# US 4,735,726 A · Plasmapheresis by reciprocatory pulsatile filtration

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- Number: US 4,735,726 A
- Document ID: US4735726A
- Status: Granted
- Kind: A
- Application number: 07/009,003
- Filed: 1987-01-28
- Granted: 1988-04-05
- Earliest claimed: 1981-07-22
- Assignees: E. I. Du Pont de Nemours and Company
- Inventors: Ray B. Duggins
- Web page: https://patentgrep.com/patent/US4735726A

## CPC

- B01D 61/147: {Microfiltration}
- A61M 1/3496: {Plasmapheresis; Leucopheresis; Lymphopheresis (A61M1/3472 takes precedence)}
- A61M 1/3604: {in opposite directions}
- A61M 60/113: in other functional devices, e.g. dialysers or heart-lung machines
- A61M 60/279: Peristaltic pumps, e.g. roller pumps
- A61M 60/37: Haemodialysis, haemofiltration or diafiltration
- A61M 60/851: Valves
- B01D 65/08: Prevention of membrane fouling or of concentration polarisation
- B01D 2321/2066: Pulsated flow
- B01D 2321/2083: By reversing the flow
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}

## Abstract

A process for continuous plasmapheresis, which process comprises conducting blood over a microporous membrane in reciprocatory pulsatile flow, and preferably further comprises reducing the transmembrane pressure difference to below zero during each forward and reverse flow. Apparatus for carrying out the process are also disclosed.

## Claims

### Claim 1

Improved method for plasmapheresis wherein whole blood is introduced and conducted in a forward direction from an upstream area of a first surface of each of one or more membranes having cell-retaining pores to a downstream area of the first surface, plasma-depleted blood is collected from the downstream area of the first surface, and plasma is separately collected from a second surface of each of the one or more membranes, in a system closed off from the atmosphere, comprising:
(a) while maintaining a net positive transmembrane pressure difference across said one or more membranes, conducting plasma-depleted blood in the reverse direction over the first surface by delivering collected plasma-depleted blood to the downstream area of the first surface and reducing the transmembrane pressure difference across said one or more membranes in the upstream area whereat whole blood is introduced to about .ltoreq.0 by either withdrawing and collecting blood from the upstream area of the first surface or increasing the pressure on a second surface of the one or more membranes, while collecting blood from the upstream area of the first surface, so that blood in the upstream area of the first surface is at a pressure which is lower than the downstream plasma-depleted blood pressure;
(b) terminating the reverse conducting of step (a);
(c) while maintaining the net positive transmembrane pressure difference across the membrane, conducting whole blood in the forward direction over the first surface by delivering collected blood from step (a) to the upstream area of the first surface and reducing the transmembrane pressure difference across said one or more membranes in the downstream area whereat plasma-depleted blood is collected to about .ltoreq.0 by either withdrawing and collecting plasma-depleted blood from the downstream area of the first surface or increasing the pressure on a second surface of the one or more membranes, while collecting plasma-depleted blood from the downstream area of the first surface, so that plasma-depleted blood in the downstream area of the first surface is at a pressure which is lower than the upstream blood pressure;
(d) repeating steps (a) to (c) in sequence; and
(e) collecting plasma at a rate of at least about 0.01 mL/min/cm.sup.2 of membrane and plasma-depleted blood having a hematocrit of at least about 60%.

### Claim 2 (depends on 1)

Method of claim 1 wherein the transmembrane pressure difference is reduced to below zero.

### Claim 3 (depends on 1)

Method of claim 1 which comprises conducting the blood forward and reverse at a velocity up to about 400 mm-sec.sup.-1.

### Claim 4 (depends on 1)

Method of claim 1 wherein the transmembrane pressure difference is reduced from a peak of about 1.5 psi (10 kPa) to below zero.

### Claim 5 (depends on 4)

Method of claim 4 in which blood is conducted forward and reverse across each of one or more planar membrandes in flow paths having a height of about 4 to 10 mils (102 to 254 .mu.m) at a pulsation frequency of about 40 to 80 pulsations per minute and at a velocity up to about 450 mm-sec.sup.-1.

