CA1269620A - Plasmapheresis by reciprocatory pulsatile filtration - Google Patents
Plasmapheresis by reciprocatory pulsatile filtrationInfo
- Publication number
- CA1269620A CA1269620A CA000598189A CA598189A CA1269620A CA 1269620 A CA1269620 A CA 1269620A CA 000598189 A CA000598189 A CA 000598189A CA 598189 A CA598189 A CA 598189A CA 1269620 A CA1269620 A CA 1269620A
- Authority
- CA
- Canada
- Prior art keywords
- blood
- plasma
- membranes
- module
- membrane
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
Landscapes
- External Artificial Organs (AREA)
Abstract
TITLE
Plasmapheresis by Reciprocatory Pulsatile Filtration ABSTRACT OF THE DISCLOSURE
A process for continuous plasmapheresis which process comprises conducting blood over a microporous membrane in reciprocatory pulsatile flow, and prefer-ably 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.
Plasmapheresis by Reciprocatory Pulsatile Filtration ABSTRACT OF THE DISCLOSURE
A process for continuous plasmapheresis which process comprises conducting blood over a microporous membrane in reciprocatory pulsatile flow, and prefer-ably 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.
Description
TITLE
Plasmapheresi~ by Reciprocatory Pulsatile Fil~ration TECHNICAL FIELD
This invention pertains to a process and an apparatus for plasmapheresis by reciprvcatory pulsatile filtration with microporous membranes.
BACKGRoUND INFORMATION
Plasmapheresis is a process of separating plasma from whole blood. The plasma-depleted blood is comprised principally of cellular components~
e.g., red blood cells, white blood cells and plate-lets. Plasma is compxised largely of water, but also contains proteins and various other noncellular compounds~ both organic and inorganic.
Continuous plasmapheresis is the process of ~0 continuously separating plasma from whole bloodO
Plasmapheresis is currently used to obtain plasma for various transfusion n~eds, e.g., preparation of fresh-fro~en plasma, for subsequent fractionation to obtain specific proteins such as serum albumin, to produce cell culture media, and or disease therapies involving either the replacement of plasma or removal of specific disease-contributing factors from the plasma.
Plasmapheresis can be carried out by centrifugation or by filtration, Generally, in known filtration apparatus, whole blood is conducted in a laminar flow path across one ~urface, i.e., the blood side surface, of a microporous me~brane. Useful microporous membranes have pores which substantially retain the cellular components of blood bu~ allow ~' :`
plasma to pass through. Such pores are referred to herein as cell-reta1ning poresO Typically, cell retaining pore diameters are 0.1 ~m to 1.0 ~.
In such known apparatus, as the blood flows through the flow path, the cellular components tend to migrate towards the center or axis of the path~
Ideally, plasma occuples the periphery oP the path so that it is predominantly pla~ma ~ha~ contacts the membrane. A pressure difference across the membrane 10 causes some of the plasma to pass through ~he pores of the ~embrane while plasma deplet~d blo~d contlnues to 10w to the end of the pathO Ideally, ~he filtrate is cell free; the plasma-depleted blood collec~ed at the end of the flow pa~h i~
concentrated9 i.e. 9 is depleted in plasma and therefore has an increased hematocrit ~volume percent o~ red blood cells).
P,f ter blood has been conducted across the surface o a membrane at normal venous flow ra~es or 20 some time, the transmembrane flow of plasma becomes impaired. This phenomenon ls herein sometimes referred to as membran~ fouling or simply as fouling. Rnown ~echniques Çor reducing fouling, i.e~, increasing ~he len~th of time for which the process can be carried out withou~ the occurrence of significant impairment of plasma flow, include varying the flow path si2e so as to op~imize the wall shear rate along the leng~h of the f low path as disclosed in U.S. Patent 4,212,742, and recycling a portion of the plasma-depleted blood ~o increase the velocity of blood in ~he Çlow pa~h the latter technique may result in less plasma-depletionO
Various fil~ra~ion devices for plasmapheresis are di~closed in the litera~ure. U.S.
3,705,100 disclose~ a center-fed circular membrane .
~ ' . ~ ,' ' ' :
:
having a spiral flow path. U~S. ~,212,7~2 ~iscloses a device having divergent flow channels. German Patent 2g925~143 discloses a filtration apparatus having parallel blood flow paths on one side of a membrane and parallel plasma flow paths, which are perpendicular to the blood flow paths, on the opposite surface of the membrane. U.~. Patent Application 2,037,614, published July 16, 1980, discloses a rectilinear double-membrane envelope in which the membranes are sealed together at the ends of the blood flow path~ U.K. Patent Specification 1,555,389 discloses a circular, center-fed, double-mem~rane envelope in which the membranes are sealed around their peripheries. German Patent 2,653,875 discloses a circular~ centre-fed doubl~-membrane device in which blood flows through slot-shaped filter chambers.
It is an object of this invention to provide a process and apparatus for plasmapheresis by filtration. It is a further object to provide such a process and apparatus whereby higly concentrated, plasma-depleted blood can be continuously collected without significant hemolysis and with reduced membrane fouling.
BRIEF DESCRIPTION OF THE DRAWINGS
_ FIG. 1 is a cross-section of a double-membrane filtration module which may be used in the process o the invention, taken along line I-I
of FIG. 2.
FIG. 2 is a perspective view of an illustrative embodiment of the filtration module of FIG. 1 having a loop and an oscillator to oscillate blood in a blood flow path between inlet and outlet.
FIG. 3 is a perspective view of a module having an end plate which has reciprocatory pulse cavities.
DISCLOSURE OF THE INVENTION
For further comprehension of the invention and of the objec~s and advantages thereo, reference may be made to ~he following description and to the appended claims in which v~rious novel features of the invention are more particularly set forth, It has been found that the above objects can be ac~.ieved by conducting blood over the surface of a membrane in reciprocatory pulsatile flow. In 10` particular, the invention resides in a method for continuously separating plasma from blood, which method comprises:
(1) conducting blood in a forward direction over a first surface, i.e., a blood side surface, of each of onP or more membranes having cell-retaining pores, while maintaining a net positive transmembrane pressure difference;
- (2) terminating the forward conducting of blood over the first surface of the membrane;
~3~ conducting the blood in the reverse direction over ~aid first surface, the volume of blood flowed in the reverse direction ~eing less than the volume of blood flowed in the forward direction in s~ep ~1);
~4) repeating steps (1)-(3) in sequence and collecting plasma which pa~ses through each membrane from a second surface, i,e., a plasma side surface, thereof and collecting plasma-depleted blood from said first surfaceO
The inv~ntion further resides in said process wherein the transmembrane pressure difference is reduced during periods of f1OWJ preferably to below zero.
The invention also resides in apparatus for carrying out the aforesaid steps. In particular, the invention also resides in apparatus for separating plasma from blood which apparatus comprises one or more membranes-having cell-retaining pores, means ll ;: . ;
:, ' :- ~ '; : ' .
Plasmapheresi~ by Reciprocatory Pulsatile Fil~ration TECHNICAL FIELD
This invention pertains to a process and an apparatus for plasmapheresis by reciprvcatory pulsatile filtration with microporous membranes.
BACKGRoUND INFORMATION
Plasmapheresis is a process of separating plasma from whole blood. The plasma-depleted blood is comprised principally of cellular components~
e.g., red blood cells, white blood cells and plate-lets. Plasma is compxised largely of water, but also contains proteins and various other noncellular compounds~ both organic and inorganic.
Continuous plasmapheresis is the process of ~0 continuously separating plasma from whole bloodO
Plasmapheresis is currently used to obtain plasma for various transfusion n~eds, e.g., preparation of fresh-fro~en plasma, for subsequent fractionation to obtain specific proteins such as serum albumin, to produce cell culture media, and or disease therapies involving either the replacement of plasma or removal of specific disease-contributing factors from the plasma.
Plasmapheresis can be carried out by centrifugation or by filtration, Generally, in known filtration apparatus, whole blood is conducted in a laminar flow path across one ~urface, i.e., the blood side surface, of a microporous me~brane. Useful microporous membranes have pores which substantially retain the cellular components of blood bu~ allow ~' :`
plasma to pass through. Such pores are referred to herein as cell-reta1ning poresO Typically, cell retaining pore diameters are 0.1 ~m to 1.0 ~.
In such known apparatus, as the blood flows through the flow path, the cellular components tend to migrate towards the center or axis of the path~
Ideally, plasma occuples the periphery oP the path so that it is predominantly pla~ma ~ha~ contacts the membrane. A pressure difference across the membrane 10 causes some of the plasma to pass through ~he pores of the ~embrane while plasma deplet~d blo~d contlnues to 10w to the end of the pathO Ideally, ~he filtrate is cell free; the plasma-depleted blood collec~ed at the end of the flow pa~h i~
concentrated9 i.e. 9 is depleted in plasma and therefore has an increased hematocrit ~volume percent o~ red blood cells).
P,f ter blood has been conducted across the surface o a membrane at normal venous flow ra~es or 20 some time, the transmembrane flow of plasma becomes impaired. This phenomenon ls herein sometimes referred to as membran~ fouling or simply as fouling. Rnown ~echniques Çor reducing fouling, i.e~, increasing ~he len~th of time for which the process can be carried out withou~ the occurrence of significant impairment of plasma flow, include varying the flow path si2e so as to op~imize the wall shear rate along the leng~h of the f low path as disclosed in U.S. Patent 4,212,742, and recycling a portion of the plasma-depleted blood ~o increase the velocity of blood in ~he Çlow pa~h the latter technique may result in less plasma-depletionO
Various fil~ra~ion devices for plasmapheresis are di~closed in the litera~ure. U.S.
3,705,100 disclose~ a center-fed circular membrane .
~ ' . ~ ,' ' ' :
:
having a spiral flow path. U~S. ~,212,7~2 ~iscloses a device having divergent flow channels. German Patent 2g925~143 discloses a filtration apparatus having parallel blood flow paths on one side of a membrane and parallel plasma flow paths, which are perpendicular to the blood flow paths, on the opposite surface of the membrane. U.~. Patent Application 2,037,614, published July 16, 1980, discloses a rectilinear double-membrane envelope in which the membranes are sealed together at the ends of the blood flow path~ U.K. Patent Specification 1,555,389 discloses a circular, center-fed, double-mem~rane envelope in which the membranes are sealed around their peripheries. German Patent 2,653,875 discloses a circular~ centre-fed doubl~-membrane device in which blood flows through slot-shaped filter chambers.
It is an object of this invention to provide a process and apparatus for plasmapheresis by filtration. It is a further object to provide such a process and apparatus whereby higly concentrated, plasma-depleted blood can be continuously collected without significant hemolysis and with reduced membrane fouling.
BRIEF DESCRIPTION OF THE DRAWINGS
_ FIG. 1 is a cross-section of a double-membrane filtration module which may be used in the process o the invention, taken along line I-I
of FIG. 2.
FIG. 2 is a perspective view of an illustrative embodiment of the filtration module of FIG. 1 having a loop and an oscillator to oscillate blood in a blood flow path between inlet and outlet.
FIG. 3 is a perspective view of a module having an end plate which has reciprocatory pulse cavities.
