CA1248325A - Purification apparatus and method employing a regenerable ligand - Google Patents
Purification apparatus and method employing a regenerable ligandInfo
- Publication number
- CA1248325A CA1248325A CA000480357A CA480357A CA1248325A CA 1248325 A CA1248325 A CA 1248325A CA 000480357 A CA000480357 A CA 000480357A CA 480357 A CA480357 A CA 480357A CA 1248325 A CA1248325 A CA 1248325A
- Authority
- CA
- Canada
- Prior art keywords
- membrane
- ligand
- ligate
- fluid stream
- fluid
- 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
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/5302—Apparatus specially adapted for immunological test procedures
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/16—Blood plasma; Blood serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/026—Wafer type modules or flat-surface type modules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2311/00—Details relating to membrane separation process operations and control
- B01D2311/26—Further operations combined with membrane separation processes
- B01D2311/2626—Absorption or adsorption
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2321/00—Details relating to membrane cleaning, regeneration, sterilization or to the prevention of fouling
- B01D2321/04—Backflushing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N2030/524—Physical parameters structural properties
- G01N2030/527—Physical parameters structural properties sorbent material in form of a membrane
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
Abstract
ABSTRACT OF THE DISCLOSURE
There is disclosed a system and apparatus for purifying a fluid stream which employ a fixed ligand to absorb a ligate carried in the fluid stream. The system and apparatus each includes a bed of ligands affixed to a semipermeable membrane. The ligand has a binding constant which, in the environment normally present in the fluid stream, will predictably bind the ligate and thus remove it from the fluid stream. An agent which regenerates the ligand is conveyed to the ligand bed by diffusion across the semi-permeable membrane. The diffused agent breaks the ligate-ligand bond. The ligand is regenerated for subsequent use, and the ligate is freed for disposal.
There is disclosed a system and apparatus for purifying a fluid stream which employ a fixed ligand to absorb a ligate carried in the fluid stream. The system and apparatus each includes a bed of ligands affixed to a semipermeable membrane. The ligand has a binding constant which, in the environment normally present in the fluid stream, will predictably bind the ligate and thus remove it from the fluid stream. An agent which regenerates the ligand is conveyed to the ligand bed by diffusion across the semi-permeable membrane. The diffused agent breaks the ligate-ligand bond. The ligand is regenerated for subsequent use, and the ligate is freed for disposal.
Description
~4~3;~5 BACKGROU~'D OF THE I~'YE~'TION:
The use of adsorption to purify fluid streams is known.
During the process of adsorption, an immobolized molec~le (known as a "ligand") forms 2 chemical bond with another molecule carried by ~
fluid stream (known as the "ligate"). The ligand thus removes the ligate from the fluid stream, thereby purifying the fluid stream.
It is desirable that the ligand which is used have a highly selective binding constant for the target ligate, so that other substances in the fluid stream whose removal is not desired are not bound by the ligand. Hi~hly selective ligands, however, tend to be CQStly .
One way of reducing the overall cost of a specific adsorption system is to employ a ligand which is capable of regeneration. A
regenerable ligand has a binding constant which, under one set of li circumstances, is high and which, under another set of circumstances, is lo~. During the latter circumstances, the ligand will release any bound ~igate and is thereby made available for subsequent use.
Short cycles of adsorption and regeneration tend to minimize the ligand required to achieve a given rate of ligat~ removal (e.g., ~O in grams per minute~, and thus further reduce the overall cost of the adsorption system. Conventionally, the regeneratio,n agent is conveyed to the ligand alonQ the same fluid path which the ~ te follows.
Therefore, the possibility of shortening the cycle length is ultimately limited by the time required to displace a ligate-bearing
The use of adsorption to purify fluid streams is known.
During the process of adsorption, an immobolized molec~le (known as a "ligand") forms 2 chemical bond with another molecule carried by ~
fluid stream (known as the "ligate"). The ligand thus removes the ligate from the fluid stream, thereby purifying the fluid stream.
It is desirable that the ligand which is used have a highly selective binding constant for the target ligate, so that other substances in the fluid stream whose removal is not desired are not bound by the ligand. Hi~hly selective ligands, however, tend to be CQStly .
One way of reducing the overall cost of a specific adsorption system is to employ a ligand which is capable of regeneration. A
regenerable ligand has a binding constant which, under one set of li circumstances, is high and which, under another set of circumstances, is lo~. During the latter circumstances, the ligand will release any bound ~igate and is thereby made available for subsequent use.
Short cycles of adsorption and regeneration tend to minimize the ligand required to achieve a given rate of ligat~ removal (e.g., ~O in grams per minute~, and thus further reduce the overall cost of the adsorption system. Conventionally, the regeneratio,n agent is conveyed to the ligand alonQ the same fluid path which the ~ te follows.
Therefore, the possibility of shortening the cycle length is ultimately limited by the time required to displace a ligate-bearing
2; flui~ stream from the fluid path, replace it with the regeneration agent, then displace the regeneration agent, and finally reintroduce the ligate-bearing fluid stream. Regeneration by conventional methods thus tends to be time consuming and inefficient.
One of the principal objects of this invention is to provide
One of the principal objects of this invention is to provide
3~ an apparatus~and system which p~rify a fluid stream by adsorption usin~ a ligand which is repeatedly regenerated in a fast and efficient manner.
i .
~248325 SUMMARY OF THF JNYE~T10~:
To this end, the ;nvention provides a system and apparatus for purifying a fluid stream which employ a fixed ligand to adsorb a ligate carried in the fluid stream. The system and spparatus each includes a bed of ligands affixed to a semipermeable membrane. The ligand has a binding constant which, in the environment normally present in the fluid stream, will predictably bind the ligate and thus remove it from the fluid s~ream.
In accordance with the inYention, an agent which regenerates the ligand is conveyed to the ligand bed by diffusion across the semipermeable membrane. The diffused agent breaks the ligate-ligand bond. The ligand is regenerated for subsequent use, ~nd the ligate i5 freed for disposal.
The system and apparatus which e~body th~'features of the ij invention are cycled through three operative mod ~ .
In the first mode~ the ligate-carrying fluid strea~ is conducted along the membrane to which the li~ands are affixed. The desired ligate-ligand bonds are thus formed.
In the second mode, the regeneration agent is conveyed to the side of the membrane opposite to the fluid stream. The agent is transported to the ligands by diffusion across the me~brane. The ligate-ligand bonds are broken, freeing the ligate and the ligand.
In the third mode, the freed ligates are removed from the apparatus.
The system and apparatus can be repeatedly and quickly cyc~ed through the three modes, until the desired volume of fluid has been purified.
.
.
BR~EF DESCRI~ION D TH D~AWI~GS
Fig. 1 is an exploded perspective view of the apparatus which embodies the feature of the invention;
Fio. 2 is a side section view of the apparatus shown in Fig.
1 after assembly;
Fig. 3A is an enlarged diagrammatic section view of a portion of the membrane carried within the apparatus shown in Figs 1 and 2;
Fig. 3B is an alternate embodiment o~ the membrane portion of the apparatus shown in Fig. 3A;
Fig. 4 is a system which embodies the features of the invention and which employs the apparatus shown in ~igs. 1 and 2;
Figs. 5A, 5B, 5C, 5D, and 5E are diagrammatic views of the operation of the apparatus as it is cycled through an Adsorption Mode, a Regeneration Mode, and a Rinse ~ode in accordance ~ith the features 1~ of th~ invention;
Fig. 6 is a graph showing the pH of the fluid conveyed through the apparatus as a function of time and illustrating the change effected in the pH to regenerate the apparatus in aceordance with the features of the invention; and Fig. 7 is a graph showing the operation of a system and apparatus which embody the features of the-inYention.
Before explaining the embodiments of the invention in detail, it is to be understood that the invention i5 not limited in this application to the details of construction and the arrangement of components as set forth in the ~ollowing description or as illustrated in the accompanied drawings. The invention is c~pable of other embodi~ents and of bein~ practiced or carried out in various ways.
Furthermore, it is to be understood that the phraseology and terminology employed is for the purpose of description and should not be regarded 25 llmitin;.
.
;
~æ~3~5 DESCRIPT~O~ OF THE PRE~ERRED EMBODIME~TS:
An apparatus 10 for purifying a ~luid stream 11 by ads~rption is shown in Figs. 1 and 2.
In accordance with one aspect of the inYention~ the apparatus 5 10 includes one or more semipermeable membranes 16 Dn which immobili~ed molecules 12 (hereafter referred to as "ligands") are affixed in a predetermined pattern (see Figs. 1 and 3A/3B).
In accordance with another aspect of the invention, the selected ligand 12 has a binding constant which, in the environment normal,y present in the fluid stream 11, will predictably form a chemical b~nd 13 with another molecule 14 carried in the ~luid strean 11 (hereafter referred to as the "li~ate"). Through this process (which is generally shown in Fig. 5B), the ligand 12 removes the ligate 14 from the fluid stream 11, thereby purifying it.
1~ The binding constant of ~he selected ligand 12 will predictably decrease when the normal env;ronment of the fluid stream 11 is purposely changed by exposure to a particular selected external agent 18. By lowering the binding constant, the agent 18 breaks the ligand-ligate bond 13 (a process which is generally shown in Fig. 5D), ~ but not in 2 manner which destroys the li~and 12. The ligand 12 is regenerated for subsequent use, and the ligate 14 is freed for disposal (see Fig. 5~). The external agent 18 will hereafter be referred to as the "regeneration agent".
In accordance ~ith yet another aspect of the invention, the 2i regeneration agent 18 is conYeyed into the apparatus 10 on the side cf the membrane 16 opposite to ~here the ligand 12 is affixed (see Fi~s.
5C and D). The agent 18 is transported to the ligands 12 by diffusion across the me~brane 16.
The membrane 16 can be variously configured. For example, in 30 one arrange~ent (not shown), ~t can be shaped as a hollow flber. In this arrangement, the ligands 12 are affixed-along the interior luminal surface of the bore.
~.æ~æ~ , hlternately, as shown in the lllustrated embodiment, the membrane 16 is shaped as a flat sheet, and the ligands 12 are affixed to the surface which ls exposed to the ligate-carryins fluid stream 11.