### Claim 6 (depends on 5)

Method of claim 5 in which blood is conducted over membranes having cell retaining pores, 0.4 to 0.5 .mu.m in average diameter, having elongation of less than about 65%, modulus of at least about 10 kpsi (70 MPa) and tensile strength of at least about 3000 psi (20 MPa), when tested wet, and being supported on plasma sides.

### Claim 7 (depends on 5)

Method of claim 5 in which blood is conducted from the centers of each of a plurality of circular membranes having cell retaining pores, 0.1 to 1.0 .mu.m in average diameter, and being supported on plasma sides.

### Claim 8 (depends on 7)

Method of claim 7 in which the transmembrane pressure difference is reduced to about -0.8 to -1.0 psi (-5.3 to -6.9 kPa).

### Claim 9 (depends on 7)

Method of claim 7 in which blood is conducted over smooth capillary pore membranes having cell retaining pores, 0.4 to 0.5 .mu.m in average diameter, having elongation of less than about 65%, modulus of at least about 3000 psi (20 MPa), when tested wet, and being supported on plasma sides.

### Claim 10 (depends on 9)

Method of claim 9 in which blood is conducted between two membranes.

### Claim 11 (depends on 10)

Method of claim 10 in which the membranes are supported on both sides, each plasma side support comprising a fabric-like material.

### Claim 12 (depends on 11)

Method of claim 11 in which each plasma side support comprises a plurality of layers of a nonwoven polyester fabric.

### Claim 13 (depends on 12)

Method of claim 12 in which there is an elastomeric seal between each membrane and each plate and the blood side support comprises a plurality of smooth pillars.

### Claim 14

Improved plasmapheresis apparatus comprising one or more membranes having cell-retaining pores, means for conducting blood through a blood flow path forward at a net positive transmembrane pressure difference and reverse over a first surface of each membrane, means for reducing the transmembrane pressure difference during the forward and reverse conducting of blood, means for collecting plasma which passes through each membrane from a second surface thereof, means for withdrawing and collecting blood from each said first surface, means for withdrawing and collecting plasma-depleted blood from each said first surface, means for delivering collected blood to each said first surface, means for delivering collected plasma-depleted blood to each said first surface and means for operating the apparatus closed off from the atomosphere.

### Claim 15 (depends on 14)

Apparatus of claim 14 wherein the means for conducting blood over the first surface of each membrane include means for reducing the transmembrane pressure difference to below zero.

### Claim 16 (depends on 14)

Apparatus of claim 14 which comprises means for conducting the blood forward and reverse at a velocity up to about 400 mm-sec.sup.-1.

### Claim 17 (depends on 14)

Apparatus of claim 14 wherein the means for conducting blood over the first surface of each membrane include means for reducing the transmembrane pressure difference from a peak of about 1.5 psi (10 kPa) to below zero.

### Claim 18 (depends on 17)

Apparatus of claim 17 comprising one or more planar membranes having cell retaining pores, means defining flow paths having a height of about 4 to 10 mils (102 to 254 .mu.m) and means for conducting the blood forward and reverse at a frequency of about 40 to 80 pulsations per minute and a velocity up to about 250 mm-sec.sup.-1.

### Claim 19 (depends on 18)

Apparatus of claim 18 wherein said one or more planar membranes comprise membranes having cell-retaining pores, 0.4 to 0.5 .mu.m in average diameter, having elongation of less than about 65%, modulus of at least about 10 kpsi (70 MPa) and tensile strength of at least about 3000 psi (20 MPa), when tested wet, which are supported on the plasma sides.

### Claim 20 (depends on 18)

Apparatus of claim 18 wherein said one or more planar membranes comprise a plurality of circular membranes having cell-retaining pores, 0.1 to 1.0 .mu.m in average diameter, which are supported on the plasma sides and means for conducting blood from the centers of the membranes.

