spring 42, thus increasing the downward biasing force on the plunger and accordingly result¬ ing in a higher maximum transmembrane pressure being selected. Rotation counterclockwise reduces the spring force and lowers the maximum transmembrane pressure which will be permitted by the apparatus.

As shown in Figure 7, the cap bears indicia of the pressure that is being selected. In the illustrated embodiment the cap is calibrated for maximum transmembrane pressure, and bears numbers and raised ribs 116 indicating a maximum transmembrane pressure between 50 and 120 mmHg. The raised ribs 116 and numerals may be aligned with rib 118 on the plasma outlet for selection of that particular trans- membrane pressure. Thus, if an operator is working with a filter module in which the preferred maximum transmembrane pressure is 110 mmHg., he or she may turn the dial until the number 110 and its reference mark is aligned with the raised rib 118 on the plasma outlet. As described earlier, a coil spring is 5 selected which has a spring constant so that when compressed in the amount resulting from rotation of the cap, it will exert a downward biasing force on the plunger which is only overcome when the blood inlet pressure exceeds the value BP _max which pro-

10 vides a maximum transmembrane pressure at the up¬ stream end of the membrane of 110 mmHg.

It is also within the scope of the present invention to calibrate the dial in units other than mmHg., or the indicia may be chosen to be represent-

_5. ative of spmething other than maximum transmembrane pressure. For example, the dial may also have indicia representative of different commercially available filter modules, each indicia being repre¬ sentative of the transmembrane pressure preferred for

20 that particular filter module, thus further easing operator burden. Also, the dial 114 may have indicia representing an adjustment preferred after a period of operation to compensate for filter clogging or coating which, if uncompensated for, will decrease

25 filter membrane performance.

Figure 9 depicts yet a further alternative apparatus embodying the present invention for preven¬ ting the backflow of plasma when the plasma pressure (PP) exceeds the blood inlet pressure (BPi). Addi-

30 tionally, depending on the nature of the biasing force, the embodiment in Figure 9 may actually oper- ate in a substantially different mode from the other embodiments of the present invention. In Figure 9, the biasing force is illustrated generally, rather than particularly, and the upstanding -center portion 84 of the housing is open at the top. The embodiment in Figure 9 incorporates a back flow prevention means in the form of a sleeve 44 associated with the stem 98 of the plunger 40. The sealing sleeve is of pre¬ ferably resilient elastometric material such as sili- cone rubber or similar material. The sealing sleeve is mounted over the reduced diameter portion 102 of the stem 98, and may further be sealed to the stem by solvent or the like to prevent the escape of liquid. The upper end of the seal comprises a larger dia- meter skirt or bellows portion 120, which terminates in a thickened rim 122. The thickened rim is cap¬ tured between a locking ring 124 and the top edge of the upstanding center portion 84. The locking ring 124 has a depending internal peripheral lip 126 which forms an undercut in the ring 124 that receives the thickened rim 122 in fluid-tight engagment.

At the lower end of the sleeve 44, there is a radially extending sealing flange 128, which is wider than the opening 130 in the top portion of the housing, through which the stem 98 extends. The sleeve 44 is positioned on the stem 98, so that when the plunger 40 is raised, the radial flange 128 is lifted from shoulder 132 surrounding opening 130, permitting plasma to flow from the inlet 82 to the outlet 86. The bellows portion of the seal permits reciprocal movement of the plunger while also sealing the open upper end of the upstanding portion 84 of the housing.

In the event that the blood pressure BP is less than the plasma pressure PP, the force exerted by the plasma will push plunger 40 completely down¬ wardly until the sealing flange 128 closes against the annular shoulder 132 surrounding aperture 130, thus preventing back flow of plasma toward the filter membrane. This may occur, for example, when plasma is being collected in a suspended container and there is a gravity pressure head. Upon shutdown of blood pump 46, the gravity head may tend to create a reverse flow of plasma back through the membrane and into the blood flow path. The backflow prevention valve of the present invention, prevents this from occurring.

The embodiment of Figure 9 may also operate

« in a substantially different mode than the other em¬ bodiments of the present invention, which assures that the plasmapheresis will be conducted at the desired optimal transmembrane pressure. For this mode of operation, the sleeve 44 is positioned on stem 98 to block the plasma flow path when the down¬ ward biasing force 41 is greater than the force exerted by the inlet blood pressure. Thus, no plasma can be collected until the inlet blood pressure BPi reaches e.g., by increasing pump speed, the desired maximum value BPi_max to achieve the desired transmem¬ brane pressure. In other words, only when the blood inlet pressure equals or exceeds BPi_max will the plunger move upwardly, raising sealing flange 128 from annular shoulder 132, and affording plasma flow to the collection container.