DISCLOSURE OF THE INVENTION
For further comprehension of the invention and of the objec~s and advantages thereo, reference may be made to ~he following description and to the appended claims in which v~rious novel features of the invention are more particularly set forth, It has been found that the above objects can be ac~.ieved by conducting blood over the surface of a membrane in reciprocatory pulsatile flow. In 10` particular, the invention resides in a method for continuously separating plasma from blood, which method comprises:
(1) conducting blood in a forward direction over a first surface, i.e., a blood side surface, of each of onP or more membranes having cell-retaining pores, while maintaining a net positive transmembrane pressure difference;
- (2) terminating the forward conducting of blood over the first surface of the membrane;
~3~ conducting the blood in the reverse direction over ~aid first surface, the volume of blood flowed in the reverse direction ~eing less than the volume of blood flowed in the forward direction in s~ep ~1);
~4) repeating steps (1)-(3) in sequence and collecting plasma which pa~ses through each membrane from a second surface, i,e., a plasma side surface, thereof and collecting plasma-depleted blood from said first surfaceO
The inv~ntion further resides in said process wherein the transmembrane pressure difference is reduced during periods of f1OWJ preferably to below zero.
The invention also resides in apparatus for carrying out the aforesaid steps. In particular, the invention also resides in apparatus for separating plasma from blood which apparatus comprises one or more membranes-having cell-retaining pores, means ll ;: . ;
:, ' :- ~ '; : ' .
2~
for conductin~ blood forward at a net positive transmembrane pressure difference and reverse over a first surface of each membrane, means for collecting plasma which passes through each membrane from a second surface, i.e., a plasma side surface, thereof and means for collecting plasma~depleted blood from said first surface. The invention also resides in said apparatus comprising means for reducing the transmembrane pressure difference during periods of flow, preferably, means for reducing said pressure difference to below zero.
Further, the invention reside in the membrane filter module which comprises:
first and second opposing module housing plates having circular recesses within opposing surfaces so as to form a blood flow r~gion ~ between two plasma flow regions, there being a - central blood inlet port connected to the blood flow region;-a blood collection channel, around the blood flow region, connect to a plasma-d~pleted blood outlet port; and a plasma collection channel around each plasma flow region connected ko a plasma outlet port;
a plasma-side support within each plasma flow region; and 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.
The invent;on also resides in such a filtration module in which blood side supports are located between the membranes. Such module may have means for imparting reciprocatory pulsatile flow to blood in the 10w path connected thereto.
By comprises is meant that the invention includes the aforesaid steps and elements although it is to be understood that other steps and elements are S
. ~ :
no~ excluded from the invention, e~gD~ recycling ~he plasma-deple~ed blood, treating plasma during filtra-tion, diluting the blood with a compatible fluid and measuring various biologically ~ignificant fac~ors and means thereforu In the following description and examples of the inven~ion, the term ~forward~ is used to idicate a direction generally away from the source of blood;
reverse indicates a direction ger.erally towards the source of bloodO Transmembrane pressure difference is determined by subtracting the pressure on the plasma side, i.e.~ the second surface of the membrane, from the pressure on the blood side, i.e.~ the first surface of the membrane. It is to be understood that the transmembrane pressure varies across the membrane with the distance the blood has traveled from the source. Thus, with regard to this invention, since localized transmembrane pressure differences across the membrane may be eith~r positive or negative, only the system transmembrane pressure differences are reported, being referred to herein as net trans-membrane pressure differences. The term ~fouling~
is used to describe the impairment of plasma flow through a membrane~
In ~he invention, blood may be conducted in a forward direction in A flow path over the first surface of a membrane by any means which does not cause significant damage to cellular components, which does not cause significant discomfort or danger to a donor or patient, which provides sufficient forward flow rate and pressure to efficiently fractionate blood in the manner and under the conditions described below, and which allows the forward flow to be periodically interrupted as described below. Examples include variou~ pumps such as a rotary peristaltic pump, a piston or syr~nge pump, and a plunger or hose pump; even manually operated devices such as a flexible blood-containing chamber which can conduct blood forward when compr e s s ed may be u ~ ed .
The m~mbrane ls made of any ~ )d~compatible ma~erial, and has cell-retairling pores, i.20 ~ pores 5 which substantially retain cellular component~ but allow plasma to pass through ~uch pores are typically abou~ 0-1 ~o ~ . O ~n average di ~neter O The selection of a pore size may vary with the goal of a part:icular treatment. IJseful membranes are described in so~e of the above-ci~ed referenc~s relating ko plasmapheres 1 s . The membrane may be of any 5Ui ~able shape , e .g ., tubular , such as hollcw fibers or any planar sha~e. When planar membranes are used, membranes having low elongation , e .g ., less than 15 about 65%, h~gh modulus, e.g., at least about 10 kp~i (70 MPa), and high ~ensile strength, e.g., at lea~
about 3000 psi (20 MPa), when tested wet in accordance with standard procedure~, are pref~rred, because they are dimen~ionally stable. As exemplary of membranes having these preferxed properties are mentioned the ~T 450 polysulfone membrane commercially available from Gelman Sciences, Inc~ and the palyester and polyc rbonate membranes commer~ially available from Nuclepore Corpora~ionO
Of these, thin ; e .g ., less than about 1 mil (25 ~m), preferably les~ ~han 0. 5 mil (13 ~m), smoo~ch polycarbonate or polyes~er capillary pore membranes are preferred because, in laboratory experiment-~, such membranes were found, in general, to perform 30 better than the tortuou~ pa'ch membranes which were tested. Under various conditions of practice, however, any of the above-descrlbed or other types of membranes may prove to be more or le3s advantageous.
I is to be unders~ood that more than one membrane in 35 any arrangement may be used. Convenierltly, several membranes are stacked withln an enclosed module so that blood is fractionated by more than one membrane simultaneously. A planar membrane is preferably supported on the plasma side and more preferably on both sides by, e.g., supports comprising plates having grooves, pores or projec~ions or fabric-like materials. A preferred plasma side support comprises a plurality of layers of a nonwoven polyester fabric.
From the location at which the blood first contacts the membrane, which may or may not be near a point on an edge or end of the membrane, blood i5 conducted in a forward direction in one or more flow paths~ A flow path is the spac~ through which the blood flows on the first surface of the membrane.
lS For example, in a preferred embodiment, the membrane is planar and circular, the location at which the blood contacts the membrane is near the center thereof, and the flow path extends radially, ending -near the periphery of the membrane. It is apparent that~when the membrane is tubular and blood is conducted within the tube, the membrane may alone define the flow path. Typically the depth of blood in each flow path is less than about 30 mils ~G.76 mm). Preferably, said depth is also at least about 4 mils tO.10 mm) but, preferably no more than about 10 mils ( Or 25 mm) ~
The rate at which blood is conducted over the first surface of the membrane is at least as high as may be needed to provide a ne~ positive trans-membrane pressure difference. The flow velocitytypically varies during each period o fo~ward flow7 The preferred average orward flow rate from the source to the membrane is about S0 to 60 ~l-min~l when the source of blood is a vein of a normal human donor although the process may be carried out at higher or lower flow rates~
Plasma is driven through the cell-retaining pores in the membrane at a practical rate by a positive transmembrane pressure difference.
Typieally, positive transmern~rane pressure difference is generated primarily by resis~ance ~o for~ard flow~
but it can also be generated in other ways~ e.g., by decreasing pressure on the plasma on ~he second surface.
It has been found that the amount of transmembrane pressure differenee that can be with-stood by blood without hemolysis is largely a function of cell retaining pore size. For most purposes, the preferred pore diameter is about 074 to 0O~ ~m. In this range, a positive transmembrane pressure differ-ence of up to about 4 psi (28 kPa) is desirable although up to about 1.5 psi (10 kPa) is believed to be preferred. When the pore diame~er is smaller or largerr hi~her or lower transmembrane pressure dif-ferences, respectively, are acceptable. It is to-be understood that the pressure on the blood side and the plasma side surfaces, and the transmembrane-pressure difference, may vary during the course of a treatment and in different regions of the flow path.
After the conducting of blood over the first surface of the mem~rane with a positive transmembrane pressure difference is continued for some time, the membrane becomes progressively fouledv i.e., the flow of plasma through the membrane becomes increasingly impaired. The 1 ngth of time for which blood can be so conducted is beli~ved to depend upon several factors such as, e.g., flow velocity, hematocrit, pore size, transmembrane pressure difference, and the individual characteristics of the blood being treated.
The frequency and volume of the reciprocatory pulses are selected to maximize the flow of plasma through ~he membrane w thout causing extensive blood trauma.
In planar blood flow paths having a height of about 4 to 10 mils (100 to 254 ~m), a useful frequency and volume are about 20 to 140 pulsations per minute, preferably 40 to 80 pulsations per minute, and 0.5 to ~ mL per pulsation, perferably about 3 mL~ By pulsations per minute, also referred to herein as cycles per minute, is meant the number of tim~s per minute the blood is conducted throught a cycle, a cycle consisting of one forward movement and one reverse (backward) movement of blood across the membrane. Said parameters should be selected to provide a mean linear velocity up to about 400 mm-sec~l, preferably, up to about 250 mm sec~l.
These parameteres may be adjusted during a particular treatmen~, but conveniently may be selected and fixed ~or an entire treatment.
After the forward conducting of blood is terminated, blood is conducted in the reverse direc-tion in each flow pathO The termination of forwardflow and the conducting of blood in the reverse direction need not occur simulataneously over the entire membrane. Because blood is conducted in for-ward and reverse direction with a ne~ forward flow during the procedure, the blood flow is referred to as reciprocatory pulsatile flow.
In a preferred embodiment, the transmembrane pressure difference is reduced when conducting blood in either direction. The preferred method is by using a pulse pump connected to the module blood inlet and outlet. The pulse pump suction produces a negative pressure at peak flow rate over the portion of the filtration membrane from which pulse blood is being drawn for that portion of the pulse cycle.
Another method is to increase plasma side pressure so that the blood in the downstream area of ~he membrane can be at pressure which is positive but lower than the upstream blood pressure and lower than the plasma side pressure. Other means will beeome apparent hereinafter. It is to be understood that said reduction need not occur simultaneously over the entire membrane, e.g., at any given inRtant, there may be areas on the membranQ with high transmembrane , :: :
2~
pressure difference and o~her areas with low transmembrane pressure difference and, at any given point on the membrane, the ~ransmembrane pressure difference may continuously fluctuate. Preferably, the transme~brane pressure difference i5 reduced to below zero, e.g., about -.1 to -3.0 p5i ( -- . 7 to -20.7 kPa), and, more preferably, to about -0.8 to -1.0 psi (-5.3 to -6O9 kPa). Preferably, a large amount of plasma backflow through the membrane is avoided.
The dura~ion of the reverse flow of blood is selected to main~ain substantially unimpaired flow of plasma ~hrough the membrane as well as to increase the distance which the blood travels across the mem-brane~ A wide ran~e of reverse flow durations are useful. The volume of blood flowed in the reverse direction is less than the volume of blood flowed forward.