The ligands 12 can be affixed to the membrane 16 by various means. For example, a chemical ooupling agent, such as 1,1'-carbonyl~diimidazole, can be used, as well as any other comparable method conventionally employed to bond a ligand to a fixed surface.
Regardless of the specific configuration of the membrane 16, 10 the ligands 12 are preferably affixed along the surface of the me~brane 14 which is exposed to the fluid stream 11. This assures that the ligands 12 are ~ully accessible to the ligates 14 carried in the fluid stream, as well as fully access~ble to the regen~ration ~gent 18 diffused across the ~embrane 16.
1~ The permeability characteristics o~ the membrane 16 can vary. However, 2S sho~n in Figs. 3A and 3B, in the surface region 20 of the membrane 16 where the ligand 12 is concentrated, the membrane 16 should be sufflciently porous to allow ~dequate contact bet~een the ligate 12 and ligand 14. However, in the regions 22 of the membrane 20 16 spaced away from the ligands 12, the membrane 15 should be sufficiently impermeable to preYent convective transp~rt of the fluid stream 11 ~cross the membrane 16 in response to pressure differentials. By the same token, however, the membrane 16 should be sufficiently perme~ble to the regeneration agent 18 to allow 25 diffusional transport across the membrane 16 when concentration differences exist.
The membrane 16 c~n be constructed in various ways to ~chieve the above objectiYes. In the embodiment shown in F~g. 3A, the membrane 16 is of uniform porosity ~cross its width. ln the 30 embodiment shown in F~g. 3B, a multiple layer membrane 16 Is used. In this arrange~ent, the surface region 20 is more porous than the Interior regions 22. The ligands 12 are affixed to the ~ore porous reg~on 20.
33~
It sh~uld be appreciated that the pores 21 cf the membrane 16 c~n cDnstitute straight, unif~rm paths 25 ShDWn in Figs. 3A ~nd 3B, ~r they can constitute a series of nonunif~rm, t~rtuous p~ths.
The apparatus 10 may be v~riously cDnstructed t~ support the membrane 16. In the illustrated embDdiment, a~ best sh~wn ~n Fi~s. 1 and 2, the apparatus lO includes a pair of semipermeable membranes 24 ~nd 26, which are each cDnfigured as a flat sheet.
The facin~ surfaces 28 of the membranes 24 and 26 ~re kept a fixed d~stance apart by ~ sp~cer element 30 (see Fig. 2), thereby 10. fDrming a- ~ uid path 32 of predetermined thickness and v~lume between.
the membr~nes 24 and 26. The regenerable ligands 12 are ~f~ixed t~
the facinq me~brane surfaces 28 (see Fig. 1) in a predetermined pattern,- ~5 will be descr~bed in greater detail later.
~ It is desirable to minimize the spacing between the membrane1~ surfaces 2B ~s much ~s p~ssible, consistent with the desired fluid thr~ugh-put of the apparatus 10. Prefer~bly, the flu~d path 32 shwld be n~ more th~n 200 microns across. This minimizes the vclume ~f the fluid path 32. This al50 assvres that the d~st~nce a giYen ligate 14 Qust travel ~cross the width cf the fluid path 32 t~ cont~ct a ligand 2D 12 can be traveled ~n the time i~ ~akes the ligate 14 to traverse the over211 length of the fluid p~th 32.
In the ~llustr~ted embDdiment, the apparatus 10 includes mating housing portions 34 and 35 which to~ether enclose the membranes 24 and 26. The app~ratus 10 also ~ncludes ~n inlet 36 f~r c~nducting 25 the lig~te-c~rrylng fluid strea~ ~nt~ the fluid pa$h 32 ~nd ~n outlet 38 fDr c~nducting the purified ~i.e., lig~te-free) fluid stream DUt Df the fluid pa~h 32.
The ~paratus 10 further ~ncludes flu~d passages 40 and 42 formed along the Qpp~s~te surface of the membranes 24 and 26, 30 which do not face the fluid path 32.
:. .`1'-' .
,.
: ' , 3~i The fluid passages 4D ~nd 42 can be vari~usly formed, depending ~p~n the specific configvration of the membranes used. In the illustrated embDdiment, ~ membrane suppDrt element 51 and 52 m~intains ~n open flow path through the assDciated passage 4G ~nd 42, as well as assures a unifDrm distribution of fluid within the associated p~ssage 40 and 42.
Each pass~ge 40 and 42 includes ~n inlet 4~ for conducting fluid into the ~ssociated passage and zn outlet ~0 for conduc~ing fluid out of the ~ssociated passage.
The appar2tus 10 as heretofore described c~n cDnstitute ~
single ~ uid p~th 32 with a~ assoeiated pair of fluid p2ssages, as shown in Fig. 2. However, two or more of the ~pparatus 10 shown in Fig. 2 can be stacked one atop the other to form multiple fluid paths ~nd ~ssDciated fluid passages. lt should be appreciated that the axis 1; of the ~ uid pa~h 32 can e~tend either hori~ontally or vertically.
The purification apparatus 1~ as heretofDre ~escribed can form a part of a purification system ~4, which is shcwn in Fig. 4.
~he system 54 ~ncludes an inlet conduit 56 which connects the inlet 36 of the ~pparatus 10 with a source ~8 of fluid which is to be 20 purified. A pump 6D tr~nsp~rts the fluid through the inlet conduit ~6. An inline clamp 62 selectively opens and closes the inlet conduit ~6 to fluid flow.
An Dutlet condvit 64 communicates with the Dutlet 38 of the 2pp~ratus 10 ~nd conduct5 the purified fluid stream ~rsm the apparatus 2~ 10. A pump 66 can be e~plDyed to control the flow through the outlQt conduit 64, if desired. An inline clamp 6R selectively ~pens and closes the outlet conduit 64 to ~luid flow.
Inlet and outlet conduits 70 ~nd 72 com~uniGate, respectively, with the inlet and outlet 48 ~nd 50 of each p~ss~ge 40 30 and 42. ~he inlet conduit 7D selectively c~m~unicates throu~h a suit~ble valve 71 wi~h e~ther the s~urce 74 of ~ first solution ~r the 2~i g source 76 of a second solution. A pump 78 serves tc transport the selected solution through the inlet conduit 70 into the passages 40 and 42. The outlet conduit 72 transports the selected sslutiDn out of the passages 40 and 42 for discharge or recirculation.
The first solution in the source 74 has a chemical csmposition which mimicks the chemical composition of the fluid in the source ~8, which is to be purified. In other words, the chemical composition of the first solution constitutes an environment favorable to the formation of the desired ligate-ligand bond 13.
The second solution in the source 76 constitutes the selected regeneration agent 18. As such, it has a chemical composition which differs from that of the fluid to be purified and, when in contact with the ligands 12, changes the environment to one which is unfavorable to the formation of the ligate-ligand ~onds 13.
In accordance with the invention, a ~oncentration difference exists between the second solution lbeing of a highçr concentration) and the fluid in the fluid path 32 (being of 8 lower concentration).
Because of this concentration difference, the second solution is diffused from the passages 40 and 42 across the membrane toward the fluid path 32.
The concentration difference may be achieved in various ways. The concentration difference can arise due to differences in ionic strengths, with the second solution having a higher concentration of ions than that of the ftuid path 32. The 2~ concentration difference can also arise due to a difference in pH, with the second solution being more acidic or more alkaline than that of the fluid path 32. The concentratlon difference can also ~rise due to a difference in the concentratisn of molecules smaller than the ligate 14, with the second solution having the higher concentration of 30 these molPcules.
~ ~6~
~lD-In the lllustr2ted embodimen., p~ differentials ~r~ employed to cause diffusional transport. In this arr~ngement, the fir~
solutiDn has a pH which generally equals She p~ of the flu~d to be purified, which, for the sake Df description, is ~ssumed tD be neutral. The second solutiDn h2s ~ p~ ~hich is less than ~i.e., more ~cidic), and preferably significantly less than, the pH sf ~he neutral fluid.
The system ~4 furSher includes a discharge conduit B0 which, in the illustrated emb~diment, communicates with the inlet oonduit ~6 1~ bet~een the.inlet clamp 62 and the ~pparstus inlet 36. The discharge conduit 80 transports ligates ~4 ~reed by the regeneration ~gent 18 away fr~m the fluid path 32 for disposal. An ~nline cl~mp 82 selectively Dpens and closes the disch~rge conduit 80 to fluid flow.
~he discharge conduit 8D can, in ~n alternate arran~ement, be 1~ positiDned in comMunication with the outlet conduit 64.
~he sy~tem ~ ~ay also further include a rinse conduit 8~
: positioned on the side of the apparatus 10 opposite to the discharqeconduit 80. In the illustrated embodiment, the rinse c~nduit 84 co x unicate5 with the outlet cond~it 64 between the outlet cl~mp 68 and the Dutlet 38 of the apparatus lOo ~he rinse c~ndu~t B4 alsD
com~unicates with a source 86 of a rinse sDlution. The rinse solution may be used to speed the tr~nsport of lig~tes 14 ~way frDm the fluid path 32 ~fter re~eneration. An inline clamp 8~ and pump 90 selectively control the flo~ Df rinse sDlution thr~ugh the rinse 2~ conduit ~.
DPE
The operation of the apparatus 10 within the syste~ ~4 is sho~n sequentially in Figs. 5A thr~ugh SE. As shown, the apparatus lD
is cycled through three operati~e mDdes.
483~5 The first mode (shown in Fig. 5B) is the Adsorption Mode.
During this Mode, the ligate-carrying f1uid stream (identified by numeral ~2) is conducted through the fluid path 32 for pur~fication.
As shown in Fig. 5B, it is durins this ~ode that the ligate-ligand bonds 13 are formed along the facing surfaces 28 of the membranes 24 and 26. The ligate-free (i.e., purified) fluid stream (identified by nu~eral 943 is conducted from the apparatus 10.
The next ~ode (shown in Fig. 5C and 5D) is the P~egeneration Mode. During this Mode, the regeneration agent 18 (from the source 76) is caused to diffuse across the membranes 24 and 26. It is during this Mode that the ligate-ligand bond5 i3 formed during the preceding Adsorption Mode are broken. The diffused regeneration agent 18 frees the ligate 14 from the ligand 12 for disposal. At the same time, the ligand 12 is freed for subsequent use.