One other alternative construction of the present invention is depicted in Figure 10, which shows apparatus of the present invention wherein the biasing force is exerted in a different direction than shown in the preferred embodiment. Figure 10 shows control means 26 in which the housing 54 has a flexible upper portion 134 and a lower portion 136, peripherally sealed together to define an interior chamber. A flexible diaphragm or membrane 138, which is peripherally sealed between the housing portions, divides the interior chamber into the subchambers 140 and 142. Plasma flows into the device through inlet 144. A plasma outlet 146 is defined by a grommet 148 in the center of the lower portion 136. A movable member 150 mounted within the housing, on the under¬ side of the diaphragm, forms a portion of a valving arrangement which controls the flow of plasma through the outlet 146. The member 150 has a generally flat top surface 152 which directly underlies the membrane 138, and a depending center cylindrical portion 154 which is movable into and away from contact with the grommet 148. Means for exerting a biasing force on the member 150 is provided in the form of a connecting member 156 which extends through the flexible upper housing portion 134 and through the diaphragm 138, and is fixedly attached within the center cylinderi- cal portion 154 of member 150. A biasing force of selected amount exerted upwardly on the connecting

- JRϊq

OMPI member normally maintains the center cylindrical por¬ tion 154 in a spaced-apart relationship with the grommet 148 at the plasma outlet, providing a plasma flow path through the housing in a normally open con- dition. Blood from the blood flow line 30 upstream of the filter membrane communicates with the upper chamber 140 via condui^'t 28, and exerts a downward pressure on the diaphragm 138 and member 150. When the force of the whole blood pressure on the member 150 exceeds the selected biasing force, it pushes the member toward the outlet grommet 144, reducing the space between the grommet and the cylindrical portion 154 of the member, thereby reducing the plasma flow rate and increasing the plasma pressure to maintain the transmembrane pressure of the filter module substantially constant. In the event the whole blood pressure falls below the value resulting in the maxi¬ mum transmembrane pressure, the biasing force tends to open the plasma flow path, resulting in lower plasma flow pressure.

In summary, the present invention provides new and unique means and method for controlling the transmembrane pressure in membrane plasma filtration apparatus and systems, regardless of whether pressure variations in the plasma-containing fluid flow line occur upstream or downstream of the filter membrane. Although the present invention has been described in terms of the preferred and alternative embodiments for use in a plasmapheresis system, it is understood that the present invention is defined in the accom- panying claims and it is not intended that the present invention be limited to the specific embodiments shown and described.

Claims

WHAT IS CLAIMED IS:

1. A plasma filtration method for separat¬ ing a plasma filtrate from a plasma-containing fluid comprising: introducing a flow of plasma-containing fluid subject to a determinable inlet pressure into one end of a fluid path defined at least in part by one side of a membrane which has a pore size suited for filtering plasma filtrate from the plasma_containing fluid; removing said fluid from the other end of the fluid path; conducting said plasma filtrate subject to a determinable pressure through a flow path communicating with the other side of said membrane; varying the size of said plasma filtrate flow path inversely with respect to changes in said plasma-containing fluid inlet pressure to control the difference between said fluid inlet pressure and said plasma filtrate pressure.

2. A plasma filtration method in accord¬ ance with Claim 1 wherein said plasma-containing fluid is whole blood and said plasma filtrate is plasma.

3. A plasma filtration method in accord¬ ance with Claim 1 wherein said plasma-containing fluid is essentially plasma and said plasma filtrate is selected plasma proteins.

4. A plasma filtration method in accordance with Claim 1 further comprising the step of preventing the flow of plasma filtrate toward said membrane when said plasma-containing fluid inlet pressure is below a selected level.

5. A plasma filtration method in accordance with Claim 1 including the steps of maintaining said plasma filtrate flow path in an open condition when the plasma-containing fluid inlet pressure is below a selected value, and reducing the size of said plasma flow path when said fluid inlet pressure exceeds said selected level.

6. A plasma filtration method in accordance with Claim 5 wherein the difference between said selected level of plasma-containing fluid inlet pressure and said plasma filtrate pressure is less than the level at which significant hemolysis occurs in the whole blood.

7. A plasma filtration method in accordance with Claim 6 wherein said pressure difference is less than 120 mmHg.

8. A plasma filtration apparatus in accordance with Claim 6 wherein said pressure differ¬ ence is substantially less than the pressure differ¬ ential at which hemolysis occurs.