It is to be understood that reverse flows of blood may begin in some regions of the flow paths prior to cessation of the forward flow of blood in other, or even in the same, regions, i.e., forward and reverse flows may overlap. It is preferred tha~
the frequency of the reciprocatory pulsations be low, but at least twenty, in the early stages cf a treatment and then be gradually raised to a desirable requency. It may be necessary to adjust the apparatus during a procedure to maintain desirable pressures and flows~
The blood which approaches the ends of each flow path is plasma-depleted blood. It is collected and conducted away from the membrane by any suitable means, as is the plasma which flows through the membrane.
The reciprocatory pulsations and transmembrane pressure difference reductions, as is apparent from the above discussion, can be carried out in numerous ways~ Typically, the means include a plurality of coordinated pumps and valves positioned - . : ., -on bloQd, plasma-depleted blood and/or plasma lines.
Pressure accum~lators, nr ~urye chamber~, may also be useful. Some Yuch useful mean~ are disclosed ln the ollowing examples, which are illus~rative only, of S treatm~nts in accordanse wi~h ~he Invention. ~ther means will be obvious to persons skilled in the art.
Referring ~o FIG. 1, a ~ ra~ion module, which may be u~ed wi~h reciproca~ory pulsa~ile flow and may have means for yeneratlng reciproca~ory pulsa~ions connected theretop comprises ~wo circular opposing mo~ule housing plates lA, lB which are prepared from a blood compa~ible material. A
circular blood flow region 2 is recessed within an opposing surface of one or both plates. Further reces3ed within each plate is a plasma flow region 3A, 3B. Typically, though not necessarily, the plasma flow region ~s of smaller diameter than the blood flow region.
The dep h of the plasma flow region is typically about 5 ts 20 mils ~127 to 508 ~m)~ The surface of the plasma flow region may be smooth or grooved to enhance radial flow of plasma. ~n the plasma flow region, or connected thereto, may be means f or treating the plasma f or the removal of 25 disease-contributing factors.
One or both plates lA, lB have plasma outlet ports 4A, ~B connected to the plasma flow regions 3A, 3B via a plasma collection channel around the plasma flow regions, e.g., about 3 mm deep and 1.5 mm wide.
30 There may be one or more of such ports in ei~her or both plates. The ports and channel may be located at any position but preferably, as herein illust:rated~
are located near the periphery of each plasma flow reg~ on.
. :
. ~
~96~
Near the center of plate LA is ~lood ~nlet port 5, the walls 6 of which extend through plasma flow region 3A ~o the blood flow region 20 Around tne periphery of blood flow region 2 is a plasma-depleted blood collection channel 7, This channel connec~s to one or more plasma-depleted blood outlet ports 8.
Within each plasma flow region is a plasma side membr3n~ suppor~ 9~f 9B which may be, e.g.~ a plate having ~rooves, pores or pro~ections nr fabric-like materials. hs illustrated, the plasma cide suppor~s are comprised of layer~ of fabric-like material~, such as layers of a nonwoven polyester fabric. The preferred support is three layers of 4 mil (102 ~m) thick ~ollytex, made by calendering Du Pont Reema~ spunbonded polyes~er, because it provides adequate support while allowin~ tran~verse and radial flow o~ plasma. The support 9A which fits in plasma flow region 3A is provided with an ap~rture which its around wall 6 of bl~od inlet port 5.
Within each blood flow region is a membrane lOA, lOB. Membrane lOA which fits in blood flow region 2 in plate lA is provided with an aperture which lies approxima~ely in regis~ry with bl~od inlet port 5.
The membr2nes lOA, 10~ are adhered to the plates near the peripheral edges of the membranes and, in the case of the membrane lOA, near the edge of the aperture in the membrane which is in registry with blood inlet port 5, with an elastomeric adhesive. Use of an elastomeric seal provides sufEicient flexibility to avoid rupture of tbe membranes during use. Th~ ar~as of membranes lOA, lOB which are adhered to plates lA, lB are identified in FIG. 1 by the number 11.
.
1~
It has been found that when thin polycarbonate or polyester mem~ranes which have low break elongation, l.e., le~s than about 40~r are employed in fllter modules in which, ~s herein S illustrated, the membranes are not rigldly ~upported a~ross a large part of their surface area~, it ig advantageous ~o employ an elastameric seaI be~ween the membrane3 and supports. Use of an elastomerlc ~eal provides sufficient flexibility ~o avoid rupture 10 of the membranes during use. When such membrane~ ar~
employed, ~he seal preferably has a break elon~ation of at least about 100%. The optimal break elongation will depend on several factors which ~ e obviou~
to persor~s skilled in the art, including the thickness of the seal. An elastcmer~c ~eal which has been found to perform well wi~h such membranes is an adhesive having a break elongation of about 400% and applied in a layer about 3 mils ~76 ~o) ~hick9 When the module is assembled, the corres~onding flow reqions of each plate are ad;acent. The plates are held together by any ~uitable means, e.g., clamp~, bolts and adhesives.
An O-ring 12 can be used to seal the plates. The region between ~he membranes is the blood flow pa~h.
The to~al effec~ive surface area of the membranes, i.e~, the sum o~ the areas on both membranes through whic~ plasma can flow, is about .02 to .06 m~.
Blood side supports 13 are located between the membranes. Blood side supports, though not necessary~ have been found to be advantageous when nonrigid plasma side supports, such as layers of ~ollytex, which may tend to buckle durin3 use, are employed. Various suitable supports are described in the literature. The illustrated and preferred suppor~s comprise a plurality of smooth pillars, , " , .
, ~ , : - '.
':.
e.9., substantlally c1rcular, do'cs of cured adhe~ive o~ the type used to adhere the membranes to 'che plates. These have sufficient sof tness ~o avoid breakage of the membranes during use.
FIG. 2 is an illustration of an embodiment of the inventiorl in whlch the filtration module of FIG. 1 ls used. The loop for generating r~ciprocatory pulsatlons as illu~trated herein is ~he inverl~ion of one other than ~he inventor herein.
la Blood is conducted from the source ~co ~he blood 10w path v~ a blood inlet port 5 in module housing plate lA. Plasma which passes through the membranes exi ~s ~rom 1:he module through a plasma ou~clet port ~A, and a second plasma outlet port ~ n4t shown .
15 Plasma-deple~ed blood from the end o the blood flow path exits from 'che module through plasma-deple~ed blood outle~ port 8. In addition, blood flow is pulsed in reciprocatory fashion by a peristaltic oscillator 15, which ~s connected to cen~ral and 2û peripheral porJcs 16 and 17 through loop 18, which per~pheral ports are connected to areas near an end of the flow- path, directly, or indirec~ly via a blood collection channel, not shown, The loop is preferably short so that blood in the loop is 25 f requently mixed and exchanged wi~h blood in the flow path . q`here pref erably ~s li ttle or no exchange of blood across the oscillator. Any suitable type o pump may be used to cause the reciproca~ory pulsations. Such p~nps axe described in the 3û literature and in the ~3xamples below; a peristaltic pump is preferred. Preferably, though not necessarily, the oscillator is connected ~o the ~lood flow path via one centrally located port and two peripherally lc~ated ports, a~ shown, s:~r to the blood 35 inlet and plasma-depleted blood outlet lines at a ~
' loca~ion close to the moduleO The duratlon and frequency of oscillations can be regulated by ad~usting ~che oscillator. The forward and reverse strokes are typically of equal volume.
FIG. 3 illustrates a module having an end plate, 1.~. 9 module housing plate, which has reciproca~ory pulse cavi~ies integral therewi~h, The end plate i8 ~he 3 nverltion o~ one o~her than tlle inventor hereln.
Blood is c:onducted into the module v~a an inlet, not shown, in end plate 19B and is condus::ted ~hrough a matched port 20 in end pla~e 19~lo From port ~0 in end pla~e l~A, ~he blood is con~ucted through ~hallow channel 21, O, 2 inch IS. l mm) wide x O. 06 inch (1. 5 ~n) deep, into inlet reciproca'cory pulse cavity 22 which has a volume o~ abou~ 3 mL and is about 2 inches ( S0. 8 mm) in diameter x 0~, 06 inch (1. S mm) deep O Cavi ty 22 is employed in ~he generat~on o~ recipl:ocatory pul~atlon~ as described below. From cavity 22, the blood i~ conducted through shallow channel 23t 0.5 inch (127 nm~ wide x 0013 incb (3.3 mm) deep, to blood flow path inle'c 24 whi~:h is about 0.38 inch (9. 7 mm) in diameterO The blood is conducted throu~h port 24 into a blood flow region between 'c~ membrane~ as described above.
Plasma-deple~e~l blood i~ conducted thrvugh flow path outlets 25 and through branch channels 26 to outlet reciproca~ory pulse cavi~y 27 in end plate 19~. The brancb channels from the four outlet3 25, which are equidistant from each other, begin as four channels each about .250 inch (6.4 mm) wide x .060 inch (1. 5 mm) deep and merge into ~wo channels each about . 500 inch (12. 7 mm) wide x . 060 inch (1. 5 nun) deep. The branch channel3 are of e~ual leng~h and cross-sectlor so as to produce substantially egual pressure conditions during use. Cavity 27 i8 also employed in the qeneration of reciprocatory pul~ations as described below~ From cavity 27, ~he plasma-depleted blood is conduc~ced ~hrough shallow channel 28, .200 S inch (5,.1 nun) wide x ~060 inch (1.5 mm) deep, and through plasma depleted bloo~ ou~let 29 which extends through a matched por~c in end plate 19B.
!~lasma which passes through 'cAe membranes flows radially in a plasma flow path and through a 10 plasma collection channel, as described above~ to an outlet port, no~ shown, in end plate l9B.
The en~i re modu~e is enclosed by enYelope 30 wbich is comprised of two shee~s of a flexibl~ blood impermeable material , such as poly (vinyl chloride), 15 ~he shee~s being joined toge~her at seal 31 arouns~
the perimet~r of the s~ack. The envelope thus provides a unitary flexible enclosure-for the module, The three apert ures irl end plate l9B mate with tube connectors in envelope 30.
13nvelope 30 coYers and seals the various channels; cavi~ies and apertures in end plate 19~ and forms a flexible diaphragm over each cavity 22, 27.
A perimeter lip, no~ shown, around each cavity and channel in end plate l9A aids in sealing.
Reciproca~ory pulsations are generated by alternately compressing the diaphraglll over each cavity 22, 27 such as by the use of reciprocating plunger~.
All of the above illustrated modules must be clamped using pressure which i-~ at least sufficient to offset internal pre~sure. In the examples, below, a series of C-clamps around the perimeter of each module was employed.
EXAIIPLES
In all of the following examples, which are 35 illustrative of single pa~s treatmen~s to separate ~;26~
plasma f rom blood in accord~nce s~ith the lnvention, compatibility-matched human blood coll~cted in ei~her ACD or hepa~in wa~ used. The hematocrit of the blood, which was maintained at 37C during treatment, 5 was 37~38%.
In all Examples, planar circular supported membranes were encased in membrane filter modules made from Du Pont Luf~te~ acrylic resin~ The membrane filter modules each compr ised two circular 10 discs between which were placed one or ~cwo supported membranes. Blood was fed to an inl~t port a~ ~he center of ~he module and conducted rad~ally therefrom across the surface of each membrane. Plasma-deple~:ed blood and plasma were collected by méans of 15 p~ripheral channels, cut into ~he discs, which led to outlet ports.