1~ The next mode (shown in Fig. 5E) is the Rinse Mode. During this Mode, the ~reed ligates 14 and any diffused regeneration agent 18 which has entered the fluid path 32 are conveyed by fluid strea~ 96 from the fluid path 32 for disposal.
As shown in Fig. ~A, following the Rinse M~de, the apparatus 10 is again ready to commence another Adsorption ~10de, followed by subsequent Regenerat;on and Rinse Modes.
Each of the three Mod s will now be described in greater detail.
THE ADSORPTION MODE
2i At the start of the procedure, all inline clamps 621 68, 82, and 88 are closed. To begin the Adsorption Mode, the clamps 62 and 68, at the inlet and outlet 36 and 38 of the apparatus 10, are opened (as shown d~agram~atically in Fig. 5A). The ligate-carrying flu;d stream 92 is conducted by the pump 60 through the fluid path 32.
3LZ4~332~i As the ligates 14 are exposed to the ligands 12S the ligate-ligand bonds 13 successively form along the ~embrane surfaces 28 (as shown ~n Fig. 5B). -The purified, ligate-free fluid stream 94 is conducted thrDugh the ~utlet 38 and into the outlet conduit 64.
As shown in phantom lines in Fig. 5B, if desired during the Adsorption Mode, the valve 71 can be positioned to convey the first solution from the source 74 into each of the fluid passages 40 and 42. This will assure that dif~usional transport does not occur across ~he membranes during this Mode.
A fixed volu~e of the first solutiDn may be conveyed into the fluid passages 40 and 42 during the Adsorption Mode, or the solution may he continuously circulated through the passages 40 and 42, as shown in phantom lines in Fig. ~B.
The presence of the first solution in the fluid passages 40 1~ and 42 is not essential for adiorption to occur within the fluid path 32. However, if the purified fluid stream is ~ntended to be introduced into the human body, or if it is Qtherwise intended for a purpose requiring relatively stringent quality control standards, the presence of the first solution in the fluid passages 40 and ~2 during the Adsorption ~lode is preferred.
At the outset of the Adsorption Mode lsee Fig. 5A), each ligand 12 is available to bind d ligate 14. Ligate-ligand bonds 13 form readily, and the ligate concentration in the stream 94 at the outlet 38 will be essentially zero (as shown in Fig. 5B). However, after bonds 13 are formed at more and more ligand sites, the liQands 12 will become more and more saturated with ligate5 14, 2nd the ligate concentration in the outlet stream 94 wilt begin to rise. This will be referred to as the ~break-through point" of the apparatus lQ.
Eventually, adsorption w~ll cease, and the ligate concentration in the outlet strea~ 94 will eq.al the.lig-te concentration in the inlet . ~ .
stream g2. The amDunt and n2ture ~f the ligand 12; the veloc;ty of ~he fluid stream 92; and the initi~l c~ncentratlon ~f the ligate 14 in ~he inlet stre2m 92 ~ll c~ntribute tO the specific bre~k-thr~ugh psin~
cf 'che appar2tus 10.
I~ is desirable to use a suitable deviee 98 (see ~ig. 4) to moni~Dr the concentr3ti~n ~f ligates 14 in the outlet ~luid stream 94 to detect when the break-through pDint has ~crurred. The monit~r device 98 can employ ultr~violet spectroph~to~etry Dr any compar~ble technique for thls purp~se ~hen the hre~k-~hrough p~int is reached, it ~s necessary to regenerate the ~igand 12 so that purificati~n Df the fluid stream 92 can resume.
REGEN~RATIDN MODE
In ~ccordance with the invention, the R~generation M~de is l~ begun ~s sD~n as pDssible after the system's bre~k-through point is .
detected. As shown diagram~atically in Fig. ~C, the inlet and Dutlet clamps 62 and 6~ are closed, le2vins a volume of flui~ 96 occupying the fluid pa~h 32.
At this time, the valve 71 i5 pDSitioned tD intrDduce the second soluti~n fi.e., the regenerativn agent 18) from the s~urce 76 tnto the fluid passeges 40 and 42. A concentration difference is created ~cross the rem~r~nes 24 ~nd 26. As sh~wn in Fi9. ~C, the regener2tion agent l~ has ~ ~lecular size sufficiently small enDugh to diffuse thr~ugh the membranes 24 ~nd 26 in respDnse tD the .
2; concentration differential cre~ted.
~ s the regener~tiDn agent lB diffvses across the membranes 24 ~nd ~6, it changes ~he envlronment surrounding the ligands 12, lowering the binding const~nt of the lig~nd 1~. As shDwn in Fig. ~D, the l~gand 12 then releases the previously ~und l~gate 14 int~ the surrounding fluid v~lume 96. The 1ig~nd 12 is thereby als~ freed for subsequent use.
. ~ . . ~ , ~L2~8~
-14~
The length of the Regeneration Mode is dependent upon the concentration differential obtained on opposite sides of the ~embranes 24 and 26, which controls the rate of diffusion. Th~ length of the Mode is also dependent upon the effective pore size, or "tightness", of the membranes 24 and 26 and its thickness in the regions spaced a~ay from the ligand bed 12. Both of these membrane-related factors also control the rate of diffusion. In this respect, attention is directed to Stevenson et al, "An Unsteady State Method ~or ~leasuring the Per~eability of Small Tubular Membranes", Al~hE Journal, Vol. 21, No. 6, pp. 1192 to 1199, November 1975. The length of the Regeneration ~lode is further dependent upon the amount of the regeneration agent 18 and its inherent effectiveness, which control the speed and efficiency at which the ligate-ligand bonds 13 are broken.
~y controlling these parameters, the rate of diffusion and the overall time of regeneration can be closely controlled.
Diffusional transport across the membrane oonstitutes a significantly faster and more efficient method of deliveriny the regeneration agent 18 to the ligands 12 than conventional practices, which rely upon transporting the regeneration agent 18 within the fluid path 32 to contact the ligands 12.
THE RINSE MODE
The fluid volume 96 occupying the fluid path 32 now contains all of the ligates 14 which have been removed during the preceding 2~ Adsorption M~de, as well as any diffused regeneration agent 18 which may have entered the ~luid path 32 during the Re~enerat;on Mode.
Preferably, the rate of diffusion is controlled closely enough so that only a small Yolume of the regeneration agent 18 is present in the fluid volume 96.
.
3:~5 Tha Rinse M~de is begun to convey ~he ligat~-laden fluid v~lume 96 ~ut of the appara~us 1~. The Rinse M~de can be variDusly conducted.
In the illustrated embodiment (see Fig. 4), the discharge clamp82 and outletclamp 68 ean be opened simultaneously to displace the 1ig2te-laden fluid volume 96 wlth ~n equal volume of the purified fluid stream 94, which, in this ~rrangement, is back-flushed thrDugh the apparatus 10.
. Alternately, if-the discharge. c~nduit 8D is situa~ed at ~he ovtlet ~8 of the apparatus 10, the ligate-laden ~1uid YDlume 96 can- be replaced ~ith an equal ~olume of the unpurified fluid stream 92.
Still alternately, the r~nse solution c~n be conveyed thr~u~h the rinse conduit 8~ to displace the ligate-laden fluid volume g6 from the apparatus 10.
As the 1ig2te-laden fluid volume is being rinsed from the 2pp~ratus 10, the valve 71 is pDsiti~ned to ~gain convey the first .
solution into the fluid passages 40 and 42. Diffusion across the ~em~r~ne reverses, ~nd the regeneration agent lB is rem~ed fr~m the vicinity of the ligands 12 to return to th~ opposite ~O surfaces 29 of the m~mbranes 24 and 26. The env~ronment favorable to the f~nmatiDn ~f ligate~ and bonds 13 returns to the facing surfaces 28 of the ~embranes 24 ~nd 26.
~ this time, the Ads~rption ~ode c~n begin again, follDwed by yet another Regenerati~n ~nd Rinse Mode, over ~nd ~ver until the decired YDlume of flu~d has been purified.
~ ec~use the inventiQn employs diffusiDn ~ the method o~
regenerating of the ligand 12 the apparatus 10 can ~e quickly ~nd repeatedly regenerated during 3 pur~f~c~tion pr~cedure. In arcordance with the inventlon, then, the amount ~f li~ana 12 required ~or ~ given rate of 1ig2nd removal can be ~inimized t~ the fullest extent poss~ble. At the same time, the v~rlD~s.opertting par~meters of the system can ~l-so be ~ptimized to the full~st extent p~ss~ble~
In this regard, reference ~s m~de to the following ExanlplesO
EXAMPLE I
The purpose of this Example is to illustrate how the various operatin~ parameters associated with a giYen purification procedure affect the design of the apparatus 10 which embodies the features of the invention. The Example also demonstrates how the invention can be used to optimize the performance objectives of the purification procedure.
In this Example, the system will be used fDr the treatment of ~yasthenia Gravis. Myasthenia Gravis is a disease in which antibodies carried by the blood plasma of a patient block normal neuro-muscular junctions. It has been observed that the removal of these antibodies from the patient's plasma exerts a beneficial therapeutic effect.
Thesè antibodies (or ligates) can be removed from the plasma by adsorption, using an antibody-specific antigen (or ligand) a'fixed 1~ to a semipermeable membrane and regenerated in accordance with the invention.
The various clinical operating parameters associated with the extracorporeal treatment of ~yasthenia 6raYis by adsorption include:
(a~ A typical patient has about 100 x 10 9 moles of ~0 undesired antibodies per liter of plasma;
(b) For the patient's comfort and well being, an extracorporeal treatment time should not exceed 240 minutes;
. (c) For the comfort of the pa~ient, the rate at which plasma is removed for treatment should not exceed 70 cc/min.
2~ Typically, durin~ the treatment, the whole blood will be withdrawn from the patent and passed through a centrifuge or filter to first separate the cellu7ar eomponents of the blood (red blood cells platelets, and leukocytes) from the plasma. The cellular co~ponents will be returned to the patient, while the plasma is next conYeyed through the~apparatus 10 as heretofore described to remoYe the offending antibodies. The purified, antibody-free plasma i5 then returned to the patient.