### Claim 21 (depends on 20)

Apparatus of claim 20 which includes means for reducing the transmembrane pressure difference to about -0.8 to -1.0 psi (-5.3 to -6.9 kPa).

### Claim 22 (depends on 20)

Apparatus of claim 20 wherein said one or more planar membranes comprise thin, smooth capillary pore membranes having cell-retaining pores, 0.4 to 0.5 .mu.m in average diameter, having elongation of less than about 65%, modulus of at least about 10 kpsi (70 MPa) and tensile strength of at least about 3000 psi (20 MPa), when tested wet, which are supported on the plasma sides.

### Claim 23 (depends on 22)

Apparatus of claim 22 having the blood flow path 2 between two membranes.

### Claim 24 (depends on 23)

Apparatus of claim 23 in which the membranes are supported on both sides and each plasma side support comprises a fabric-like material.

### Claim 25 (depends on 24)

Apparatus of claim 24 in which each plasma side support comprises a plurality of layers of a nonwoven polyester fabric.

### Claim 26

Improved apparatus including a plasmapheresis membrane filter module comprising:
first and second opposing module housing plates having circular recesses within opposing surfaces so as to form a blood flow region between two plasma flow regions; said plates defining a central blood inlet port connected to the blood flow region, a plasma depleted blood outlet port, a blood collection channel, around the blood flow region, connected to said plasma-depleted blood outlet port, a plasma output port and a plasma collection channel around each plasma flow region connected to said plasma outlet port;
a plasma-side support within each plasma flow region;
a pair of membranes, having cell-retaining pores, between each plasma flow region and the blood flow region, there being an elastomeric seal between each membrane and each plate and a blood flow path between the membranes;
means for conducting blood forward at a net positive transmembrane pressure difference and reverse over a first surface of each membrane;
means for reducing the transmembrane pressure difference during the forward and reverse conducting of blood;
means for collecting plasma which passes through each membrane from a second surface thereof;
means for withdrawing and collecting blood from the blood flow region;
means for delivering collected blood to the blood flow region;
means for withdrawing and collecting plasma-depleted blood from the blood flow region;
means for delivering plasma-depleted blood to the blood flow region; and
means for operating the apparatus closed off from the atmosphere.

### Claim 27 (depends on 26)

The apparatus of claim 26 in which the depth of the blood flow region between the membranes is at least about 4 mils (102 .mu.m) and the seal is an elastomeric adhesive.

### Claim 28 (depends on 27)

The apparatus of claim 27 in which the depth of the blood flow path between the membranes is about 4 to 10 mils (102 to 254 .mu.m).

### Claim 29

The apparatus of clalim 28 in which the membranes are comprised of polyester or polycarbonate and are less than about 1 mil (25 .mu.m) thick.

### Claim 30 (depends on 29)

The apparatus of claim 29 in which the membranes are less than about 0.5 mil (13 .mu.m) thick and the adhesive has a break elongation of at least about 100%.

### Claim 31 (depends on 29)

The apparatus of claim 29 in which the adhesive has a break elongation of about 400%.

### Claim 32 (depends on 29)

The apparatus of claim 29 in which the membranes provide an effective surface area of about 0.02 to 0.06 m.sup.2 and have cell-retaining pores of about 0.1 to 1.0 .mu.m in averge diameter.

### Claim 33 (depends on 29)

The apparatus of claim 29 in which blood side supports comprised of a plurality of smooth pillars are located between the membranes.

### Claim 34 (depends on 33)

The apparatus of claim 33 in which the plasma side supports are comprised of layers of fabric-like materials.

### Claim 35 (depends on 34)

The apparatus of claim 34 in which the membranes have a total effective surface area of about 0.02 to 0.06 m.sup.2 and the cell-retaining pores are about 0.4 to 0.5 .mu.m in average diameter.

### Claim 36 (depends on 35)

The apparatus of claim 35 having blood side supports between the membranes which supports comprise substantially circular dots of an elastomeric adhesive.