The membranes were polycarbonate capillary pore membranes, available from Nuclepore Corporatlon, having average c~ Æetaining pore diameters of about 20 0.4 ~Im and about 10% pore area and were about 10 ~Jm thick .
Three materials were alternatively used in ~he con~truction of membrane supports. One of these was ~ollyte~c and two were high density polyethylene.
25 ~ollytex is a nonwoven polyester fabric produced from layers of Du Pont Reemay~) spunbonded polyester by a calendering procedure. ~he Hollytex material was used in layers 10 mils (254 llm) or 4 mils tlO2 ~
~hick. The polyethylene materials were porous plates 30 about 6. 3 mils ~160. 0 lJm) thick; one had pores which were about 70 llm and ~he other, about 120 ~m, in diameter. Radial chamlels in the disc below the polyethylene plate allowed or lateral flow of plasma Prior to each 'creatment, the module was 35 purged of air by flushing with saline. The ~ollytex .
' ~ :
~upport3 were fir~t solvent-exchanged in isopropanol, soaked in saline and then placed wet ~.n the membrane filter module. The membrarle filter module was submerged in saline, 37C, during treatment to 5 prevent air leakage. Removing air from and maintaining air out of the apparat~s is important.
The transmembrane pressure dif~erence was measured by means of pressure straln gauge transducers and moni tored near the center and/or near 10 ~he peripher~ of the module and was recorded 7 usually at 5 to lû min. intervalsO The plasma side of the apparatus was vented, except where noted, and was assumed to be a~ atmospheric pressure.
~emolysis was determined by visual observation of sample8 of plasma periodically collected during each treatment.
The opera~ing conditions and results o~ each example are tabulated af ter a general descr iption of the apparatus used therein. Elapsed time is in 20 minutes and indicates the times during each treatment when measurements were taken. Peak and low pressures are in psig (kPa) and were measurPd near the indical~ed location~. Blood flow rate is thé rate of flow of whole blood ~rom the sou~ce to the module in 25 mL per min, Plasma flow rate is the flow rate of collected plasma in n~ per min. The hematocrit (~Ict . ) of plasma-depleted blood which was collected was calculated. Flux is mL of plasma collected per min. per cm2 of membrane filter.
30 EXAMPL~ lo This example illus~rates plasmapheres 1 by reciprocatory pulsatile filtration using two membranes in a membrane filter module such that blood is filtered by both membrane~ simultaneously.
Two layers of Hollytex w~ re placed b~tween 35 two membranes 80 ~hat blood ~lowed across the fir~t .. . . .
~ . ', ', ' . ', : , :
surfaces of both ~embranes wlthln recessed flow regions cut ~nto the inside surfaces of ~h~ ~isc and plasma which pa~sed through the membrane3 flowed radially through the ~upport between the membranes.
5 The blood flow paths were abou~ 8 mil~ (203~2 ~m3 in dep~h and had a combined surface area of ~bout .05 m2. Plasma-deple~ed blood from the ends of ~he flow paths was conducted fur~her through outle~ ports and collection tubing ~o a collection vess~l~
Blood was conducted forward and reverse by ~wo pumps which were similar ~o ~he hose pump deæcribed in ~OXo Specifica~on 2,020,735, published November 21, 1979, except that the ou~le~ valves were removed, and which were positioned between the blood ba~ and the membrane filter module. Each pump comprised an inle~ valve and a 4~ (10~2 ~m) plunger.
Th~ inlet valves were closed while the plungers were rising and were par~ially closed while ~he plungers w~re withdrawing so tha~ blood was ~onducted from the directions of the blood bag and of the membrane fil~er module as ~he plungers were withdrawing. The plunger~ never completely occluded the tubing. Each pump di~placed about 3.2 mL during each forward pulse.
Blood pa~sed fro~ the blood bag through a single tubing which was divided into two lines. ~ach line passed through one of the pumps and was rejoined into a single line.
Blood wa~ also conducted ~n the reverse direction by pressure which accumulated in a surge chambe~ of about 50 mL which was connected by tubing to the blood flow path at two locations near the end of the flow path.
A ~33 p~i ~2.3 kPa) check v~lve prevented back~low of blood to the blood bag. ~ control valve on the plasma-depleted blood collection line was ad~usted during the trea~men~ to control blood side pressures and transmembrane pressure difference.
Th~ oondi'cions and results of this example are in Table 1.
s lû
..
..
S X ~ ~ ~
:~ o ~ o o o C:~ o o o o ~ ........... ~
I ~ ~.a u~ ~D ~1 ~` O O ~ O
~ ~ o m ~ 0 U~
~ , n ~ ~0 ~ o a~ ~ ~ _ _ .~
~ ~ ., O O O
~ o CD
~ ~ ~ ~ O ~ ~ ~o ~ m JJ -J~ T ~
~ o a~
~1 ~ ~ I I I I ~ I I I
!~3 ~ ~ ô ~ ~ û~ U~
e~ o . . . . . .
2Q ~ ~ ;~ ~
g~ ~ ~ O ~ ~ ~ O S`
~ a ¦ --1 N C~ J ~`i t`i ~ ~ U~ ~
;i~l~ ~ o 0 o ~ Q~
for conductin~ blood forward at a net positive transmembrane pressure difference and reverse over a first surface of each membrane, means for collecting plasma which passes through each membrane from a second surface, i.e., a plasma side surface, thereof and means for collecting plasma~depleted blood from said first surface. The invention also resides in said apparatus comprising means for reducing the transmembrane pressure difference during periods of flow, preferably, means for reducing said pressure difference to below zero.
Further, the invention reside in the membrane filter module which comprises:
first and second opposing module housing plates having circular recesses within opposing surfaces so as to form a blood flow r~gion ~ between two plasma flow regions, there being a - central blood inlet port connected to the blood flow region;-a blood collection channel, around the blood flow region, connect to a plasma-d~pleted blood outlet port; and a plasma collection channel around each plasma flow region connected ko a plasma outlet port;
a plasma-side support within each plasma flow region; and 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.
The invent;on also resides in such a filtration module in which blood side supports are located between the membranes. Such module may have means for imparting reciprocatory pulsatile flow to blood in the 10w path connected thereto.
By comprises is meant that the invention includes the aforesaid steps and elements although it is to be understood that other steps and elements are S
. ~ :
no~ excluded from the invention, e~gD~ recycling ~he plasma-deple~ed blood, treating plasma during filtra-tion, diluting the blood with a compatible fluid and measuring various biologically ~ignificant fac~ors and means thereforu In the following description and examples of the inven~ion, the term ~forward~ is used to idicate a direction generally away from the source of blood;
reverse indicates a direction ger.erally towards the source of bloodO Transmembrane pressure difference is determined by subtracting the pressure on the plasma side, i.e.~ the second surface of the membrane, from the pressure on the blood side, i.e.~ the first surface of the membrane. It is to be understood that the transmembrane pressure varies across the membrane with the distance the blood has traveled from the source. Thus, with regard to this invention, since localized transmembrane pressure differences across the membrane may be eith~r positive or negative, only the system transmembrane pressure differences are reported, being referred to herein as net trans-membrane pressure differences. The term ~fouling~
is used to describe the impairment of plasma flow through a membrane~
In ~he invention, blood may be conducted in a forward direction in A flow path over the first surface of a membrane by any means which does not cause significant damage to cellular components, which does not cause significant discomfort or danger to a donor or patient, which provides sufficient forward flow rate and pressure to efficiently fractionate blood in the manner and under the conditions described below, and which allows the forward flow to be periodically interrupted as described below. Examples include variou~ pumps such as a rotary peristaltic pump, a piston or syr~nge pump, and a plunger or hose pump; even manually operated devices such as a flexible blood-containing chamber which can conduct blood forward when compr e s s ed may be u ~ ed .
The m~mbrane ls made of any ~ )d~compatible ma~erial, and has cell-retairling pores, i.20 ~ pores 5 which substantially retain cellular component~ but allow plasma to pass through ~uch pores are typically abou~ 0-1 ~o ~ . O ~n average di ~neter O The selection of a pore size may vary with the goal of a part:icular treatment. IJseful membranes are described in so~e of the above-ci~ed referenc~s relating ko plasmapheres 1 s . The membrane may be of any 5Ui ~able shape , e .g ., tubular , such as hollcw fibers or any planar sha~e. When planar membranes are used, membranes having low elongation , e .g ., less than 15 about 65%, h~gh modulus, e.g., at least about 10 kp~i (70 MPa), and high ~ensile strength, e.g., at lea~
about 3000 psi (20 MPa), when tested wet in accordance with standard procedure~, are pref~rred, because they are dimen~ionally stable. As exemplary of membranes having these preferxed properties are mentioned the ~T 450 polysulfone membrane commercially available from Gelman Sciences, Inc~ and the palyester and polyc rbonate membranes commer~ially available from Nuclepore Corpora~ionO
Of these, thin ; e .g ., less than about 1 mil (25 ~m), preferably les~ ~han 0. 5 mil (13 ~m), smoo~ch polycarbonate or polyes~er capillary pore membranes are preferred because, in laboratory experiment-~, such membranes were found, in general, to perform 30 better than the tortuou~ pa'ch membranes which were tested. Under various conditions of practice, however, any of the above-descrlbed or other types of membranes may prove to be more or le3s advantageous.
I is to be unders~ood that more than one membrane in 35 any arrangement may be used. Convenierltly, several membranes are stacked withln an enclosed module so that blood is fractionated by more than one membrane simultaneously. A planar membrane is preferably supported on the plasma side and more preferably on both sides by, e.g., supports comprising plates having grooves, pores or projec~ions or fabric-like materials. A preferred plasma side support comprises a plurality of layers of a nonwoven polyester fabric.
From the location at which the blood first contacts the membrane, which may or may not be near a point on an edge or end of the membrane, blood i5 conducted in a forward direction in one or more flow paths~ A flow path is the spac~ through which the blood flows on the first surface of the membrane.
lS For example, in a preferred embodiment, the membrane is planar and circular, the location at which the blood contacts the membrane is near the center thereof, and the flow path extends radially, ending -near the periphery of the membrane. It is apparent that~when the membrane is tubular and blood is conducted within the tube, the membrane may alone define the flow path. Typically the depth of blood in each flow path is less than about 30 mils ~G.76 mm). Preferably, said depth is also at least about 4 mils tO.10 mm) but, preferably no more than about 10 mils ( Or 25 mm) ~
The rate at which blood is conducted over the first surface of the membrane is at least as high as may be needed to provide a ne~ positive trans-membrane pressure difference. The flow velocitytypically varies during each period o fo~ward flow7 The preferred average orward flow rate from the source to the membrane is about S0 to 60 ~l-min~l when the source of blood is a vein of a normal human donor although the process may be carried out at higher or lower flow rates~
Plasma is driven through the cell-retaining pores in the membrane at a practical rate by a positive transmembrane pressure difference.
Typieally, positive transmern~rane pressure difference is generated primarily by resis~ance ~o for~ard flow~
but it can also be generated in other ways~ e.g., by decreasing pressure on the plasma on ~he second surface.