9. A plasma filtration method in accord¬ ance with Claim 5 wherein the difference between said selected level of plasma-containing fluid inlet pres¬ sure and said plasma filtrate pressure is the pres- sure differential at which plasma filtration is most efficient.

10. A plasma filtration method in accord¬ ance with Claim 5 wherein said plasma-containing fluid is substantially continuously introduced at an inlet pressure above said selected value.

11. In plasma filtration apparatus of the type employing a filter membrane adapted to separate plasma filtrate from plasma-containing fluid as the plasma-containing fluid flows across the surface thereof, said apparatus having an inlet adapted to receive plasma-containing fluid, an outlet for remov¬ al of said fluid, one side of said membrane defining at least a portion of the fluid flow path between said inlet and outlet, and means defining a plasma filtrate flow path communicating with the other side of said membrane for removing the separated plasma filtrate, the improvement comprising, in combination: means for controlling the differential pressure across said membrane, said control means being cooperatively associated with said plasma fil¬ trate flow path and in fluid communication with said plasma-containing fluid flow path at a location up¬ stream of said membrane, said control means being operable to vary the size of said plasma filtrate flow path inversely with respect to the pressure changes in said plasma-containing fluid flow path to control the differential pressure across said mem¬ brane.

12. Plasma filtration apparatus in accord¬ ance with Claim 11 wherein said control means is re¬ mote from said plasma-containing fluid flow path, said apparatus further comprising conduit means com- municating between said fluid flow path and said con¬ trol means.,

13. Plasma filtration apparatus in accordance with Claim 11 wherein said control means defines a portion of said plasma-containing fluid flow path upstream of said membrane.

14. Plasama filtration apparatus in accordance with Claim 11 wherein said control means is disposed to maintain said plasma filtrate flow path in a normally open position.

15. Plasma filtration apparatus in accordance with Claim 11 further comprising means exerting a force of a certain amount to bias said control means to a normally open flow path condition.

16. Plasma filtration apparatus in accordance with Claim 14 wherein the fluid in said plasma-containing fluid flow path communicates with said control means to exert a force on said control means opposing the force exerted by said biasing means, said control means being operable to restrict the size of said plasma filtrate flow path when the pressure of the fluid in said plasma-containing fluid flow path exceeds a selected level.

17. Plasma filtration apparatus in accordance with Claim 16 further comprising means for adjusting the biasing force.

18. Plasma^' filtration apparatus in ^■accordance with Claim- 15 further comprising means for selectively changing the amount of force exerted by said biasing means.

19. Plasma filtration apparatus in accordance with Claim 11 further comprising means associated with said control means operable to close said plasma filtrate flow path against the flow of plasma filtrate when the pressure in said plasma-containing fluid flow path upstream of said membrane is below a selected level.

20. Plasma filtration apparatus in accordance with Claim 11 further comprising means associated with said control means operable to close said plasma filtrate flow path against the flow of

, —O P_ So -39-

plasma filtrate toward said membrane when the plasma filtrate is pressure greater than the pressure of said plasm-containing fluid upstream of said membrane.

21. Plasma filtration apparatus in accordance with Claim 11 wherein said control means is disposed to maintain said plasma filtrate flow path in a normally open condition and is operable to reduce the size of said plasma filtrate flow path when the pressure in said plasma-containing fluid flow path upstream of said membrane exceeds a selected level.

22. Plasma filtration apparatus in accord¬ ance with Claim 11 wherein said control means in¬ cludes means movable to define the size of said plas¬ ma filtrate flow path, said movable means being mov- able at least between a first position wherein said plasma filtrate flow path is open and a second posi¬ tion wherein said plasma filtrate flow path is smal¬ ler than in said first position, said plasma filtra¬ tion apparatus further comprising means exerting a force of certain amount to bias said movable means to the open flow path position, said movable means being in fluid communication with said plasma-containing fluid flow path upstream of said membrane such that said plasma-containing fluid exerts a force on said movable means opposing said biasing force, whereby said movable means is movable to said second flow path condition when the force exerted by the fluid in said plasma-containing fluid flow path exceeds said biasing force.

23. Plasma filtration apparatus in accordance with Claim 15, wherein said certain biasing force is representative of a desired maximum plasma-containing fluid flow pressure upstream of the filter membrane.