133:25 ~7 (d) The antigen known to bind the antibody ~ssociated ~ith Myasthenia ~ravis is the ~cetylcholine receptor obt~ined from the ~uscle tissue of the electric fish torpedo c~lifornicus. This ligand 12 is not 2a5ily obtained and is therefore c05tly. A system which embodies the feature of the invention c~n significantl~ reduce the cost of tr~atment. By regenerating the antigen N-times, the ~mDunt of antigen used can be reduced by 1/~. In this ~xample, the antigen will be re~enerated lD0 times dvrinQ the 240 minute procedure, thereby reducing the antigen-related CD5t of the system-~y i/100. This effectively reduces the C05t of the ligand 12 required for a single treatment frDm more than $1,DD~ to the range of S10.
(e) Given the objective of regenerating 100 times~ the o~erall tre~tment period will be divided into treatment cycles of 2.4 . ~inutes each (24D minutes/100 reQenerations). Each treatment cycle 1~ will, in turn, be divided ints modes embodying the features of the invention, as foll~ws:
~1~ Adsorption Mode 2.0 minutes (2) Regeneration Mode 18 seconds (3) Rinse Mode 6 seconds This treabment cycle is shown diagrammatic~lly in Fig. 6.
From these operatin~ goals ~nd parameters, the s ke ~f the purifica.ion apparatus 10 can be c~lculated:
(f) The number of ligands (i.e.~ ~ntigens) thdt are requ~red to bond all of the the l~gdtes (i.e., ~ntibodies) traversing the appsra~us 10 during e~ch two minute Adsorption MDde (~Li is:
NL ~ 2 Min x 70 x 10-3 liters x 100 x 10-9 nm x 6 x 1023 molecules le ~in ~ ----lr~b~---- (AVD8adrO'S ~umber) ~ L e 8.4 x 101~ ligand;. This is the number ~f ligands which will be plAced w~thin the apparatus. In th~s Ex~mple, tt is ~ssumed that one ligand ~Dlecule will bind one l~gate molecule.
.
- ~
3325i -1&-(g) It is desirable to pr~perly space the l~ands upDn ~he surf~ce Gf the mem~rane to ~v~id overcrowding, which can, in turn, adversely effect the rate of adsDrpticn. It is pre~erred that each ligand 12 cccupy on the ~embrane ~n area of n~ less ~h~n 16D~ A2 ; (1~00 x 10 1~ cm2). Therefore, the t~tal membrane surface are2 (~A) required is:
MA ~ NL x 16DD x 1~ 16 cm2 - 8.4 x lD1~ Ligands x lSD~ x 1~ 16 cm2 ~ 1344 cm2 .
(H) Since, in the illustr~ted embDdiment, tw~ flat sheets are used, MA 02n be divided in half, i.e., 672 cm2.
(i) FDr ~ fluid path thickness of .01 cm, the YDlume of the fluid path ~p) i5:
Yp ~ 672 cm x .01 cm 1~ Yp 6.72 cc M~re particularly, at a pl2sma flDw ratè of 70 cc~minute through the ~bove-described treatmenS appar~tus 10, abDut 140 cc of pl2sm2 will bs purified during e~ch two minute Adsorption ~de. Of this volume9 6.72 cc of pl~s~ will n~t be returned tD the paSient.
Instead, this ~olume of plasma (c~nstituting the fluid volume 96 shown in Fiss. ~C, D, and F) witl be discharged-during the Rinse l~de to cDnvey ~ll the ligates adsDrbed during the preceding AdsorptiDn Mode a~2y from the appar~tus lDo The overall p'1asm~ loss r~te of the ~bove-described app~ratus 10 due to regeneration sf the llgand is thus 2~ only 4-8O~
FurthermDre, because the ~ntigen is regenerated lD~ times during the procedure, the c~st of the antigen used for the ~re~Sment ~s reduced 100 times.
. ~
, ~.~4~32~
It should now be appreciated that the various operatin~
parameters and purification objectives of the system and apparatus 10 made in accordance with the invention can be mer~ed to obtain the desired performance results.
EXAMPLE II
the purpose of this Example is to illustrate that an apparatus 10 which embodies the features of the invention can be repeatedly cycled thrDugh successive Adsorption, Regeneration, ard Rinse Modes.
l~ The ligand 12 employed in the apparatus 10 was an acetylcholine analog. It wac affixed to the facing surfaces of a pair of flat cellulose dialysis membranes 24 and 26. A fluid path 32 of 0.0126 mm separated the two membranes 24 and 26.
The ligate 14 was acetylcholine esterase present in a normal 1~ saline solution (pH 7.35) in a concentration of 8 m~/ml.
The apparatus 10 was used in association with a system ~4 as shown in Fig. 4. The solution occupying the source 74 (i.e , the solution mimicking the stream to be purified) was normal sallne. The solution occupyinQ the source 76 ~i.e., the regeneration agent 18) was a buffered citrate solution (pH 2.0). ~onmal saline solution was also employed as the rinse so~ution.
The apparatus 10 was operated through nine (9) successive cycles, each including an Adsorption ~ode, a Regeneration Mode, and a.
Rinse ~lode as heretofore des~ribed.
During each cycle, the following time periods were used:
Adsorpt1On Mode: 4.5 m~nutes Regeneration Mode: 1 minute Rinse Mode: . 1 minute ~3~5 During each Adsorption ~ode, the acetylcholine esterase solution was introduced into the apparatus at a flow rate of 3.6 mltmin. During each cycle, the concentration of the acetylcholine esterase in the ~ uid stream exiting the apparatus 10 was continuously monitored to detect the break-through point of the apparatus 10. The results are summarized in the Table.
During each Regeneration ~ode, the citric acid buffer was introduced at a flow rate of 9.6 ml/min.
The results are graphically shown in Fig. 7.
As shown in Fig. 7~ during the Adsorption Mode of the first cycle, the concentration of acetylcholine esterase in the outlet stream was zero for a period of 210 seconds. After 210 seconds, however, the ligate concentration in the outlet stream began to increase, indicating that the break-through point had been reached.
After 270 seconds~ the ligate concentration in the outlet stream 94 equaled the ligate concentration in the inlet stream. A Regeneration Mode and a Rinse Mode followed to end the cycle.
In subsequent cycles, the break-through point was reached at a successi~ely earlier time during the associated Adsorption ~ode, until the eighth cycle. In the eighth and ninth cycles, the break-through poi~t occurred after about 1~0 seconds of the associated Adsorption Mode, indicating that the apparatus had achieved a steady state operating condition.
It was observed that only about two percent (2~) of the ~; regenerat;on ager,t 1~ used during each Regeneration Mode "leaked" into the fluid strea~ and was dischar~ed during the following Rinse Mode.
The remainder of the regeneration aqent d~ffused back through the membranes for subsequent use.
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~248325 SUMMARY OF THF JNYE~T10~:
To this end, the ;nvention provides a system and apparatus for purifying a fluid stream which employ a fixed ligand to adsorb a ligate carried in the fluid stream. The system and spparatus each includes a bed of ligands affixed to a semipermeable membrane. The ligand has a binding constant which, in the environment normally present in the fluid stream, will predictably bind the ligate and thus remove it from the fluid s~ream.
In accordance with the inYention, an agent which regenerates the ligand is conveyed to the ligand bed by diffusion across the semipermeable membrane. The diffused agent breaks the ligate-ligand bond. The ligand is regenerated for subsequent use, ~nd the ligate i5 freed for disposal.
The system and apparatus which e~body th~'features of the ij invention are cycled through three operative mod ~ .
In the first mode~ the ligate-carrying fluid strea~ is conducted along the membrane to which the li~ands are affixed. The desired ligate-ligand bonds are thus formed.
In the second mode, the regeneration agent is conveyed to the side of the membrane opposite to the fluid stream. The agent is transported to the ligands by diffusion across the me~brane. The ligate-ligand bonds are broken, freeing the ligate and the ligand.
In the third mode, the freed ligates are removed from the apparatus.
The system and apparatus can be repeatedly and quickly cyc~ed through the three modes, until the desired volume of fluid has been purified.
.
.
BR~EF DESCRI~ION D TH D~AWI~GS
Fig. 1 is an exploded perspective view of the apparatus which embodies the feature of the invention;
Fio. 2 is a side section view of the apparatus shown in Fig.
1 after assembly;
Fig. 3A is an enlarged diagrammatic section view of a portion of the membrane carried within the apparatus shown in Figs 1 and 2;
Fig. 3B is an alternate embodiment o~ the membrane portion of the apparatus shown in Fig. 3A;
Fig. 4 is a system which embodies the features of the invention and which employs the apparatus shown in ~igs. 1 and 2;
Figs. 5A, 5B, 5C, 5D, and 5E are diagrammatic views of the operation of the apparatus as it is cycled through an Adsorption Mode, a Regeneration Mode, and a Rinse ~ode in accordance ~ith the features 1~ of th~ invention;
Fig. 6 is a graph showing the pH of the fluid conveyed through the apparatus as a function of time and illustrating the change effected in the pH to regenerate the apparatus in aceordance with the features of the invention; and Fig. 7 is a graph showing the operation of a system and apparatus which embody the features of the-inYention.
Before explaining the embodiments of the invention in detail, it is to be understood that the invention i5 not limited in this application to the details of construction and the arrangement of components as set forth in the ~ollowing description or as illustrated in the accompanied drawings. The invention is c~pable of other embodi~ents and of bein~ practiced or carried out in various ways.
Furthermore, it is to be understood that the phraseology and terminology employed is for the purpose of description and should not be regarded 25 llmitin;.
.
;
~æ~3~5 DESCRIPT~O~ OF THE PRE~ERRED EMBODIME~TS:
An apparatus 10 for purifying a ~luid stream 11 by ads~rption is shown in Figs. 1 and 2.
In accordance with one aspect of the inYention~ the apparatus 5 10 includes one or more semipermeable membranes 16 Dn which immobili~ed molecules 12 (hereafter referred to as "ligands") are affixed in a predetermined pattern (see Figs. 1 and 3A/3B).