It has been found that the amount of transmembrane pressure differenee that can be with-stood by blood without hemolysis is largely a function of cell retaining pore size. For most purposes, the preferred pore diameter is about 074 to 0O~ ~m. In this range, a positive transmembrane pressure differ-ence of up to about 4 psi (28 kPa) is desirable although up to about 1.5 psi (10 kPa) is believed to be preferred. When the pore diame~er is smaller or largerr hi~her or lower transmembrane pressure dif-ferences, respectively, are acceptable. It is to-be understood that the pressure on the blood side and the plasma side surfaces, and the transmembrane-pressure difference, may vary during the course of a treatment and in different regions of the flow path.
After the conducting of blood over the first surface of the mem~rane with a positive transmembrane pressure difference is continued for some time, the membrane becomes progressively fouledv i.e., the flow of plasma through the membrane becomes increasingly impaired. The 1 ngth of time for which blood can be so conducted is beli~ved to depend upon several factors such as, e.g., flow velocity, hematocrit, pore size, transmembrane pressure difference, and the individual characteristics of the blood being treated.
The frequency and volume of the reciprocatory pulses are selected to maximize the flow of plasma through ~he membrane w thout causing extensive blood trauma.
In planar blood flow paths having a height of about 4 to 10 mils (100 to 254 ~m), a useful frequency and volume are about 20 to 140 pulsations per minute, preferably 40 to 80 pulsations per minute, and 0.5 to ~ mL per pulsation, perferably about 3 mL~ By pulsations per minute, also referred to herein as cycles per minute, is meant the number of tim~s per minute the blood is conducted throught a cycle, a cycle consisting of one forward movement and one reverse (backward) movement of blood across the membrane. Said parameters should be selected to provide a mean linear velocity up to about 400 mm-sec~l, preferably, up to about 250 mm sec~l.
These parameteres may be adjusted during a particular treatmen~, but conveniently may be selected and fixed ~or an entire treatment.
After the forward conducting of blood is terminated, blood is conducted in the reverse direc-tion in each flow pathO The termination of forwardflow and the conducting of blood in the reverse direction need not occur simulataneously over the entire membrane. Because blood is conducted in for-ward and reverse direction with a ne~ forward flow during the procedure, the blood flow is referred to as reciprocatory pulsatile flow.
In a preferred embodiment, the transmembrane pressure difference is reduced when conducting blood in either direction. The preferred method is by using a pulse pump connected to the module blood inlet and outlet. The pulse pump suction produces a negative pressure at peak flow rate over the portion of the filtration membrane from which pulse blood is being drawn for that portion of the pulse cycle.
Another method is to increase plasma side pressure so that the blood in the downstream area of ~he membrane can be at pressure which is positive but lower than the upstream blood pressure and lower than the plasma side pressure. Other means will beeome apparent hereinafter. It is to be understood that said reduction need not occur simultaneously over the entire membrane, e.g., at any given inRtant, there may be areas on the membranQ with high transmembrane , :: :
2~
pressure difference and o~her areas with low transmembrane pressure difference and, at any given point on the membrane, the ~ransmembrane pressure difference may continuously fluctuate. Preferably, the transme~brane pressure difference i5 reduced to below zero, e.g., about -.1 to -3.0 p5i ( -- . 7 to -20.7 kPa), and, more preferably, to about -0.8 to -1.0 psi (-5.3 to -6O9 kPa). Preferably, a large amount of plasma backflow through the membrane is avoided.
The dura~ion of the reverse flow of blood is selected to main~ain substantially unimpaired flow of plasma ~hrough the membrane as well as to increase the distance which the blood travels across the mem-brane~ A wide ran~e of reverse flow durations are useful. The volume of blood flowed in the reverse direction is less than the volume of blood flowed forward.
It is to be understood that reverse flows of blood may begin in some regions of the flow paths prior to cessation of the forward flow of blood in other, or even in the same, regions, i.e., forward and reverse flows may overlap. It is preferred tha~
the frequency of the reciprocatory pulsations be low, but at least twenty, in the early stages cf a treatment and then be gradually raised to a desirable requency. It may be necessary to adjust the apparatus during a procedure to maintain desirable pressures and flows~
The blood which approaches the ends of each flow path is plasma-depleted blood. It is collected and conducted away from the membrane by any suitable means, as is the plasma which flows through the membrane.
The reciprocatory pulsations and transmembrane pressure difference reductions, as is apparent from the above discussion, can be carried out in numerous ways~ Typically, the means include a plurality of coordinated pumps and valves positioned - . : ., -on bloQd, plasma-depleted blood and/or plasma lines.
Pressure accum~lators, nr ~urye chamber~, may also be useful. Some Yuch useful mean~ are disclosed ln the ollowing examples, which are illus~rative only, of S treatm~nts in accordanse wi~h ~he Invention. ~ther means will be obvious to persons skilled in the art.
Referring ~o FIG. 1, a ~ ra~ion module, which may be u~ed wi~h reciproca~ory pulsa~ile flow and may have means for yeneratlng reciproca~ory pulsa~ions connected theretop comprises ~wo circular opposing mo~ule housing plates lA, lB which are prepared from a blood compa~ible material. A
circular blood flow region 2 is recessed within an opposing surface of one or both plates. Further reces3ed within each plate is a plasma flow region 3A, 3B. Typically, though not necessarily, the plasma flow region ~s of smaller diameter than the blood flow region.
The dep h of the plasma flow region is typically about 5 ts 20 mils ~127 to 508 ~m)~ The surface of the plasma flow region may be smooth or grooved to enhance radial flow of plasma. ~n the plasma flow region, or connected thereto, may be means f or treating the plasma f or the removal of 25 disease-contributing factors.
One or both plates lA, lB have plasma outlet ports 4A, ~B connected to the plasma flow regions 3A, 3B via a plasma collection channel around the plasma flow regions, e.g., about 3 mm deep and 1.5 mm wide.
30 There may be one or more of such ports in ei~her or both plates. The ports and channel may be located at any position but preferably, as herein illust:rated~
are located near the periphery of each plasma flow reg~ on.
. :
. ~
~96~
Near the center of plate LA is ~lood ~nlet port 5, the walls 6 of which extend through plasma flow region 3A ~o the blood flow region 20 Around tne periphery of blood flow region 2 is a plasma-depleted blood collection channel 7, This channel connec~s to one or more plasma-depleted blood outlet ports 8.
Within each plasma flow region is a plasma side membr3n~ suppor~ 9~f 9B which may be, e.g.~ a plate having ~rooves, pores or pro~ections nr fabric-like materials. hs illustrated, the plasma cide suppor~s are comprised of layer~ of fabric-like material~, such as layers of a nonwoven polyester fabric. The preferred support is three layers of 4 mil (102 ~m) thick ~ollytex, made by calendering Du Pont Reema~ spunbonded polyes~er, because it provides adequate support while allowin~ tran~verse and radial flow o~ plasma. The support 9A which fits in plasma flow region 3A is provided with an ap~rture which its around wall 6 of bl~od inlet port 5.
Within each blood flow region is a membrane lOA, lOB. Membrane lOA which fits in blood flow region 2 in plate lA is provided with an aperture which lies approxima~ely in regis~ry with bl~od inlet port 5.
The membr2nes lOA, 10~ are adhered to the plates near the peripheral edges of the membranes and, in the case of the membrane lOA, near the edge of the aperture in the membrane which is in registry with blood inlet port 5, with an elastomeric adhesive. Use of an elastomeric seal provides sufEicient flexibility to avoid rupture of tbe membranes during use. Th~ ar~as of membranes lOA, lOB which are adhered to plates lA, lB are identified in FIG. 1 by the number 11.
.
1~
It has been found that when thin polycarbonate or polyester mem~ranes which have low break elongation, l.e., le~s than about 40~r are employed in fllter modules in which, ~s herein S illustrated, the membranes are not rigldly ~upported a~ross a large part of their surface area~, it ig advantageous ~o employ an elastameric seaI be~ween the membrane3 and supports. Use of an elastomerlc ~eal provides sufficient flexibility ~o avoid rupture 10 of the membranes during use. When such membrane~ ar~
employed, ~he seal preferably has a break elon~ation of at least about 100%. The optimal break elongation will depend on several factors which ~ e obviou~
to persor~s skilled in the art, including the thickness of the seal. An elastcmer~c ~eal which has been found to perform well wi~h such membranes is an adhesive having a break elongation of about 400% and applied in a layer about 3 mils ~76 ~o) ~hick9 When the module is assembled, the corres~onding flow reqions of each plate are ad;acent. The plates are held together by any ~uitable means, e.g., clamp~, bolts and adhesives.
An O-ring 12 can be used to seal the plates. The region between ~he membranes is the blood flow pa~h.
The to~al effec~ive surface area of the membranes, i.e~, the sum o~ the areas on both membranes through whic~ plasma can flow, is about .02 to .06 m~.
Blood side supports 13 are located between the membranes. Blood side supports, though not necessary~ have been found to be advantageous when nonrigid plasma side supports, such as layers of ~ollytex, which may tend to buckle durin3 use, are employed. Various suitable supports are described in the literature. The illustrated and preferred suppor~s comprise a plurality of smooth pillars, , " , .
, ~ , : - '.
':.
e.9., substantlally c1rcular, do'cs of cured adhe~ive o~ the type used to adhere the membranes to 'che plates. These have sufficient sof tness ~o avoid breakage of the membranes during use.
FIG. 2 is an illustration of an embodiment of the inventiorl in whlch the filtration module of FIG. 1 ls used. The loop for generating r~ciprocatory pulsatlons as illu~trated herein is ~he inverl~ion of one other than ~he inventor herein.
la Blood is conducted from the source ~co ~he blood 10w path v~ a blood inlet port 5 in module housing plate lA. Plasma which passes through the membranes exi ~s ~rom 1:he module through a plasma ou~clet port ~A, and a second plasma outlet port ~ n4t shown .
15 Plasma-deple~ed blood from the end o the blood flow path exits from 'che module through plasma-deple~ed blood outle~ port 8. In addition, blood flow is pulsed in reciprocatory fashion by a peristaltic oscillator 15, which ~s connected to cen~ral and 2û peripheral porJcs 16 and 17 through loop 18, which per~pheral ports are connected to areas near an end of the flow- path, directly, or indirec~ly via a blood collection channel, not shown, The loop is preferably short so that blood in the loop is 25 f requently mixed and exchanged wi~h blood in the flow path . q`here pref erably ~s li ttle or no exchange of blood across the oscillator. Any suitable type o pump may be used to cause the reciproca~ory pulsations. Such p~nps axe described in the 3û literature and in the ~3xamples below; a peristaltic pump is preferred. Preferably, though not necessarily, the oscillator is connected ~o the ~lood flow path via one centrally located port and two peripherally lc~ated ports, a~ shown, s:~r to the blood 35 inlet and plasma-depleted blood outlet lines at a ~
' loca~ion close to the moduleO The duratlon and frequency of oscillations can be regulated by ad~usting ~che oscillator. The forward and reverse strokes are typically of equal volume.
FIG. 3 illustrates a module having an end plate, 1.~. 9 module housing plate, which has reciproca~ory pulse cavi~ies integral therewi~h, The end plate i8 ~he 3 nverltion o~ one o~her than tlle inventor hereln.