24. Plasma filtration apparatus in accordance with Claim 11 wherein said control means includes means defining a movable surface disposed for contact with fluid of said plasma-containing fluid flow path, said surface being movable by pressure of fluid in said fluid flow path to vary the* size of said plasma filtrate flow path.

25. Plasma filtration apparatus in accordance with Claim 24 further including means exerting a selected biasing force on said movable surface to bias said movable surface toward a position wherein said plasma filtrate flow path is normally open.

26. Plasma filtration apparatus in accordance with Claim 25 wherein said biasing means includes means for changing the amount of force biasing said movable surface to a normally open position.

DMPI_ ξ TATlO.Φ' -41-

27. Plasma filtration apparatus in accord¬ ance with Claim 26 wherein said changing means in¬ cludes indicia representative of the maximum differ¬ ential pressure across said membrane resulting from said selected amount of biasing force.

28. In plasma filtration apparatus of the type employing a filter membrane adapted to separate plasma filtrate from plasma-containing fluid as the fluid flows across the surface thereof, said appara- tus having an inlet adapted to receive plasma-con¬ taining fluid, an outlet for removal of said fluid, one side of said membrane defining at least a portion of the plasma-containing fluid path between said in¬ let and outlet, and means defining' a plasma filtrate flow path communicating with the other side of said membrane for removing the separated plasma filtrate, the improvement comprising, in combination: means for controlling the maximum differen- tial pressure across said membrane, including control means cooperatively associated with said plasma fil¬ trate flow path and movable to vary the size of said plasma filtrate flow path at least between a first open condition and a second condition in which the size of said plasma flow path is smaller than in said first condition, means exerting a certain force to bias said control means to and first open condition, and means providing fluid communication between said control means and said plasma-containing fluid flow path at a location upstream of said membrane such that the fluid in said fluid flow path is disposed to

-TST^WXPO"" *-* ^ATI0t_§ exert a force on said control means opposing said biasing force, said control means being movable to said second second condition when pressure in said plasma-containing fluid flow line exceeds a desired level, so as to restrict the flow of plasma and thus limit the maximum transmembrane pressure which may occur.

29. Apparatus in accordance with Claim 28, wherein said control means is movable through an infinite range of plasma filtrate flow path sizes between an open condition and a closed position.

30. Apparatus in accordance with Claim 28 wherein said control means comprises means defining a movable surface in fluid communication with said plasma-containing fluid flow path upstream of said membrane, and means associated with said movable surface to change the size of said plasma filtrate flow path upon movement of said surface, said biasing force being exerted against said surface in a direction opposing the force of fluid exerted thereon by fluid in said plasma-containing, fluid flow path.

31. Apparatus in accordance with Claim 28 further comprising means selectively operable to change said biasing force.

32. Apparatus in accordance with Claim 28 further comprising flow prevention means for preventing flow of plasma filtrate when said pressure

^~ E ^~γ-

OMPI lTιo ' in said plasma-containing fluid flow path is below said desired level.

33. Apparatus in accordance with Claim 28 further comprising flow prevention means for preventing flow of plasma filtrate toward said membrane when the plasma filtrate pressure is greter than the pressure in said plasma-containing fluid flow path upstream of said membrane.

34. Apparatus in accordance with Claim 28 wherein said means for varying the size of said plasma filtrate flow path comprises means defining a housing, plunger means reciprocally mounted within said housing, one end of said plunger means being disposed for pressure contact with fluid of said plasma-containing fluid flow path, the other end being cooperatively associated with said plasma filtrate flow path to vary the size of said flow path at least between said first and second conditions upon movement of said plunger means, said certain biasing force being disposed to bias said plunger means to said first filtrate flow path condition.

35. Apparatus in accordance with Claim 34 further comprising a flexible diaphragm disposed within said housing, said plasma-containing fluid flow path communicating with one side of said diaphragm and said one end of said plunger means cooperatively engaging the other side of said

-44-

diaphragm.

36. Apparatus in accordance with Claim 34 wherein said housing and said other end of said plunger means define a portion of said plasma filtrate flow path therebetween whereby the size of said flow path is varied by varying the space between them.

37. . Apparatus in accordance with Claim 34 wherein said means exerting a biasing force is adjustable to change the force biasing said plunger to said first filtrate flow path condition.

38. Apparatus in accordance with Claim 34 further comprising back flow prevention means for preventing flow of plasma filtrate toward said membrane, said back flow prevention means including seal means carried by said other end of said plunger and disposed to block said plasma filtrate flow path when said plasma filtrate pressure is greater then the pressure in said plasma-containing fluid flow path upstream of said membrane.