In accordance with another aspect of the invention, the selected ligand 12 has a binding constant which, in the environment normal,y present in the fluid stream 11, will predictably form a chemical b~nd 13 with another molecule 14 carried in the ~luid strean 11 (hereafter referred to as the "li~ate"). Through this process (which is generally shown in Fig. 5B), the ligand 12 removes the ligate 14 from the fluid stream 11, thereby purifying it.
1~ The binding constant of ~he selected ligand 12 will predictably decrease when the normal env;ronment of the fluid stream 11 is purposely changed by exposure to a particular selected external agent 18. By lowering the binding constant, the agent 18 breaks the ligand-ligate bond 13 (a process which is generally shown in Fig. 5D), ~ but not in 2 manner which destroys the li~and 12. The ligand 12 is regenerated for subsequent use, and the ligate 14 is freed for disposal (see Fig. 5~). The external agent 18 will hereafter be referred to as the "regeneration agent".
In accordance ~ith yet another aspect of the invention, the 2i regeneration agent 18 is conYeyed into the apparatus 10 on the side cf the membrane 16 opposite to ~here the ligand 12 is affixed (see Fi~s.
5C and D). The agent 18 is transported to the ligands 12 by diffusion across the me~brane 16.
The membrane 16 can be variously configured. For example, in 30 one arrange~ent (not shown), ~t can be shaped as a hollow flber. In this arrangement, the ligands 12 are affixed-along the interior luminal surface of the bore.
~.æ~æ~ , hlternately, as shown in the lllustrated embodiment, the membrane 16 is shaped as a flat sheet, and the ligands 12 are affixed to the surface which ls exposed to the ligate-carryins fluid stream 11.
The ligands 12 can be affixed to the membrane 16 by various means. For example, a chemical ooupling agent, such as 1,1'-carbonyl~diimidazole, can be used, as well as any other comparable method conventionally employed to bond a ligand to a fixed surface.
Regardless of the specific configuration of the membrane 16, 10 the ligands 12 are preferably affixed along the surface of the me~brane 14 which is exposed to the fluid stream 11. This assures that the ligands 12 are ~ully accessible to the ligates 14 carried in the fluid stream, as well as fully access~ble to the regen~ration ~gent 18 diffused across the ~embrane 16.
1~ The permeability characteristics o~ the membrane 16 can vary. However, 2S sho~n in Figs. 3A and 3B, in the surface region 20 of the membrane 16 where the ligand 12 is concentrated, the membrane 16 should be sufflciently porous to allow ~dequate contact bet~een the ligate 12 and ligand 14. However, in the regions 22 of the membrane 20 16 spaced away from the ligands 12, the membrane 15 should be sufficiently impermeable to preYent convective transp~rt of the fluid stream 11 ~cross the membrane 16 in response to pressure differentials. By the same token, however, the membrane 16 should be sufficiently perme~ble to the regeneration agent 18 to allow 25 diffusional transport across the membrane 16 when concentration differences exist.
The membrane 16 c~n be constructed in various ways to ~chieve the above objectiYes. In the embodiment shown in F~g. 3A, the membrane 16 is of uniform porosity ~cross its width. ln the 30 embodiment shown in F~g. 3B, a multiple layer membrane 16 Is used. In this arrange~ent, the surface region 20 is more porous than the Interior regions 22. The ligands 12 are affixed to the ~ore porous reg~on 20.
33~
It sh~uld be appreciated that the pores 21 cf the membrane 16 c~n cDnstitute straight, unif~rm paths 25 ShDWn in Figs. 3A ~nd 3B, ~r they can constitute a series of nonunif~rm, t~rtuous p~ths.
The apparatus 10 may be v~riously cDnstructed t~ support the membrane 16. In the illustrated embDdiment, a~ best sh~wn ~n Fi~s. 1 and 2, the apparatus lO includes a pair of semipermeable membranes 24 ~nd 26, which are each cDnfigured as a flat sheet.
The facin~ surfaces 28 of the membranes 24 and 26 ~re kept a fixed d~stance apart by ~ sp~cer element 30 (see Fig. 2), thereby 10. fDrming a- ~ uid path 32 of predetermined thickness and v~lume between.
the membr~nes 24 and 26. The regenerable ligands 12 are ~f~ixed t~
the facinq me~brane surfaces 28 (see Fig. 1) in a predetermined pattern,- ~5 will be descr~bed in greater detail later.
~ It is desirable to minimize the spacing between the membrane1~ surfaces 2B ~s much ~s p~ssible, consistent with the desired fluid thr~ugh-put of the apparatus 10. Prefer~bly, the flu~d path 32 shwld be n~ more th~n 200 microns across. This minimizes the vclume ~f the fluid path 32. This al50 assvres that the d~st~nce a giYen ligate 14 Qust travel ~cross the width cf the fluid path 32 t~ cont~ct a ligand 2D 12 can be traveled ~n the time i~ ~akes the ligate 14 to traverse the over211 length of the fluid p~th 32.
In the ~llustr~ted embDdiment, the apparatus 10 includes mating housing portions 34 and 35 which to~ether enclose the membranes 24 and 26. The app~ratus 10 also ~ncludes ~n inlet 36 f~r c~nducting 25 the lig~te-c~rrylng fluid strea~ ~nt~ the fluid pa$h 32 ~nd ~n outlet 38 fDr c~nducting the purified ~i.e., lig~te-free) fluid stream DUt Df the fluid pa~h 32.
The ~paratus 10 further ~ncludes flu~d passages 40 and 42 formed along the Qpp~s~te surface of the membranes 24 and 26, 30 which do not face the fluid path 32.
:. .`1'-' .
,.
: ' , 3~i The fluid passages 4D ~nd 42 can be vari~usly formed, depending ~p~n the specific configvration of the membranes used. In the illustrated embDdiment, ~ membrane suppDrt element 51 and 52 m~intains ~n open flow path through the assDciated passage 4G ~nd 42, as well as assures a unifDrm distribution of fluid within the associated p~ssage 40 and 42.
Each pass~ge 40 and 42 includes ~n inlet 4~ for conducting fluid into the ~ssociated passage and zn outlet ~0 for conduc~ing fluid out of the ~ssociated passage.
The appar2tus 10 as heretofore described c~n cDnstitute ~
single ~ uid p~th 32 with a~ assoeiated pair of fluid p2ssages, as shown in Fig. 2. However, two or more of the ~pparatus 10 shown in Fig. 2 can be stacked one atop the other to form multiple fluid paths ~nd ~ssDciated fluid passages. lt should be appreciated that the axis 1; of the ~ uid pa~h 32 can e~tend either hori~ontally or vertically.
The purification apparatus 1~ as heretofDre ~escribed can form a part of a purification system ~4, which is shcwn in Fig. 4.
~he system 54 ~ncludes an inlet conduit 56 which connects the inlet 36 of the ~pparatus 10 with a source ~8 of fluid which is to be 20 purified. A pump 6D tr~nsp~rts the fluid through the inlet conduit ~6. An inline clamp 62 selectively opens and closes the inlet conduit ~6 to fluid flow.
An Dutlet condvit 64 communicates with the Dutlet 38 of the 2pp~ratus 10 ~nd conduct5 the purified fluid stream ~rsm the apparatus 2~ 10. A pump 66 can be e~plDyed to control the flow through the outlQt conduit 64, if desired. An inline clamp 6R selectively ~pens and closes the outlet conduit 64 to ~luid flow.
Inlet and outlet conduits 70 ~nd 72 com~uniGate, respectively, with the inlet and outlet 48 ~nd 50 of each p~ss~ge 40 30 and 42. ~he inlet conduit 7D selectively c~m~unicates throu~h a suit~ble valve 71 wi~h e~ther the s~urce 74 of ~ first solution ~r the 2~i g source 76 of a second solution. A pump 78 serves tc transport the selected solution through the inlet conduit 70 into the passages 40 and 42. The outlet conduit 72 transports the selected sslutiDn out of the passages 40 and 42 for discharge or recirculation.
The first solution in the source 74 has a chemical csmposition which mimicks the chemical composition of the fluid in the source ~8, which is to be purified. In other words, the chemical composition of the first solution constitutes an environment favorable to the formation of the desired ligate-ligand bond 13.
The second solution in the source 76 constitutes the selected regeneration agent 18. As such, it has a chemical composition which differs from that of the fluid to be purified and, when in contact with the ligands 12, changes the environment to one which is unfavorable to the formation of the ligate-ligand ~onds 13.
In accordance with the invention, a ~oncentration difference exists between the second solution lbeing of a highçr concentration) and the fluid in the fluid path 32 (being of 8 lower concentration).
Because of this concentration difference, the second solution is diffused from the passages 40 and 42 across the membrane toward the fluid path 32.
The concentration difference may be achieved in various ways. The concentration difference can arise due to differences in ionic strengths, with the second solution having a higher concentration of ions than that of the ftuid path 32. The 2~ concentration difference can also arise due to a difference in pH, with the second solution being more acidic or more alkaline than that of the fluid path 32. The concentratlon difference can also ~rise due to a difference in the concentratisn of molecules smaller than the ligate 14, with the second solution having the higher concentration of 30 these molPcules.
~ ~6~
~lD-In the lllustr2ted embodimen., p~ differentials ~r~ employed to cause diffusional transport. In this arr~ngement, the fir~
solutiDn has a pH which generally equals She p~ of the flu~d to be purified, which, for the sake Df description, is ~ssumed tD be neutral. The second solutiDn h2s ~ p~ ~hich is less than ~i.e., more ~cidic), and preferably significantly less than, the pH sf ~he neutral fluid.
The system ~4 furSher includes a discharge conduit B0 which, in the illustrated emb~diment, communicates with the inlet oonduit ~6 1~ bet~een the.inlet clamp 62 and the ~pparstus inlet 36. The discharge conduit 80 transports ligates ~4 ~reed by the regeneration ~gent 18 away fr~m the fluid path 32 for disposal. An ~nline cl~mp 82 selectively Dpens and closes the disch~rge conduit 80 to fluid flow.
~he discharge conduit 8D can, in ~n alternate arran~ement, be 1~ positiDned in comMunication with the outlet conduit 64.