Blood is c:onducted into the module v~a an inlet, not shown, in end plate 19B and is condus::ted ~hrough a matched port 20 in end pla~e 19~lo From port ~0 in end pla~e l~A, ~he blood is con~ucted through ~hallow channel 21, O, 2 inch IS. l mm) wide x O. 06 inch (1. 5 ~n) deep, into inlet reciproca'cory pulse cavity 22 which has a volume o~ abou~ 3 mL and is about 2 inches ( S0. 8 mm) in diameter x 0~, 06 inch (1. S mm) deep O Cavi ty 22 is employed in ~he generat~on o~ recipl:ocatory pul~atlon~ as described below. From cavity 22, the blood i~ conducted through shallow channel 23t 0.5 inch (127 nm~ wide x 0013 incb (3.3 mm) deep, to blood flow path inle'c 24 whi~:h is about 0.38 inch (9. 7 mm) in diameterO The blood is conducted throu~h port 24 into a blood flow region between 'c~ membrane~ as described above.
Plasma-deple~e~l blood i~ conducted thrvugh flow path outlets 25 and through branch channels 26 to outlet reciproca~ory pulse cavi~y 27 in end plate 19~. The brancb channels from the four outlet3 25, which are equidistant from each other, begin as four channels each about .250 inch (6.4 mm) wide x .060 inch (1. 5 mm) deep and merge into ~wo channels each about . 500 inch (12. 7 mm) wide x . 060 inch (1. 5 nun) deep. The branch channel3 are of e~ual leng~h and cross-sectlor so as to produce substantially egual pressure conditions during use. Cavity 27 i8 also employed in the qeneration of reciprocatory pul~ations as described below~ From cavity 27, ~he plasma-depleted blood is conduc~ced ~hrough shallow channel 28, .200 S inch (5,.1 nun) wide x ~060 inch (1.5 mm) deep, and through plasma depleted bloo~ ou~let 29 which extends through a matched por~c in end plate 19B.
!~lasma which passes through 'cAe membranes flows radially in a plasma flow path and through a 10 plasma collection channel, as described above~ to an outlet port, no~ shown, in end plate l9B.
The en~i re modu~e is enclosed by enYelope 30 wbich is comprised of two shee~s of a flexibl~ blood impermeable material , such as poly (vinyl chloride), 15 ~he shee~s being joined toge~her at seal 31 arouns~
the perimet~r of the s~ack. The envelope thus provides a unitary flexible enclosure-for the module, The three apert ures irl end plate l9B mate with tube connectors in envelope 30.
13nvelope 30 coYers and seals the various channels; cavi~ies and apertures in end plate 19~ and forms a flexible diaphragm over each cavity 22, 27.
A perimeter lip, no~ shown, around each cavity and channel in end plate l9A aids in sealing.
Reciproca~ory pulsations are generated by alternately compressing the diaphraglll over each cavity 22, 27 such as by the use of reciprocating plunger~.
All of the above illustrated modules must be clamped using pressure which i-~ at least sufficient to offset internal pre~sure. In the examples, below, a series of C-clamps around the perimeter of each module was employed.
EXAIIPLES
In all of the following examples, which are 35 illustrative of single pa~s treatmen~s to separate ~;26~
plasma f rom blood in accord~nce s~ith the lnvention, compatibility-matched human blood coll~cted in ei~her ACD or hepa~in wa~ used. The hematocrit of the blood, which was maintained at 37C during treatment, 5 was 37~38%.
In all Examples, planar circular supported membranes were encased in membrane filter modules made from Du Pont Luf~te~ acrylic resin~ The membrane filter modules each compr ised two circular 10 discs between which were placed one or ~cwo supported membranes. Blood was fed to an inl~t port a~ ~he center of ~he module and conducted rad~ally therefrom across the surface of each membrane. Plasma-deple~:ed blood and plasma were collected by méans of 15 p~ripheral channels, cut into ~he discs, which led to outlet ports.
The membranes were polycarbonate capillary pore membranes, available from Nuclepore Corporatlon, having average c~ Æetaining pore diameters of about 20 0.4 ~Im and about 10% pore area and were about 10 ~Jm thick .
Three materials were alternatively used in ~he con~truction of membrane supports. One of these was ~ollyte~c and two were high density polyethylene.
25 ~ollytex is a nonwoven polyester fabric produced from layers of Du Pont Reemay~) spunbonded polyester by a calendering procedure. ~he Hollytex material was used in layers 10 mils (254 llm) or 4 mils tlO2 ~
~hick. The polyethylene materials were porous plates 30 about 6. 3 mils ~160. 0 lJm) thick; one had pores which were about 70 llm and ~he other, about 120 ~m, in diameter. Radial chamlels in the disc below the polyethylene plate allowed or lateral flow of plasma Prior to each 'creatment, the module was 35 purged of air by flushing with saline. The ~ollytex .
' ~ :
~upport3 were fir~t solvent-exchanged in isopropanol, soaked in saline and then placed wet ~.n the membrane filter module. The membrarle filter module was submerged in saline, 37C, during treatment to 5 prevent air leakage. Removing air from and maintaining air out of the apparat~s is important.
The transmembrane pressure dif~erence was measured by means of pressure straln gauge transducers and moni tored near the center and/or near 10 ~he peripher~ of the module and was recorded 7 usually at 5 to lû min. intervalsO The plasma side of the apparatus was vented, except where noted, and was assumed to be a~ atmospheric pressure.
~emolysis was determined by visual observation of sample8 of plasma periodically collected during each treatment.
The opera~ing conditions and results o~ each example are tabulated af ter a general descr iption of the apparatus used therein. Elapsed time is in 20 minutes and indicates the times during each treatment when measurements were taken. Peak and low pressures are in psig (kPa) and were measurPd near the indical~ed location~. Blood flow rate is thé rate of flow of whole blood ~rom the sou~ce to the module in 25 mL per min, Plasma flow rate is the flow rate of collected plasma in n~ per min. The hematocrit (~Ict . ) of plasma-depleted blood which was collected was calculated. Flux is mL of plasma collected per min. per cm2 of membrane filter.
30 EXAMPL~ lo This example illus~rates plasmapheres 1 by reciprocatory pulsatile filtration using two membranes in a membrane filter module such that blood is filtered by both membrane~ simultaneously.
Two layers of Hollytex w~ re placed b~tween 35 two membranes 80 ~hat blood ~lowed across the fir~t .. . . .
~ . ', ', ' . ', : , :
surfaces of both ~embranes wlthln recessed flow regions cut ~nto the inside surfaces of ~h~ ~isc and plasma which pa~sed through the membrane3 flowed radially through the ~upport between the membranes.
5 The blood flow paths were abou~ 8 mil~ (203~2 ~m3 in dep~h and had a combined surface area of ~bout .05 m2. Plasma-deple~ed blood from the ends of ~he flow paths was conducted fur~her through outle~ ports and collection tubing ~o a collection vess~l~
Blood was conducted forward and reverse by ~wo pumps which were similar ~o ~he hose pump deæcribed in ~OXo Specifica~on 2,020,735, published November 21, 1979, except that the ou~le~ valves were removed, and which were positioned between the blood ba~ and the membrane filter module. Each pump comprised an inle~ valve and a 4~ (10~2 ~m) plunger.
Th~ inlet valves were closed while the plungers were rising and were par~ially closed while ~he plungers w~re withdrawing so tha~ blood was ~onducted from the directions of the blood bag and of the membrane fil~er module as ~he plungers were withdrawing. The plunger~ never completely occluded the tubing. Each pump di~placed about 3.2 mL during each forward pulse.
Blood pa~sed fro~ the blood bag through a single tubing which was divided into two lines. ~ach line passed through one of the pumps and was rejoined into a single line.
Blood wa~ also conducted ~n the reverse direction by pressure which accumulated in a surge chambe~ of about 50 mL which was connected by tubing to the blood flow path at two locations near the end of the flow path.
A ~33 p~i ~2.3 kPa) check v~lve prevented back~low of blood to the blood bag. ~ control valve on the plasma-depleted blood collection line was ad~usted during the trea~men~ to control blood side pressures and transmembrane pressure difference.
Th~ oondi'cions and results of this example are in Table 1.
s lû
..
..
S X ~ ~ ~
:~ o ~ o o o C:~ o o o o ~ ........... ~
I ~ ~.a u~ ~D ~1 ~` O O ~ O
~ ~ o m ~ 0 U~
~ , n ~ ~0 ~ o a~ ~ ~ _ _ .~
~ ~ ., O O O
~ o CD
~ ~ ~ ~ O ~ ~ ~o ~ m JJ -J~ T ~
~ o a~
~1 ~ ~ I I I I ~ I I I
!~3 ~ ~ ô ~ ~ û~ U~
e~ o . . . . . .
2Q ~ ~ ;~ ~
g~ ~ ~ O ~ ~ ~ O S`
~ a ¦ --1 N C~ J ~`i t`i ~ ~ U~ ~
;i~l~ ~ o 0 o ~ Q~
3~ H ~ ~ ~ ~ ~ ~ 0 2 5 ~o o ~ u~ ~ ~ a~ ~ l~ ~` ~
~ ~ ~ ~; 0 ~ o ~ ~ o u~ uO
~1 ~ ns ~ ~ u~ ~ t~ ~ ~ r~ r~ o ~Q ~
~ d~
~ o o o o ~ o o o ~ _ o U~ o o U~ o U~
O u~, O O
.
2~
No hemolysis was observed during ~he flrs~
39.5 minu~es. Hemolysis was o~served during the period when the frequency of pulsations was lncreased to 100 as a resul~, it i5 believed, o ~he hlgh 5 frequency and the high p~ak transmembrane pressure difference. After the pump speed and pressure were reduced, the pl~sma began to clear, i nd~catin~ that hemoly~is had cea~ed or was lessening.
EX~MPLE 2. This example illustrates plasmapheresi~
10 by reciprocatory pulsatile filtration as per the 1 nvention using a single membrane .
The membrane was support~d by a polyethylene plate tl20 ~Im pores~. The ~low path surfac:e area was about .013 m~. The depth of the flow path was 15 about 5 mils ~152 ~Jm) from the cen~er ~chereof to a point along its radius abouJc 3.25~ (8. 3 cm) therefrom, from which poin~, the dep~b ~apered ~o abou~ 9 mils (229 llm) at the end of the flo~ pa~ch.
The peripheral edge of ~he membrane was pre~sed 20 between the discs. Blood flowed radially across the first ~urface of the membrane while plasma which passed through the membrane pas~ed through the pores in 'che polyethylene plate and flowed radially in a pla~ma ~low region cut into the inside surface of ~he 25 plasma-side disc.
Reciprocatory pulsa~cili ty and reductions in transmembrane pressure difference were provide~ by a peristaltic rotary pump which was modified by removal of all but one of the rollers therein. The circular 30 path of the roller was about 5. 38" (13. 65 cm) of which th~ roller occlud0d the tubing for about 5,25H
(13.34 cm); the tubing was .13" (.32 cn~) rD ~ilicon tubing. There~ore, the d~splacement of ~he pump~
which was set at 60 rpm, was about lol mL~
.
, A check valve and plasma-depleted blood contrQl valve were used~
~ he peak plasma side pressure remained at about 1.0 psi (6.9 kPa) at the center and periphery 5 of ~he module; the low plasma side pressure was about 0 to 0.3 psi (0 to 2.1 kPa) at the center and per iphery.
~ o hemolysis was observed. The conditions and results of this example are in Table 2.
. . :
. ' ' . ' .
~- ~ ~J `~ J G~ p~ J
2 ~
o o C~ o ~ o .. . . . .
J ei~ O ~
v C~i ~rt C:) U') 1~) ~ ~ ~ ~ ~ ~ U~
~ ~ co ~
15 .L~ 0 ~ ~P ~9 0 ~ U~
:1 ~3 ~_ m ~ o O
20 ~ ~
_ ,~, _ _~ _ ~a Q~
~ ~ u~
25 " ~ I _~ ^ ô
U~
~E~
. .
, ., . ~ .
EX~MæL~ 3. This example illus~rates that rec1procatory pulsa~ile flow during plasmapheresis can result in an improved eate of plasma separation per unit area of membrane as compared to pulsatile 5 flow without reciprocatory pulsations.
The membrane filter module was the same as in Example 2 except that the enti re ~low path depth was about 6 mils (152 ~m) in depth and the porous plate had pores which were about 70 ~m in diameterO
Initially, bl~od was conducted forward by a pressure infuser cuff wrapped around ~he blood bag.
A 0.5~ ~1.3 cm~ ID control valve posit~oned between the bag and the module was opened and closed at various intervals (reported in seconds) ~o generate 15 pulsatile flow. Af~er some time, the infuser cuff was removed and the rotary pUMp descr ibed above in Example 2 was utilized. Then the ro~cary pump was . disconnected and the infuser cuff system was restored.
The conditions and resul~s of this example 20 are in Table 3.
, ~ , ' :
: ' ~
: .
xu~ ~ o` `o ~ ~ ~ u~
o g ~D O1~ a ~ o o a`
O ~ D
i~ p w ~ ~ ~ ~ ~Po ~ ~, ? ,~, 7 ~ ~ ~
~ ~
~ H~ P 3D U7 ~ N
2 3 ~~ `' ~ N
_ a~
~ H~7 ~ ~r ~ ~ ~ ~
2 5 ~ N
~2 ~ ~ ~ ~o ~ ~ ~ ~
~ o 3 ~ æ ~ æ ~
~- ~
$
. .
, -' - ~ ' ' ' : .'' .
,, ~8 - Hemoly~is was observed to result when pulsations were generated by the infuser cuff~valve system but not when reciproca~ory pulsations were generated by the rotary pump.
~XAMPLE 4. In ~his example, modules su~s~an~ially as illustrated in FIGS. 1 and 2 were employ~d. The membranPs were 7 inches (178 mm) ~n diameter, and provided a total membrane surface area of about . 05 m . The membranes were adhered to circular plates, made from Du Pont Lucite~) acrylic resin, with Gener~ lectr ic RTV 102 silic:on adhesive which had a break elongation of 400%, a tensile strength of 350 psi (204 MPa), and a Shore A hardness of 30. The adhe~ive was applied by hand in a layer about 3 mils 15 (76 ym) thick.
The same adhesive was used to form blood side suppor~s by placing dots of the adhesive, between the membranes in two concentric circles. The blood flow path between the membranes was abou~ 8 mils (.20 mm) deep~ The adhesive suppor~s were cured on the blood side surface of one membrane at 60C
oYernight prior to assembly of the module. The plates were held together with clamps, without 0-rings~
The blood was condu~ted forward by a 3-arm rotary peris~altic pump. A .33 psi (2.3 x 103 Pa) check valve was located between th is pusnp and the blood reservoir.
Reciprocatory pulsations and pressure fluctuations were provided by a modified per istaltic pump, positioned on a l~op, i.e., a length of tubing~
which extended from two peripherally located por~s and one centrally located por t .. The pump was modified so ~hat a single roller, in constan~ contact with ~he tubing, oscillated in about a 50 mm s~roke 2g %~
- at about ~0 cycles-min 1, thereby displacing about 1.6 mL per s~roke. A micrometer control Yalve was placed on the plasma-depleted blood ou~let line and was adjusted during the treatment.
Re~ults and conditions of this treatmen~ are summarized in Table 4. No hemolysis was observed.
' .
3~
,~
o o o o o o o _î
C
u~
,~ ~ r ~ 0 ~J ~ ~
~ i I
~ u~
~q ~ U~
~1~ ~ ~1 7 ,~
~ o ~
P~ ~ _l ~ o o ~ In : e a) ~ _I ~ ~ ~ c~
D ~ _ _ _ _ _ ~ ~ ~ ~` ~ ~D ~
~ u~oo~a . ,.~ ~ ~ ~ ~a ~
~
.q ~æ~
~3 ^o u~ u~ o o u~
~, ~ C
- '~ '., ' .
EXAMPLE 5. The apparatus used in this example was identical to that described above in Example 4 except that the module was smaller, the membranes being about 6 inches (152 mm) in diameter and providing a 5 total membrane surface area of about .04 m .
Results and conditions of ~his treatment are summarized in Table 5O No hemolysis was observed.
.
:
~ ~ ~ ~ r~l ~
~ o o o o c:~
~ . . ~ ~ .
v ~
~ ~ ~ ~ ~ c~ ~
3 ~
~ '~c ~ ~ t~ o ~
10 ~ ~ ~
U~ o ,, ~ _, ~ ~ o ~
~ _ ~ _ ~
1~ ~ a~
U~ ~ ~ ~ ~ o ~ o~
~ ~ ~ ,', ~
. a. J~ Q~
a~ ~ ~ ,~
o _, _ _ , _ _ 20 ~ x ~- s~ o ~ u~ cr ~ s~ ~ ~~ ~ ~
lY ~
~ o~
~
~ ~ ~ O O
~ ~, 30 ~ ~ o o ~n o u~
~ æ
.
, . ~ .
, ~2~
EXAMPLE 6. The apparatus used in ~his ex~mple was subs~antially identical to 'chat described in Example 5 . The stroke leng~ch of the osci llating pump was varied during ~che treatmen~. The oscillator was 5 turned off for a three minu~ce interval so ~hatt during this period, blood was being conduc~ed Eorward only. The inlet hematocr it was 37% .
~ esults and conditlons of this ~creatment are summarized in Table 6n Slight hemolysis was briefly lG observed when the s~roke leng~h was changed from four inches (101 mm) to three inches ( 76 mm) and again when the oscillator was ~urned on after the one minute in~erval of constant flow.
3~
~ I o o o o ~ o o a) ~ I ~ o 1~ U~ a) ~ o 1 0 â~
~1 c~
~ ~ v ~ ~1 1 ~ )~o `I ,~ ~
~ . _I CO ~ _1 N ~ ~
3~ ~ 1` a) u~ ~ ~
~ '` ~
~ u~
;~ ~ ~ co m ~o~ ` ~
C~ ~ o o ~ ~
- . . . ~ .
.
', . . ~ ". " . . ' ' - ' , ' . ' ' ~2~
BEST MODE
The ~est mode for carrying out the invention is illustrated generally by Examples ~ and 5.
UTILITY
The process and appara~us of the invention have several useful applications including the treatment o certain disease states by plasma exchange or plasma therapy, the collection of plasma for various tr~nsfusion needs, for further fractionation to isolate specific serum proteins, and ~or the production of cell culture media. The invention is particularly useful ~or continuous plasmapheres is, This application is a division of copending Canadian Patent Application Serial No. 407,621, filed ~982 July 20.
~0 , ~ :,''. .
:' ;, , ,
~ ~ ~ ~; 0 ~ o ~ ~ o u~ uO
~1 ~ ns ~ ~ u~ ~ t~ ~ ~ r~ r~ o ~Q ~
~ d~
~ o o o o ~ o o o ~ _ o U~ o o U~ o U~
O u~, O O
.
2~
No hemolysis was observed during ~he flrs~
39.5 minu~es. Hemolysis was o~served during the period when the frequency of pulsations was lncreased to 100 as a resul~, it i5 believed, o ~he hlgh 5 frequency and the high p~ak transmembrane pressure difference. After the pump speed and pressure were reduced, the pl~sma began to clear, i nd~catin~ that hemoly~is had cea~ed or was lessening.
EX~MPLE 2. This example illustrates plasmapheresi~
10 by reciprocatory pulsatile filtration as per the 1 nvention using a single membrane .
The membrane was support~d by a polyethylene plate tl20 ~Im pores~. The ~low path surfac:e area was about .013 m~. The depth of the flow path was 15 about 5 mils ~152 ~Jm) from the cen~er ~chereof to a point along its radius abouJc 3.25~ (8. 3 cm) therefrom, from which poin~, the dep~b ~apered ~o abou~ 9 mils (229 llm) at the end of the flo~ pa~ch.
The peripheral edge of ~he membrane was pre~sed 20 between the discs. Blood flowed radially across the first ~urface of the membrane while plasma which passed through the membrane pas~ed through the pores in 'che polyethylene plate and flowed radially in a pla~ma ~low region cut into the inside surface of ~he 25 plasma-side disc.
Reciprocatory pulsa~cili ty and reductions in transmembrane pressure difference were provide~ by a peristaltic rotary pump which was modified by removal of all but one of the rollers therein. The circular 30 path of the roller was about 5. 38" (13. 65 cm) of which th~ roller occlud0d the tubing for about 5,25H
(13.34 cm); the tubing was .13" (.32 cn~) rD ~ilicon tubing. There~ore, the d~splacement of ~he pump~
which was set at 60 rpm, was about lol mL~
.
, A check valve and plasma-depleted blood contrQl valve were used~
~ he peak plasma side pressure remained at about 1.0 psi (6.9 kPa) at the center and periphery 5 of ~he module; the low plasma side pressure was about 0 to 0.3 psi (0 to 2.1 kPa) at the center and per iphery.
~ o hemolysis was observed. The conditions and results of this example are in Table 2.
. . :
. ' ' . ' .
~- ~ ~J `~ J G~ p~ J
2 ~
o o C~ o ~ o .. . . . .
J ei~ O ~
v C~i ~rt C:) U') 1~) ~ ~ ~ ~ ~ ~ U~
~ ~ co ~
15 .L~ 0 ~ ~P ~9 0 ~ U~
:1 ~3 ~_ m ~ o O
20 ~ ~
_ ,~, _ _~ _ ~a Q~
~ ~ u~
25 " ~ I _~ ^ ô
U~
~E~
. .
, ., . ~ .
EX~MæL~ 3. This example illus~rates that rec1procatory pulsa~ile flow during plasmapheresis can result in an improved eate of plasma separation per unit area of membrane as compared to pulsatile 5 flow without reciprocatory pulsations.
The membrane filter module was the same as in Example 2 except that the enti re ~low path depth was about 6 mils (152 ~m) in depth and the porous plate had pores which were about 70 ~m in diameterO
Initially, bl~od was conducted forward by a pressure infuser cuff wrapped around ~he blood bag.
A 0.5~ ~1.3 cm~ ID control valve posit~oned between the bag and the module was opened and closed at various intervals (reported in seconds) ~o generate 15 pulsatile flow. Af~er some time, the infuser cuff was removed and the rotary pUMp descr ibed above in Example 2 was utilized. Then the ro~cary pump was . disconnected and the infuser cuff system was restored.