~he sy~tem ~ ~ay also further include a rinse conduit 8~
: positioned on the side of the apparatus 10 opposite to the discharqeconduit 80. In the illustrated embodiment, the rinse c~nduit 84 co x unicate5 with the outlet cond~it 64 between the outlet cl~mp 68 and the Dutlet 38 of the apparatus lOo ~he rinse c~ndu~t B4 alsD
com~unicates with a source 86 of a rinse sDlution. The rinse solution may be used to speed the tr~nsport of lig~tes 14 ~way frDm the fluid path 32 ~fter re~eneration. An inline clamp 8~ and pump 90 selectively control the flo~ Df rinse sDlution thr~ugh the rinse 2~ conduit ~.
DPE
The operation of the apparatus 10 within the syste~ ~4 is sho~n sequentially in Figs. 5A thr~ugh SE. As shown, the apparatus lD
is cycled through three operati~e mDdes.
483~5 The first mode (shown in Fig. 5B) is the Adsorption Mode.
During this Mode, the ligate-carrying f1uid stream (identified by numeral ~2) is conducted through the fluid path 32 for pur~fication.
As shown in Fig. 5B, it is durins this ~ode that the ligate-ligand bonds 13 are formed along the facing surfaces 28 of the membranes 24 and 26. The ligate-free (i.e., purified) fluid stream (identified by nu~eral 943 is conducted from the apparatus 10.
The next ~ode (shown in Fig. 5C and 5D) is the P~egeneration Mode. During this Mode, the regeneration agent 18 (from the source 76) is caused to diffuse across the membranes 24 and 26. It is during this Mode that the ligate-ligand bond5 i3 formed during the preceding Adsorption Mode are broken. The diffused regeneration agent 18 frees the ligate 14 from the ligand 12 for disposal. At the same time, the ligand 12 is freed for subsequent use.
1~ The next mode (shown in Fig. 5E) is the Rinse Mode. During this Mode, the ~reed ligates 14 and any diffused regeneration agent 18 which has entered the fluid path 32 are conveyed by fluid strea~ 96 from the fluid path 32 for disposal.
As shown in Fig. ~A, following the Rinse M~de, the apparatus 10 is again ready to commence another Adsorption ~10de, followed by subsequent Regenerat;on and Rinse Modes.
Each of the three Mod s will now be described in greater detail.
THE ADSORPTION MODE
2i At the start of the procedure, all inline clamps 621 68, 82, and 88 are closed. To begin the Adsorption Mode, the clamps 62 and 68, at the inlet and outlet 36 and 38 of the apparatus 10, are opened (as shown d~agram~atically in Fig. 5A). The ligate-carrying flu;d stream 92 is conducted by the pump 60 through the fluid path 32.
3LZ4~332~i As the ligates 14 are exposed to the ligands 12S the ligate-ligand bonds 13 successively form along the ~embrane surfaces 28 (as shown ~n Fig. 5B). -The purified, ligate-free fluid stream 94 is conducted thrDugh the ~utlet 38 and into the outlet conduit 64.
As shown in phantom lines in Fig. 5B, if desired during the Adsorption Mode, the valve 71 can be positioned to convey the first solution from the source 74 into each of the fluid passages 40 and 42. This will assure that dif~usional transport does not occur across ~he membranes during this Mode.
A fixed volu~e of the first solutiDn may be conveyed into the fluid passages 40 and 42 during the Adsorption Mode, or the solution may he continuously circulated through the passages 40 and 42, as shown in phantom lines in Fig. ~B.
The presence of the first solution in the fluid passages 40 1~ and 42 is not essential for adiorption to occur within the fluid path 32. However, if the purified fluid stream is ~ntended to be introduced into the human body, or if it is Qtherwise intended for a purpose requiring relatively stringent quality control standards, the presence of the first solution in the fluid passages 40 and ~2 during the Adsorption ~lode is preferred.
At the outset of the Adsorption Mode lsee Fig. 5A), each ligand 12 is available to bind d ligate 14. Ligate-ligand bonds 13 form readily, and the ligate concentration in the stream 94 at the outlet 38 will be essentially zero (as shown in Fig. 5B). However, after bonds 13 are formed at more and more ligand sites, the liQands 12 will become more and more saturated with ligate5 14, 2nd the ligate concentration in the outlet stream 94 wilt begin to rise. This will be referred to as the ~break-through point" of the apparatus lQ.
Eventually, adsorption w~ll cease, and the ligate concentration in the outlet strea~ 94 will eq.al the.lig-te concentration in the inlet . ~ .
stream g2. The amDunt and n2ture ~f the ligand 12; the veloc;ty of ~he fluid stream 92; and the initi~l c~ncentratlon ~f the ligate 14 in ~he inlet stre2m 92 ~ll c~ntribute tO the specific bre~k-thr~ugh psin~
cf 'che appar2tus 10.
I~ is desirable to use a suitable deviee 98 (see ~ig. 4) to moni~Dr the concentr3ti~n ~f ligates 14 in the outlet ~luid stream 94 to detect when the break-through pDint has ~crurred. The monit~r device 98 can employ ultr~violet spectroph~to~etry Dr any compar~ble technique for thls purp~se ~hen the hre~k-~hrough p~int is reached, it ~s necessary to regenerate the ~igand 12 so that purificati~n Df the fluid stream 92 can resume.
REGEN~RATIDN MODE
In ~ccordance with the invention, the R~generation M~de is l~ begun ~s sD~n as pDssible after the system's bre~k-through point is .
detected. As shown diagram~atically in Fig. ~C, the inlet and Dutlet clamps 62 and 6~ are closed, le2vins a volume of flui~ 96 occupying the fluid pa~h 32.
At this time, the valve 71 i5 pDSitioned tD intrDduce the second soluti~n fi.e., the regenerativn agent 18) from the s~urce 76 tnto the fluid passeges 40 and 42. A concentration difference is created ~cross the rem~r~nes 24 ~nd 26. As sh~wn in Fi9. ~C, the regener2tion agent l~ has ~ ~lecular size sufficiently small enDugh to diffuse thr~ugh the membranes 24 ~nd 26 in respDnse tD the .
2; concentration differential cre~ted.
~ s the regener~tiDn agent lB diffvses across the membranes 24 ~nd ~6, it changes ~he envlronment surrounding the ligands 12, lowering the binding const~nt of the lig~nd 1~. As shDwn in Fig. ~D, the l~gand 12 then releases the previously ~und l~gate 14 int~ the surrounding fluid v~lume 96. The 1ig~nd 12 is thereby als~ freed for subsequent use.
. ~ . . ~ , ~L2~8~
-14~
The length of the Regeneration Mode is dependent upon the concentration differential obtained on opposite sides of the ~embranes 24 and 26, which controls the rate of diffusion. Th~ length of the Mode is also dependent upon the effective pore size, or "tightness", of the membranes 24 and 26 and its thickness in the regions spaced a~ay from the ligand bed 12. Both of these membrane-related factors also control the rate of diffusion. In this respect, attention is directed to Stevenson et al, "An Unsteady State Method ~or ~leasuring the Per~eability of Small Tubular Membranes", Al~hE Journal, Vol. 21, No. 6, pp. 1192 to 1199, November 1975. The length of the Regeneration ~lode is further dependent upon the amount of the regeneration agent 18 and its inherent effectiveness, which control the speed and efficiency at which the ligate-ligand bonds 13 are broken.
~y controlling these parameters, the rate of diffusion and the overall time of regeneration can be closely controlled.
Diffusional transport across the membrane oonstitutes a significantly faster and more efficient method of deliveriny the regeneration agent 18 to the ligands 12 than conventional practices, which rely upon transporting the regeneration agent 18 within the fluid path 32 to contact the ligands 12.
THE RINSE MODE
The fluid volume 96 occupying the fluid path 32 now contains all of the ligates 14 which have been removed during the preceding 2~ Adsorption M~de, as well as any diffused regeneration agent 18 which may have entered the ~luid path 32 during the Re~enerat;on Mode.
Preferably, the rate of diffusion is controlled closely enough so that only a small Yolume of the regeneration agent 18 is present in the fluid volume 96.
.
3:~5 Tha Rinse M~de is begun to convey ~he ligat~-laden fluid v~lume 96 ~ut of the appara~us 1~. The Rinse M~de can be variDusly conducted.
In the illustrated embodiment (see Fig. 4), the discharge clamp82 and outletclamp 68 ean be opened simultaneously to displace the 1ig2te-laden fluid volume 96 wlth ~n equal volume of the purified fluid stream 94, which, in this ~rrangement, is back-flushed thrDugh the apparatus 10.
. Alternately, if-the discharge. c~nduit 8D is situa~ed at ~he ovtlet ~8 of the apparatus 10, the ligate-laden ~1uid YDlume 96 can- be replaced ~ith an equal ~olume of the unpurified fluid stream 92.
Still alternately, the r~nse solution c~n be conveyed thr~u~h the rinse conduit 8~ to displace the ligate-laden fluid volume g6 from the apparatus 10.
As the 1ig2te-laden fluid volume is being rinsed from the 2pp~ratus 10, the valve 71 is pDsiti~ned to ~gain convey the first .
solution into the fluid passages 40 and 42. Diffusion across the ~em~r~ne reverses, ~nd the regeneration agent lB is rem~ed fr~m the vicinity of the ligands 12 to return to th~ opposite ~O surfaces 29 of the m~mbranes 24 and 26. The env~ronment favorable to the f~nmatiDn ~f ligate~ and bonds 13 returns to the facing surfaces 28 of the ~embranes 24 ~nd 26.
~ this time, the Ads~rption ~ode c~n begin again, follDwed by yet another Regenerati~n ~nd Rinse Mode, over ~nd ~ver until the decired YDlume of flu~d has been purified.
~ ec~use the inventiQn employs diffusiDn ~ the method o~
regenerating of the ligand 12 the apparatus 10 can ~e quickly ~nd repeatedly regenerated during 3 pur~f~c~tion pr~cedure. In arcordance with the inventlon, then, the amount ~f li~ana 12 required ~or ~ given rate of 1ig2nd removal can be ~inimized t~ the fullest extent poss~ble. At the same time, the v~rlD~s.opertting par~meters of the system can ~l-so be ~ptimized to the full~st extent p~ss~ble~
In this regard, reference ~s m~de to the following ExanlplesO
EXAMPLE I
The purpose of this Example is to illustrate how the various operatin~ parameters associated with a giYen purification procedure affect the design of the apparatus 10 which embodies the features of the invention. The Example also demonstrates how the invention can be used to optimize the performance objectives of the purification procedure.
In this Example, the system will be used fDr the treatment of ~yasthenia Gravis. Myasthenia Gravis is a disease in which antibodies carried by the blood plasma of a patient block normal neuro-muscular junctions. It has been observed that the removal of these antibodies from the patient's plasma exerts a beneficial therapeutic effect.
Thesè antibodies (or ligates) can be removed from the plasma by adsorption, using an antibody-specific antigen (or ligand) a'fixed 1~ to a semipermeable membrane and regenerated in accordance with the invention.
The various clinical operating parameters associated with the extracorporeal treatment of ~yasthenia 6raYis by adsorption include:
(a~ A typical patient has about 100 x 10 9 moles of ~0 undesired antibodies per liter of plasma;
(b) For the patient's comfort and well being, an extracorporeal treatment time should not exceed 240 minutes;
. (c) For the comfort of the pa~ient, the rate at which plasma is removed for treatment should not exceed 70 cc/min.
2~ Typically, durin~ the treatment, the whole blood will be withdrawn from the patent and passed through a centrifuge or filter to first separate the cellu7ar eomponents of the blood (red blood cells platelets, and leukocytes) from the plasma. The cellular co~ponents will be returned to the patient, while the plasma is next conYeyed through the~apparatus 10 as heretofore described to remoYe the offending antibodies. The purified, antibody-free plasma i5 then returned to the patient.
133:25 ~7 (d) The antigen known to bind the antibody ~ssociated ~ith Myasthenia ~ravis is the ~cetylcholine receptor obt~ined from the ~uscle tissue of the electric fish torpedo c~lifornicus. This ligand 12 is not 2a5ily obtained and is therefore c05tly. A system which embodies the feature of the invention c~n significantl~ reduce the cost of tr~atment. By regenerating the antigen N-times, the ~mDunt of antigen used can be reduced by 1/~. In this ~xample, the antigen will be re~enerated lD0 times dvrinQ the 240 minute procedure, thereby reducing the antigen-related CD5t of the system-~y i/100. This effectively reduces the C05t of the ligand 12 required for a single treatment frDm more than $1,DD~ to the range of S10.
(e) Given the objective of regenerating 100 times~ the o~erall tre~tment period will be divided into treatment cycles of 2.4 . ~inutes each (24D minutes/100 reQenerations). Each treatment cycle 1~ will, in turn, be divided ints modes embodying the features of the invention, as foll~ws:
~1~ Adsorption Mode 2.0 minutes (2) Regeneration Mode 18 seconds (3) Rinse Mode 6 seconds This treabment cycle is shown diagrammatic~lly in Fig. 6.
From these operatin~ goals ~nd parameters, the s ke ~f the purifica.ion apparatus 10 can be c~lculated:
(f) The number of ligands (i.e.~ ~ntigens) thdt are requ~red to bond all of the the l~gdtes (i.e., ~ntibodies) traversing the appsra~us 10 during e~ch two minute Adsorption MDde (~Li is:
NL ~ 2 Min x 70 x 10-3 liters x 100 x 10-9 nm x 6 x 1023 molecules le ~in ~ ----lr~b~---- (AVD8adrO'S ~umber) ~ L e 8.4 x 101~ ligand;. This is the number ~f ligands which will be plAced w~thin the apparatus. In th~s Ex~mple, tt is ~ssumed that one ligand ~Dlecule will bind one l~gate molecule.
.
- ~
3325i -1&-(g) It is desirable to pr~perly space the l~ands upDn ~he surf~ce Gf the mem~rane to ~v~id overcrowding, which can, in turn, adversely effect the rate of adsDrpticn. It is pre~erred that each ligand 12 cccupy on the ~embrane ~n area of n~ less ~h~n 16D~ A2 ; (1~00 x 10 1~ cm2). Therefore, the t~tal membrane surface are2 (~A) required is:
MA ~ NL x 16DD x 1~ 16 cm2 - 8.4 x lD1~ Ligands x lSD~ x 1~ 16 cm2 ~ 1344 cm2 .
(H) Since, in the illustr~ted embDdiment, tw~ flat sheets are used, MA 02n be divided in half, i.e., 672 cm2.
(i) FDr ~ fluid path thickness of .01 cm, the YDlume of the fluid path ~p) i5:
Yp ~ 672 cm x .01 cm 1~ Yp 6.72 cc M~re particularly, at a pl2sma flDw ratè of 70 cc~minute through the ~bove-described treatmenS appar~tus 10, abDut 140 cc of pl2sm2 will bs purified during e~ch two minute Adsorption ~de. Of this volume9 6.72 cc of pl~s~ will n~t be returned tD the paSient.
Instead, this ~olume of plasma (c~nstituting the fluid volume 96 shown in Fiss. ~C, D, and F) witl be discharged-during the Rinse l~de to cDnvey ~ll the ligates adsDrbed during the preceding AdsorptiDn Mode a~2y from the appar~tus lDo The overall p'1asm~ loss r~te of the ~bove-described app~ratus 10 due to regeneration sf the llgand is thus 2~ only 4-8O~
FurthermDre, because the ~ntigen is regenerated lD~ times during the procedure, the c~st of the antigen used for the ~re~Sment ~s reduced 100 times.
. ~
, ~.~4~32~
It should now be appreciated that the various operatin~
parameters and purification objectives of the system and apparatus 10 made in accordance with the invention can be mer~ed to obtain the desired performance results.
EXAMPLE II
the purpose of this Example is to illustrate that an apparatus 10 which embodies the features of the invention can be repeatedly cycled thrDugh successive Adsorption, Regeneration, ard Rinse Modes.
l~ The ligand 12 employed in the apparatus 10 was an acetylcholine analog. It wac affixed to the facing surfaces of a pair of flat cellulose dialysis membranes 24 and 26. A fluid path 32 of 0.0126 mm separated the two membranes 24 and 26.
The ligate 14 was acetylcholine esterase present in a normal 1~ saline solution (pH 7.35) in a concentration of 8 m~/ml.
The apparatus 10 was used in association with a system ~4 as shown in Fig. 4. The solution occupying the source 74 (i.e , the solution mimicking the stream to be purified) was normal sallne. The solution occupyinQ the source 76 ~i.e., the regeneration agent 18) was a buffered citrate solution (pH 2.0). ~onmal saline solution was also employed as the rinse so~ution.
The apparatus 10 was operated through nine (9) successive cycles, each including an Adsorption ~ode, a Regeneration Mode, and a.
Rinse ~lode as heretofore des~ribed.
During each cycle, the following time periods were used:
Adsorpt1On Mode: 4.5 m~nutes Regeneration Mode: 1 minute Rinse Mode: . 1 minute ~3~5 During each Adsorption ~ode, the acetylcholine esterase solution was introduced into the apparatus at a flow rate of 3.6 mltmin. During each cycle, the concentration of the acetylcholine esterase in the ~ uid stream exiting the apparatus 10 was continuously monitored to detect the break-through point of the apparatus 10. The results are summarized in the Table.
During each Regeneration ~ode, the citric acid buffer was introduced at a flow rate of 9.6 ml/min.
The results are graphically shown in Fig. 7.
As shown in Fig. 7~ during the Adsorption Mode of the first cycle, the concentration of acetylcholine esterase in the outlet stream was zero for a period of 210 seconds. After 210 seconds, however, the ligate concentration in the outlet stream began to increase, indicating that the break-through point had been reached.
After 270 seconds~ the ligate concentration in the outlet stream 94 equaled the ligate concentration in the inlet stream. A Regeneration Mode and a Rinse Mode followed to end the cycle.
In subsequent cycles, the break-through point was reached at a successi~ely earlier time during the associated Adsorption ~ode, until the eighth cycle. In the eighth and ninth cycles, the break-through poi~t occurred after about 1~0 seconds of the associated Adsorption Mode, indicating that the apparatus had achieved a steady state operating condition.
It was observed that only about two percent (2~) of the ~; regenerat;on ager,t 1~ used during each Regeneration Mode "leaked" into the fluid strea~ and was dischar~ed during the following Rinse Mode.
The remainder of the regeneration aqent d~ffused back through the membranes for subsequent use.
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t : t -- ~ ~ ~ C`J N ~J t~l
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of purifying a fluid stream employing a regenerable ligand to adsorb a ligate carried in the fluid stream, said method comprising the steps of conducting the fluid stream along one surface of a membrane having affixed thereto the regenerable ligand, the membrane being sufficiently impermeable to the ligate-carrying fluid stream to prevent convective transport of the ligate-carrying fluid stream across the membrane in response to pressure differentials while being suf-ficiently permeable to a selected regeneration agent for the ligand to allow diffusional transport of the selected regeneration agent across the membrane when concentration differences exist, thereby forming a ligate-ligand bond on the one surface of the membrane, terminating the conduction of the fluid stream along the one surface of the membrane, diffusing the selected regeneration agent for the ligand across the membrane from the opposite surface of the membrane to the ligand to break the ligate-ligand bond, thereby freeing the ligate from the ligand, and rinsing the freed ligate away from the freed ligand.
2. A method according to claim 1 and further including a second diffusion step comprising after said rinsing step, diffusing the regeneration agent back across the membrane from the ligand to the opposite surface of the membrane.
3. A method according to claim 2 wherein said second diffusion step includes exposing the opposite surface of the membrane to a solution having a concentration which differs from the concentration of the regeneration agent in an amount sufficient to cause the regeneration agent to diffuse back across the membrane away from the ligand.
4. A method according to claim 1 and further including the step of while said fluid stream conducting step is being carried out, maintaining an essentially zero concentration difference across the membrane to prevent diffusion while the ligate-ligand bond forms.
5. A method according to claim 1 wherein said diffusion step includes exposing the opposite surface of the membrane to a regeneration agent having a concentration which differs from the concen-tration of the fluid stream in an amount sufficient to cause the regeneration agent to diffuse across the membrane toward the ligand.
6. A method of purifying a fluid stream employing a regenerable ligand to adsorb a ligate carried in the fluid stream, said method comprising the steps of conducting the fluid stream along one surface of a membrane having affixed thereto the regenerable ligand, the membrane being sufficiently impermeable to the ligate-carrying fluid stream to prevent convective transport of the ligate-carrying fluid stream across the membrane in response to pressure differentials while being sufficiently permeable to a selected regeneration agent for the ligand to allow diffusional transport of the selected regeneration agent across the membrane when concentration differences exist, thereby forming a ligate-ligand bond on the one surface of the membrane, terminating the conduction of the fluid stream along the one surface of the membrane, leaving a fixed volume of the fluid stream in contact with one membrane surface, exposing the opposite surface of the membrane to a solution containing the selected regeneration agent for the ligand and having a pH which differs from the pH of the fluid stream in an amount sufficient to cause the regeneration agent to diffuse across the membrane to break the ligate-ligand bond, thereby freeing the ligate into the fixed fluid stream volume, and rinsing the fluid stream volume containing the freed ligate and diffused regeneration agent away from the one surface of the membrane.
7. A method according to claim 6 and further including the step of while said fluid stream conduction step is being carried out, exposing the opposite surface of the membrane to to a solution having a pH generally equal to the pH of the fluid stream, thereby preventing diffusion across the membrane while the ligate-ligand bond forms.
8. A method according to claim 6 and further including the step of after said rinsing step, exposing the opposite surface of the membrane to a solution having a pH generally equal to the pH of the fluid stream to reverse the diffusion of the regeneration agent across the membrane.
9. An apparatus for purifying a fluid stream by the removal of ligates carried therein comprising a membrane having first and second surfaces, means defining a first fluid path along said first membrane surface for conveying the ligate-carrying fluid stream, a regenerable ligand affixed to said first membrane surface, said membrane being sufficiently impermeable to the ligate-carrying fluid stream to prevent convective transport of the ligate-carrying fluid stream across the membrane in response to pressure differentials while being sufficiently permeable to a selected regeneration agent for the ligand to allow diffusional transport of the re-generation agent across the membrane when concentration differences exist, and means defining a second fluid path along said second membrane surface for conveying the selected regenera-tion agent for said ligand in a concentration sufficiently different from the concentration of the fluid stream to diffuse across said membrane toward said ligand.
10. An apparatus according to claim 9 wherein said membrane is shaped as a hollow fiber, said first fluid path being the bore of said hollow fiber, said first membrane surface comprising the interior luminal surface of said hollow fiber, and said second membrane surface comprising the exterior surface of said hollow fiber.
11. An apparatus according to claim 9 wherein said membrane is shaped as a flat sheet having oppositely facing surfaces comprising said first and second membrane surfaces.
12. An apparatus according to claim 9 wherein said membrane is of uniform porosity between said first and second surfaces.
13. An apparatus according to claim 9 wherein said first surface of said membrane includes an exterior surface region and an interior region positioned between said exterior surface region and said second mem-brane surface, wherein said exterior surface region is more porous than said interior region, and wherein said ligand is affixed to said more porous, exterior surface region.
14. An apparatus according to claim 9 wherein a plurality of said ligands are affixed to said first membrane surface.
15. An apparatus according to claim 14 wherein each of said ligands occupies on said first membrane surface an area of no less than 1600A2.
16. An apparatus according to claim 9 wherein said membrane includes a pair of membranes, each configured as a flat sheet and having first and second oppositely facing surfaces, wherein said first membrane surfaces of said pair of membranes are positioned in a facing, spaced apart configuration to form therebetween said first fluid path.
17. An apparatus according to claim 16 wherein said first fluid path between said pair of membranes is no more than 200 microns across.
18. A system for purifying a fluid stream em-ploying a regenerable ligand to adsorb a ligate carried in the fluid stream, said system comprising an apparatus as defined in claim 9 inlet means for conducting the ligate-carrying fluid stream into said first fluid path of said apparatus to form a ligate-ligand bond on said first membrane surface, outlet means for conducting the ligate-free fluid stream from said first fluid path, means for conducting the selected regeneration agent for said ligand into said second fluid path for diffusion across said membrane to break the ligate-ligand bond, thereby freeing within said first fluid path the ligate from the ligand, and means communicating with one of said inlet means and said outlet means for transporting ligates freed by the regeneration agent away from said first fluid path.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/610,368 US4741832A (en) | 1984-05-15 | 1984-05-15 | Purification apparatus and method employing a regenerable ligand |
| US610,368 | 1984-05-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1248325A true CA1248325A (en) | 1989-01-10 |
Family
ID=24444745
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000480357A Expired CA1248325A (en) | 1984-05-15 | 1985-04-30 | Purification apparatus and method employing a regenerable ligand |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4741832A (en) |
| EP (1) | EP0168140A3 (en) |
| JP (1) | JPS6131166A (en) |
| CA (1) | CA1248325A (en) |
| ES (2) | ES8700955A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8702693A (en) * | 1987-11-11 | 1989-06-01 | Tno | METHOD FOR SEPARATING AMPHOTER MIXTURES IN ADSORPTION COLUMNS AND BEDS AND DEVICE THEREFOR. |
| US5051237A (en) * | 1988-06-23 | 1991-09-24 | P B Diagnostic Systems, Inc. | Liquid transport system |
| JPH01230372A (en) * | 1988-12-28 | 1989-09-13 | Kanegafuchi Chem Ind Co Ltd | Regenerative device for processing body fluid |
| DE4108820A1 (en) * | 1991-03-18 | 1992-09-24 | Karl Dr Reuter | CONTINUOUS CHROMATOGRAPHY |
| US5770087A (en) * | 1991-03-18 | 1998-06-23 | Reuter; Karl Arnold | Continuous chromatography |
| DE4309410A1 (en) * | 1993-03-19 | 1995-02-16 | Stange Jan | Material, process and equipment for the selective separation of freely dissolved and substance-bound substances from liquid substance mixtures as well as process for the production of the material |
| JP2915812B2 (en) * | 1994-12-07 | 1999-07-05 | 科学技術振興事業団 | Transfer adhesion method of fine particle film |
| EP0787523B1 (en) * | 1996-02-01 | 2003-04-02 | MAT Adsorption Technologies GmbH & Co. KG | Apparatus and process for material-specific treatment of fluids |
| US6136199A (en) * | 1997-12-08 | 2000-10-24 | Julius James Jablonsky | Selective removal of phosphates and chromates from contaminated water by ion exchange |
| US6379973B1 (en) | 1999-03-05 | 2002-04-30 | The United States Of America As Represented By The Department Of Health And Human Services | Chromatographic separation apparatus and method |
| FR2931081B1 (en) * | 2008-05-14 | 2010-06-25 | Direction Et Pirorites | DEVICE FOR FILTRATION OF A COMPLEX LIQUID SUCH AS BLOOD, IN PARTICULAR APPLICABLE TO AN AUTOSFUSER |
| DE102013218239A1 (en) * | 2013-08-05 | 2015-02-19 | Tetec Tissue Engineering Technologies Ag | Process for the preparation of a product by means of dialysis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4375414A (en) * | 1971-05-20 | 1983-03-01 | Meir Strahilevitz | Immunological methods for removing species from the blood circulatory system and devices therefor |
| US3842000A (en) * | 1971-10-07 | 1974-10-15 | Battelle Development Corp | Process for removal of ammonia from aqueous streams |
| CS174971B1 (en) * | 1972-05-16 | 1977-04-29 | ||
| FR2199014B1 (en) * | 1972-09-12 | 1975-03-14 | Rhone Poulenc Ind | |
| US4266026A (en) * | 1975-08-04 | 1981-05-05 | Rohm And Haas Company | Catalytic process utilizing hollow fiber membranes |
| US4131544A (en) * | 1976-08-03 | 1978-12-26 | Nasik Elahi | Macroencapsulated sorbent element and process for using the same |
| JPS5551408A (en) * | 1978-10-11 | 1980-04-15 | Kuraray Co Ltd | Membrane type fluid filtering apparatus |
| US4303531A (en) * | 1978-11-28 | 1981-12-01 | Koei Chemical Co., Ltd. | Method for adsorbing and recovering phenols |
| US4361484A (en) * | 1979-06-11 | 1982-11-30 | Gambro Ab | Process for treating and/or removal of substances from liquid, especially whole blood |
| NL7909337A (en) * | 1979-12-28 | 1981-07-16 | Akzo Nv | METHOD FOR THE REGENERATION OF SORBENTIA, IN PARTICULAR ION EXCHANGERS. |
| US4441794A (en) * | 1980-08-04 | 1984-04-10 | Field Roger C | Adjustable sun screen for camera lens |
| US4612122A (en) * | 1981-06-29 | 1986-09-16 | Clara Ambrus | Removing heavy metal ions from blood |
| US4637880A (en) * | 1981-11-30 | 1987-01-20 | Cordis Laboratories, Inc. | Apparatus and method for therapeutic immunodepletion |
| SE8206708D0 (en) * | 1982-11-16 | 1982-11-25 | Gambro Ab | COLUMN FOR USE IN CONNECTION WITH ANTIBODY RECORDING |
-
1984
- 1984-05-15 US US06/610,368 patent/US4741832A/en not_active Expired - Fee Related
-
1985
- 1985-04-30 CA CA000480357A patent/CA1248325A/en not_active Expired
- 1985-05-14 ES ES543130A patent/ES8700955A1/en not_active Expired
- 1985-05-14 EP EP85303382A patent/EP0168140A3/en not_active Withdrawn
- 1985-05-14 JP JP10063385A patent/JPS6131166A/en active Granted
-
1986
- 1986-06-16 ES ES556095A patent/ES8705775A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES556095A0 (en) | 1987-05-16 |
| ES8700955A1 (en) | 1986-11-16 |
| EP0168140A2 (en) | 1986-01-15 |
| US4741832A (en) | 1988-05-03 |
| EP0168140A3 (en) | 1987-04-22 |
| JPS6131166A (en) | 1986-02-13 |
| ES543130A0 (en) | 1986-11-16 |
| JPH0214854B2 (en) | 1990-04-10 |
| ES8705775A1 (en) | 1987-05-16 |
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