The conditions and resul~s of this example 20 are in Table 3.
, ~ , ' :
: ' ~
: .
xu~ ~ o` `o ~ ~ ~ u~
o g ~D O1~ a ~ o o a`
O ~ D
i~ p w ~ ~ ~ ~ ~Po ~ ~, ? ,~, 7 ~ ~ ~
~ ~
~ H~ P 3D U7 ~ N
2 3 ~~ `' ~ N
_ a~
~ H~7 ~ ~r ~ ~ ~ ~
2 5 ~ N
~2 ~ ~ ~ ~o ~ ~ ~ ~
~ o 3 ~ æ ~ æ ~
~- ~
$
. .
, -' - ~ ' ' ' : .'' .
,, ~8 - Hemoly~is was observed to result when pulsations were generated by the infuser cuff~valve system but not when reciproca~ory pulsations were generated by the rotary pump.
~XAMPLE 4. In ~his example, modules su~s~an~ially as illustrated in FIGS. 1 and 2 were employ~d. The membranPs were 7 inches (178 mm) ~n diameter, and provided a total membrane surface area of about . 05 m . The membranes were adhered to circular plates, made from Du Pont Lucite~) acrylic resin, with Gener~ lectr ic RTV 102 silic:on adhesive which had a break elongation of 400%, a tensile strength of 350 psi (204 MPa), and a Shore A hardness of 30. The adhe~ive was applied by hand in a layer about 3 mils 15 (76 ym) thick.
The same adhesive was used to form blood side suppor~s by placing dots of the adhesive, between the membranes in two concentric circles. The blood flow path between the membranes was abou~ 8 mils (.20 mm) deep~ The adhesive suppor~s were cured on the blood side surface of one membrane at 60C
oYernight prior to assembly of the module. The plates were held together with clamps, without 0-rings~
The blood was condu~ted forward by a 3-arm rotary peris~altic pump. A .33 psi (2.3 x 103 Pa) check valve was located between th is pusnp and the blood reservoir.
Reciprocatory pulsations and pressure fluctuations were provided by a modified per istaltic pump, positioned on a l~op, i.e., a length of tubing~
which extended from two peripherally located por~s and one centrally located por t .. The pump was modified so ~hat a single roller, in constan~ contact with ~he tubing, oscillated in about a 50 mm s~roke 2g %~
- at about ~0 cycles-min 1, thereby displacing about 1.6 mL per s~roke. A micrometer control Yalve was placed on the plasma-depleted blood ou~let line and was adjusted during the treatment.
Re~ults and conditions of this treatmen~ are summarized in Table 4. No hemolysis was observed.
' .
3~
,~
o o o o o o o _î
C
u~
,~ ~ r ~ 0 ~J ~ ~
~ i I
~ u~
~q ~ U~
~1~ ~ ~1 7 ,~
~ o ~
P~ ~ _l ~ o o ~ In : e a) ~ _I ~ ~ ~ c~
D ~ _ _ _ _ _ ~ ~ ~ ~` ~ ~D ~
~ u~oo~a . ,.~ ~ ~ ~ ~a ~
~
.q ~æ~
~3 ^o u~ u~ o o u~
~, ~ C
- '~ '., ' .
EXAMPLE 5. The apparatus used in this example was identical to that described above in Example 4 except that the module was smaller, the membranes being about 6 inches (152 mm) in diameter and providing a 5 total membrane surface area of about .04 m .
Results and conditions of ~his treatment are summarized in Table 5O No hemolysis was observed.
.
:
~ ~ ~ ~ r~l ~
~ o o o o c:~
~ . . ~ ~ .
v ~
~ ~ ~ ~ ~ c~ ~
3 ~
~ '~c ~ ~ t~ o ~
10 ~ ~ ~
U~ o ,, ~ _, ~ ~ o ~
~ _ ~ _ ~
1~ ~ a~
U~ ~ ~ ~ ~ o ~ o~
~ ~ ~ ,', ~
. a. J~ Q~
a~ ~ ~ ,~
o _, _ _ , _ _ 20 ~ x ~- s~ o ~ u~ cr ~ s~ ~ ~~ ~ ~
lY ~
~ o~
~
~ ~ ~ O O
~ ~, 30 ~ ~ o o ~n o u~
~ æ
.
, . ~ .
, ~2~
EXAMPLE 6. The apparatus used in ~his ex~mple was subs~antially identical to 'chat described in Example 5 . The stroke leng~ch of the osci llating pump was varied during ~che treatmen~. The oscillator was 5 turned off for a three minu~ce interval so ~hatt during this period, blood was being conduc~ed Eorward only. The inlet hematocr it was 37% .
~ esults and conditlons of this ~creatment are summarized in Table 6n Slight hemolysis was briefly lG observed when the s~roke leng~h was changed from four inches (101 mm) to three inches ( 76 mm) and again when the oscillator was ~urned on after the one minute in~erval of constant flow.
3~
~ I o o o o ~ o o a) ~ I ~ o 1~ U~ a) ~ o 1 0 â~
~1 c~
~ ~ v ~ ~1 1 ~ )~o `I ,~ ~
~ . _I CO ~ _1 N ~ ~
3~ ~ 1` a) u~ ~ ~
~ '` ~
~ u~
;~ ~ ~ co m ~o~ ` ~
C~ ~ o o ~ ~
- . . . ~ .
.
', . . ~ ". " . . ' ' - ' , ' . ' ' ~2~
BEST MODE
The ~est mode for carrying out the invention is illustrated generally by Examples ~ and 5.
UTILITY
The process and appara~us of the invention have several useful applications including the treatment o certain disease states by plasma exchange or plasma therapy, the collection of plasma for various tr~nsfusion needs, for further fractionation to isolate specific serum proteins, and ~or the production of cell culture media. The invention is particularly useful ~or continuous plasmapheres is, This application is a division of copending Canadian Patent Application Serial No. 407,621, filed ~982 July 20.
~0 , ~ :,''. .
:' ;, , ,
Claims (11)
1. Membrane filter module which is useful for carrying out a continuous plasmapheresis and which comprises:
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, there being a central blood inlet port connected to the blood flow region; a blood collection channel, around the blood flow region, connected to a plasma-depleted blood outlet port: and a plasma collection channel around each plasma flow region connected to a 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, and means connected to the blood flow path for imparting reciprocatory pulsatile flow to blood in said path.
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, there being a central blood inlet port connected to the blood flow region; a blood collection channel, around the blood flow region, connected to a plasma-depleted blood outlet port: and a plasma collection channel around each plasma flow region connected to a 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, and means connected to the blood flow path for imparting reciprocatory pulsatile flow to blood in said path.
2. The module of Claim 1 in which the depth of the blood flow path between the membranes is at least about 4 mils (102 µm) and the seal is an elastomeric adhesive.
3. The module of Claim 2 in which the depth of the blood flow path between the membranes is about 4 to 10 mils (102 to 254 µm).
4. The module of Claim 3 in which the membranes are comprised of polyester or polycarbonate and are less than about 1 mil (25 µm) thick.
5. The module of Claim 4 in which blood side supports comprised of a plurality of smooth pillars are located between the membranes.
6. The module of Claim 4 in which membranes are less than about 0.5 mil (13 µm) thick and the adhesive has a break elongation of at least about 100%.
7. The module of Claim 4 in which the adhesive has a break elongation of about 400%.
8. The module of Claim 4 in which the membranes provide an effective surface area of about .02 to .06 m2 and have cell-retaining pores of about 0.1 to 1.0 µm in diameter.
9. The module of Claim 5 in which the plasma side supports are comprised of layers of fabric-like materials.
10. The module of Claim 9 in which the membranes have a total effective surface area of about .02 to .06 m2 and the cell-retaining pores are about 0.4 to 0.5 µm in average diameter.
11. The module of Claim 10 having blood side supports between the membranes which supports comprise substantially circular dots of an elastomeric adhesive.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000598189A CA1269620A (en) | 1981-07-22 | 1989-04-28 | Plasmapheresis by reciprocatory pulsatile filtration |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28711681A | 1981-07-22 | 1981-07-22 | |
| US287,116 | 1981-07-22 | ||
| US34937182A | 1982-02-16 | 1982-02-16 | |
| US349,371 | 1982-02-16 | ||
| CA000407621A CA1257205A (en) | 1981-07-22 | 1982-07-20 | Plasmapheresis by reciprocatory pulsatile filtration |
| CA000598189A CA1269620A (en) | 1981-07-22 | 1989-04-28 | Plasmapheresis by reciprocatory pulsatile filtration |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000407621A Division CA1257205A (en) | 1981-07-22 | 1982-07-20 | Plasmapheresis by reciprocatory pulsatile filtration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1269620A true CA1269620A (en) | 1990-05-29 |
Family
ID=27167264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000598189A Expired - Lifetime CA1269620A (en) | 1981-07-22 | 1989-04-28 | Plasmapheresis by reciprocatory pulsatile filtration |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1269620A (en) |
-
1989
- 1989-04-28 CA CA000598189A patent/CA1269620A/en not_active Expired - Lifetime
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4735726A (en) | Plasmapheresis by reciprocatory pulsatile filtration | |
| CA1258642A (en) | Hollow fiber plasmapheresis module and process | |
| US4769150A (en) | Method and apparatus for plasmapheresis by reciprocatory pulsatile filtration | |
| US6544424B1 (en) | Fluid filtration system | |
| US4075091A (en) | Method for effecting heat or mass transfer | |
| CA1173760A (en) | Reciprocating dialyzer having spacers | |
| US5695653A (en) | Device and method for separating components from a biological fluid | |
| US4936980A (en) | Apparatus and method for plasma separation | |
| AU708340B2 (en) | Extra-lumenal crossflow plasmapheresis devices | |
| US4729829A (en) | Hollow fiber plasmapheresis module | |
| CA2172350A1 (en) | Preparation of autologous plasma and fibrin gel | |
| CA1198686A (en) | Separating filtrates free of particles from liquid particle mixtures | |
| EP0070738B1 (en) | Plasmapheresis by reciprocatory pulsatile filtration | |
| US4636312A (en) | Plasmapheresis filtration module having improved end plate | |
| EP0076665B1 (en) | Method and apparatus for plasmapheresis | |
| US4746436A (en) | Membrane plasmapheresis apparatus and process which utilize a flexible wall to variably restrict the flow of plasma filtrate and thereby stabilize transmembrane pressure | |
| US3442388A (en) | Artificial kidney having a corrugated,convoluted membrane | |
| CA1269620A (en) | Plasmapheresis by reciprocatory pulsatile filtration | |
| Ding et al. | Dynamic filtration of blood: A new concept for enhancing plasma filtration | |
| EP0112094B1 (en) | Apparatus for blood treatment | |
| US4565626A (en) | Apparatus for blood treatment by pressing blood into treating material and then drawing it out | |
| JP4986285B2 (en) | Filtration method and apparatus for blood or blood components using leukocyte removal filter | |
| CA1252737A (en) | Plasmapheresis filtration module | |
| Galletti et al. | Oscillating blood flow enhances membrane plasmapheresis | |
| CA1197472A (en) | Plasmapheresis filtration module |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |