DK151180B

DK151180B - HOME OPER FUSION DEVICE

Info

Publication number: DK151180B
Application number: DK445580A
Authority: DK
Inventors: Lee R Beck; Thomas A Davis
Original assignee: Stolle Res & Dev
Priority date: 1980-10-21
Filing date: 1980-10-21
Publication date: 1987-11-09
Also published as: DK151180C; DK445580A

Description

151180151180

Opfindelsen angår et apparat til hæmoperfusion, der omfatter et aflangt hus af et impermeabelt materiale, hvilket hus i sine ender er lukket med impermeable endeplader med en tilførselsåbning i den ene af endepladerne og en afgangsåbning i den anden af endepladerne og på 5 sin inderside har en flerhed af aksialt forløbende ribber, som i alt væsentligt strækker sig gennem hele husets længde og fortsætter radialt på den sidstnævnte af endepladerne.BACKGROUND OF THE INVENTION The invention relates to an apparatus for hemoperfusion comprising an elongate housing of an impermeable material, which housing at its ends is closed with impermeable end plates with a supply opening in one of the end plates and a discharge opening in the other of the end plates and having on its inner side a a plurality of axially extending ribs extending substantially throughout the length of the housing and extending radially on the latter of the end plates.

Blodfiltrering og hæmoperfusion til rensning af blod er velkendt.Blood filtration and haemoperfusion to purify blood are well known.

Med få undtagelser er de anordninger, der anvendes til disse formål, 10 imidlertidig kun i stand til at fjerne substanser pi ikke-specifik måde. Fjernelse af toxiske eller uønskede stofarter fra blodet udføres ved dialyse på basis af molekylstørrelse, hvortil der anvendes semipermeable membraner (se. U.S.A. patent nr. 3.169.423), på basis af ionnatur ved strømning (eng: perfusion) over ionbytterharpikser (se U.S.A. patent 15 nr. 3.794.584; 4.031.010), eller på basis af affinitet til adsorbenser ved strømning over aktiveret kul. Disse metoder har alvorlige begrænsninger på grund af mangel på specificitet. I den fraktion, der fjernes fra blodet, findes hormoner, næringsstoffer, medikamenter, elektrolytter og andre stofarter, hvis fjernelse fra blod kredsløbet meget vel kan 20 medføre ugunstige virkninger på den patient, hvis blod renses ved perfusionen. Eftersom patienter, der kræver en sådan behandling, lider af medikamentel overdosering, nyre- eller leversvigt eller andre forhold, der alvorligt mindsker deres levedygtighed, kan yderligere metabolisk uligevægt dårligt tolereres. En yderligere ulempe ved hæmo-25 perfusionsanordningernes manglende specificitet er den begrænsede kapacitet for target-stoffer. Target-stofferne må konkurrere med andre substanser om de tilgængelige bindingssteder på adsorbenset. Anordninger må derfor være uforholdsvis store for at sikre tilstrækkelig kapacitet til target-stofferne.However, with few exceptions, the devices used for these purposes are only capable of removing substances in a non-specific manner. Removal of toxic or undesirable substances from the blood is performed by molecular size dialysis using semipermeable membranes (see US Patent No. 3,169,423) based on ionic nature by flow (perfusion) over ion exchange resins (see US Patent 15 No. 3,794,584; 4,031,010), or on the basis of affinity for adsorbents upon activated charcoal flow. These methods have serious limitations due to lack of specificity. In the fraction removed from the blood are hormones, nutrients, drugs, electrolytes and other substances whose removal from the blood circuit may very well have adverse effects on the patient whose blood is purified by perfusion. Since patients requiring such treatment suffer from drug overdose, renal or liver failure or other conditions that severely diminish their viability, further metabolic imbalance can be poorly tolerated. A further disadvantage of the non-specificity of the haemofusion devices is the limited capacity of target substances. The target substances must compete with other substances for the available binding sites on the adsorbent. Devices must therefore be disproportionately large to ensure sufficient capacity for the target substances.

30 Ud over problemerne med den manglende specificitet hos disse anordninger optræder der endvidere komplikationer med hensyn til struktur- og f lydeegens kåber. Der iagttages ofte beskadigelse af formede elementer og makromolekylære komponenter i blodet i form af f.eks. hæmolyse, blodpladeaggregation, fibrindannelse og leukocyt-35 destruktion, når blod udsættes for ikke-biologiske overflader eller turbulent strømning. Heparinisering af patienter er kun delvis effektiv til forebyggelse af sådan skade. Hæmoperfusionsanordninger, der inkorporerer tilfældigt fordelte, partikelformige adsorbenser, har udvist 151180 2 tilbøjelighed til pakning under forhold/ hvor der foregår strømning. Resultatet er et stort trykfald og formindsket strømning gennem anordningen. Under sådanne forhold øges blodbeskadigelsen.30 In addition to the problems with the lack of specificity of these devices, there are also complications with regard to the sheaths of the structural and sound properties. Damage to shaped elements and macromolecular components in the blood is often observed in the form of e.g. hemolysis, platelet aggregation, fibrin formation, and leukocyte destruction when blood is exposed to non-biological surfaces or turbulent flow. Heparinization of patients is only partially effective in preventing such injury. Hemoperfusion devices incorporating randomly distributed particulate adsorbents have shown propensity to pack under conditions / where flow occurs. The result is a large pressure drop and diminished flow through the device. Under such conditions, blood damage increases.

Der er gjort mange forsøg på at overvinde disse problemer og på 5 at udforme anordninger, som udviser specificitet og anvendelighed over for et større område af molekylarter, navnlig højmoiekylære stofarter. Nogle af de syntetiske matrikser, der er blevet undersøgt, udviser særlig affinitet over for visse specifikke opløste stoffer. I én af disse anordninger anvendes der fluorcarbonplast til specifik fjernelse af 10 endotoxin (U.S.A. patent nr. 3.959.128).Many attempts have been made to overcome these problems and to design devices which exhibit specificity and applicability to a wider range of molecular species, particularly high molecular weight species. Some of the synthetic matrices that have been studied exhibit particular affinity for certain specific solutes. In one of these devices, fluorocarbon plastic is used to specifically remove endotoxin (U.S. Patent No. 3,959,128).

Yderligere specificitet er blevet opnået ved brug af bioaktive substanser, der er bundet til inerte organiske eller uorganiske materialer i hæmoperfusionssystemer. Det efterfølgende er eksempler på denne type: 15 Bilirubins og chenodeoxycholinsyres affinitet for serumalbumin er blevet udnyttet af adskillige forskere. Antigen-antistof-interaktion er også blevet anvendt (Canadisk patent nr. 957.922). Immobiliserede antigener er blevet overstrømmet med blod til fjernelse af antistoffer mod BSA, DNA, HSA og Ovalbumin, mod blodfaktor VIII og mod 20 immunoglobulinfraktioner IgG og ImG. Immobiliserede antistoffer (IgG,Further specificity has been obtained using bioactive substances bound to inert organic or inorganic materials in hemoperfusion systems. The following are examples of this type: The affinity of serum albumin for bilirubin and chenodeoxycholic acid has been exploited by several researchers. Antigen-antibody interaction has also been used (Canadian Patent No. 957,922). Immobilized antigens have been flooded with blood to remove antibodies against BSA, DNA, HSA and Ovalbumin, against blood factor VIII and against 20 immunoglobulin fractions IgG and ImG. Immobilized antibodies (IgG,

IgM) er blevet anvendt i hæmoperfusionssystemer til formindskelse af kredsløbets indhold af medikamenter og endogene stofarter. Antistoffer mod digoxin, DNA, BSA, tumor-associerede antigener, donornyre-antigener og multipel myelomaprotein samt mod lavdensitetslipoproteiner 25 er blevet immobiliseret i systemer uden for kroppen med henblik på opnåelse af forskellige terapeutiske mål.IgM) has been used in hemoperfusion systems to reduce the circulation of drugs and endogenous substances. Antibodies to digoxin, DNA, BSA, tumor-associated antigens, donor kidney antigens, and multiple myeloma proteins as well as to low-density lipoproteins 25 have been immobilized in extracorporeal systems to achieve various therapeutic targets.

Blandt de enzymer, celleekstrakter og hele celler, der er blevet immobiliseret i systemer uden for kroppen (canadisk patent nr. 957.922) er urease, uricase, aspariginase, pancreasceller, leverceller og 30 levermi krosomer, nuklease og katalase.Among the enzymes, cell extracts and whole cells that have been immobilized in extracorporeal systems (Canadian Patent No. 957,922) are urease, uricase, aspariginase, pancreatic cells, liver cells and liver microsomes, nuclease and catalase.

Egenskaber ved materialer og anordninger, der bringes i kontakt med cirkulerende biologiske væsker, er blevet undersøgt indgående. Weetall et al. har i: "Some |n Vivo and |n Vitro studies of Biologically Active Molecules on Organic Matrixes for potential Therapeutic Applica-35 tions", Biomedical Applications of Immobilized Enzymes and Proteins, T.M.S. Chang, Ed., Plenum Press, New York, N.Y.; som checkliste anført nedenstående kriterier for udformning af anordninger af den omhandlede art: 3 151180 1) laminær strømning, 2) hastighedsgradienten bør være over 350/sek, 3) materiale, der kommer i kontakt med blod, skal være relativt ikke-thrombogent, 4) glatte overflader må opretholdes, 5) en mindste strømkanaldiameter pi ca. 100 øm, 6) knusnings- og male-5 virkning fra bærermateriale må undgås.Properties of materials and devices contacted with circulating biological fluids have been extensively investigated. Weetall et al. have in: "Some | n Vivo and | n Vitro Studies of Biologically Active Molecules on Organic Matrices for Potential Therapeutic Applications", Biomedical Applications of Immobilized Enzymes and Proteins, T.M.S. Chang, Ed., Plenum Press, New York, N.Y.; as a checklist, the following criteria for the design of devices of the type in question are listed: 3) 1) laminar flow, 2) the velocity gradient should be above 350 / sec, 3) material that comes into contact with blood must be relatively non-thrombogenic, 4 5) a minimum flow channel diameter p in approx. 100 seams, 6) crushing and grinding action from carrier material must be avoided.

To yderligere kriterier er af betragtelig vigtighed: 1) størst mulig belastning af aktive, blodændrende stofarter pr. "priming volumenenhed" og 2) mindst mulig modstand mod disse stofarters aktive kontakt med den blodkomponent, der skal ændres, dvs. den ved kontakten må 10 kræves mindst mulig diffusionsstyret transport, og transporten skal ske gennem mindst mulig modstandsydende stof.Two additional criteria are of considerable importance: 1) the greatest possible load of active blood-changing substances per "priming volume unit" and 2) least possible resistance to the active contact of these substances with the blood component to be altered; the contact must require as little diffusion-controlled transport as possible at the contact, and the transport must be made through the least resistance-resistant material.

Indtil i dag er der i alle hæmoperfusionssystemer, der anvender meget specifikke afgiftende stofarter, som er isoleret inden i anordningen, anvendt en af 4 arrangementer: 1) isolering af den 15 afgiftende stofart ved adskillelse fra det gennemstrømmende blod under anvendelse af semipermeable membraner (f.eks. U.S.A. patent nr. 3.619.423) eller hule fiberrør, 2) indkapsling eller fastgørelse til partikelformige materialer (f.eks. U.S.A. patent nr. 3.865.726), 3) fastgørelse af stofarterne til en ikke-porøs membran eller en anden plan 20 overflade (f.eks. U.S.A. patent nr. 3.959.128) eller 4) fastgørelse til den indre overflade af polymerslanger, gennem hvilke blodet ledes (f.eks. canadisk patent nr. 957.922).To date, in all hemoperfusion systems employing very specific detergent species isolated within the device, one of 4 arrangements has been used: 1) isolating the detoxifying drug species by separation from the flowing blood using semipermeable membranes (f e.g., U.S. Patent No. 3,619,423) or hollow fiber tubes; 2) Enclosure or attachment to particulate materials (e.g., U.S. Patent No. 3,865,726); 3) Attachment of the fabric species to a non-porous membrane or a second plane 20 surface (e.g., U.S. Patent No. 3,959,128) or 4) attachment to the inner surface of polymer tubes through which blood is passed (e.g., Canadian Patent No. 957,922).

Ingen af disse systemer opfylder alle de ovenfor anførte kriterier. Anordninger med semipermeabel membran eller hul fiber stiller for 25 opnåelse af de isolerede elementers aktive medvirken store krav til diffusionen, og de er begrænset til aktivitet over for lavmolekylære stoffer i blodet. Anordninger, der gør brug af partikelformige komponenter, i hvilke de aktive stoffer er mi kroind kapslet eller sekvestreret inden i porerne af bærerstoffer lider af de samme 30 diffusionsmodstandsbegrænsninger og udviser endvidere strømningsmodstand på grund af sammenpakning såvel som blodbeskadigelse forårsaget af den malende virkning fra partikelbevægelsen. Ikke-porøse, plane overflader og polymere slanger har et lille overfladeareal og således utilstrækkelig kapacitet for aktive elementer.None of these systems meet all of the above criteria. Devices with semipermeable membrane or hollow fiber impose high demands on the diffusion and achieve limited diffusion activity and are limited to activity against low molecular weight substances in the blood. Devices using particulate components in which the active substances are encapsulated or sequestered within the pores of carriers suffer from the same diffusion resistance limitations and further exhibit flow resistance due to compaction as well as blood damage caused by the grinding action of the particle movement. Non-porous, planar surfaces and polymeric tubing have a small surface area and thus insufficient capacity for active elements.

35 Et alternativ til disse indretninger er anvendelsen af fiberfyldte filterindsatser. Fibre har i lang tid været anvendt i blod kontaktanordninger til fjernelse af blodkomponentaggregater under transfusion (f.eks. U.S.A. patent nr. 3.462.361). Polymerfibre, der har pyrolytisk carbon aflejret på deres overflade, og som er anbragt i en tilfældig 151180 4 masse, er blevet anvendt som ikke-specifikke adsorbenser ved hæmoper-fusion (f.eks. U.S.A. patent nr. 3.972.818). Antistoffer og andre proteiner er blevet inkorporeret i cellulosefibre ved indeslutning til anvendelse ved radioimmunanalyser og til industriel brug (f.eks.An alternative to these devices is the use of fiber-filled filter cartridges. Fibers have long been used in blood contact devices to remove blood component aggregates during transfusion (e.g., U.S. Patent No. 3,462,361). Polymer fibers having pyrolytic carbon deposited on their surface and placed in a random mass have been used as nonspecific adsorbents in hemoper fusion (e.g. U.S. Patent No. 3,972,818). Antibodies and other proteins have been incorporated into cellulose fibers by containment for use in radioimmunoassays and for industrial use (e.g.

5 U.S.A. patent nr. 4.031.201). Antigener er blevet fikseret til nylonkatetere og indført i arterier til fjernelse af antistoffer fra blod kredsløbet.5 U.S.A. Patent No. 4,031,201). Antigens have been fixed to nylon catheters and introduced into arteries to remove antibodies from the blood circulation.

Inden for hæmoperfusionsområdet er anordninger, der er udformet til meget specifik ændring af blodsammensætningen, og som indeholder 10 fibre, blevet anvendt med begrænset succes. Hersh og Weetall (se ovenfor) anvendte en filterindsats indeholdende bioaktive molekyler bundet til tilfældigt fordelte, ikke-porøse polyesterfibre. Bade enzymer og antistoffer er blevet immobiliseret ved hjælp af denne teknik. Disse anordninger repræsenterer en betragtelig forbedring i forhold til 15 tidligere hæmoperfusionssystemer med hensyn til formindskelse af beskadigelsen af formede elementer i blodet. Der er dog stadig nogle problemer tilbage ved denne udformning. Ikke-fastholdte, tilfældigt dispergerede fibre har tendens til sammenpakning under de ønskede strømningshastigheder, når der er tilstrækkeligt med fiber til stede til 20 at tilvejebringe de nødvendige mængder af de bundne aktive stofarter. Ydermere nedsætter den kanaldannelse (ujævn strømningsfordeling), som er uundgåelig ved dette fiberarrangement, anordningens effektivitet.In the area of hemoperfusion, devices designed for very specific blood composition modification and containing 10 fibers have been used with limited success. Hersh and Weetall (see above) used a filter insert containing bioactive molecules bound to randomly distributed, non-porous polyester fibers. Both enzymes and antibodies have been immobilized by this technique. These devices represent a significant improvement over 15 prior hemoperfusion systems in reducing the damage of shaped elements in the blood. However, there are still some problems with this design. Non-retained, randomly dispersed fibers tend to pack at the desired flow rates when sufficient fiber is present to provide the required amounts of the bound active substance species. Furthermore, the channel formation (uneven flow distribution) which is unavoidable by this fiber arrangement reduces the efficiency of the device.

Antistoffer, der er fastgjort til et stift, fikseret 2-dimensionalt arrangement, er blevet beskrevet og anvendt til fjernelse af hele celler 25 fra blod in vitro (f.eks. U.S.A. patent nr. 3.843.324). Dette system er imidlertid ikke anvendeligt til hæmoperfusion.Antibodies attached to a rigid, 2-dimensional fixed arrangement have been described and used to remove whole cells from blood in vitro (e.g., U.S. Patent No. 3,843,324). However, this system is not applicable for hemoperfusion.

Polymerfibre, der har carbonpartikler indkapslet inden i polymeren, og som er anbragt på ikke-tilfældig måde inden i en hæmoperfu-sionfilterindsats, er blevet beskrevet af Davis et al. (Trans. Amer.Polymer fibers having carbon particles encased within the polymer and disposed non-randomly within a hemoperfusion filter insert have been described by Davis et al. (Trans. Amer.

30 Soc. Artif. Jnt. Org. 20:353). Denne anordning er begrænset til anvendelse ved ikke-specifik adsorption, men er ellers fordelagtig med hensyn til kapacitet, pris, strømningsforhold og mindre beskadigelse af det gennemstrømmende blod.Soc. Artif. Int. Org. 20: 353). This device is limited to use in non-specific adsorption, but is otherwise advantageous in terms of capacity, cost, flow ratio and minor damage to the flowing blood.

De ovenfor omtalte problemer undgås med apparatet ifølge 35 opfindelsen.The above-mentioned problems are avoided with the apparatus of the invention.

Dette opnås ved at apparatet med de indledningsvis angivne karakteristika ifølge opfindelsen er ejendommelig ved, at en impermeabel spindel er anbragt aksialt i huset og er forsynet med aksialt forløbende riller i sin omkreds og har en konisk del, der er fastgjort til den ene 5 151180 ende af spindelen og står i forbindelse med indførselsåbningen i endepladen og med rillerne, at spindelen i sin anden ende slutter i en konisk spids, som er anbragt aksialt i forhold til afgangsåbningen med et ringformet rum derimellem, at en fiber er viklet ί spiral på spindelen 5 til dannelse af en spole, der i alt væsentligt udfylder det indre af huset ud til ribberne, således at blod, der indføres gennem indførselsåbningen, strømmer langs spindelrillerne, passerer gennem fiberspolen, strømmer langs indersiden af huset mellem ribberne og derefter mellem den koniske spids og afgangsåbningen, og at der til fiberen er fastgjort 10 specifikke effektormolekyler med aktivitet til fjernelse af biologiske væske komponenter af endogen eller exogen oprindelse fra blod, der strømmer gennem apparatet.This is achieved by the apparatus having the preamble of the present invention being characterized in that an impermeable spindle is arranged axially in the housing and is provided with axially extending grooves in its circumference and has a tapered portion attached to one end thereof. of the spindle and communicates with the entry opening in the end plate and with the grooves that the spindle ends at its other end in a conical tip which is axially arranged relative to the outlet opening with an annular space therebetween, that a fiber is wound in a spiral on the spindle 5 to form a coil which substantially fills the interior of the housing to the ribs so that blood introduced through the feed opening flows along the spindle grooves, passes through the fiber coil, flows along the inside of the housing between the ribs, and then between the conical tip and the outlet orifice and 10 specific effector molecules with activity to remove biological fluid are attached to the fiber e components of endogenous or exogenous origin from blood flowing through the apparatus.

I fiberindsatsen anvendes et fikseret, ikke-tilfældig, 3-dimensionalt arrangement af fibre, hvis kemiske sammensætning er en sådan, at 15 yderligere kemiske stofarter har kunnet podes på overfladen eller indkapsles i fibrenes matrix. De yderligere stofarter er fikseret på en sådan måde, at de effektivt fremkalder meget specifikke ændringer af en biologisk væske, som strømmer gennem filterindsatsen.The fiber insert uses a fixed, non-random, 3-dimensional arrangement of fibers whose chemical composition is such that 15 additional chemical species have been able to be grafted onto the surface or encapsulated in the matrix of the fibers. The additional species are fixed in such a way that they effectively induce very specific changes in a biological fluid flowing through the filter insert.

Figur 1 er et gennemskåret perspektivbillede af en samlet hæmo-20 perfusionsfilterindsats.Figure 1 is a sectional perspective view of a total hemo-perfusion filter insert.

Figur 2 er et perspektivbillede af spindelen til filterindsatsen.Figure 2 is a perspective view of the spindle for the filter insert.

Den foreliggende opfindelse omfatter alment et fikseret 3-dimensionalt arrangement af fibre indeholdt i et hylster, hvilket muliggør en kontinuert strøm af væske gennem hylsteret med maximal kontakt mellem 25 væske og fiber. Ydermere er det en egenskab hos denne anordning, at specifikke bioaktive effektormolekyler kan bindes til fibrene, for således at muliggøre, at effektermolekylerne kontakter target-komponenter i væsken og således ændrer sammensætningen af væsken.The present invention generally encompasses a fixed 3-dimensional arrangement of fibers contained within a casing, which enables a continuous flow of liquid through the casing with maximum contact between liquid and fiber. Furthermore, it is a feature of this device that specific bioactive effector molecules can be bonded to the fibers, so as to allow the effector molecules to contact target components of the fluid and thus alter the composition of the fluid.

Det er velkendt at fæstne biologisk aktive molekyler til uopløselige 30 materialer. De specifikke uopløselige materialer, der er anvendelige i forbindelse med den foreliggende opfindelse, fastlægges af flere kriterier: 1) materialet må være i stand til at blive tildannet til fibre, der er tilstrækkeligt stærke til at blive forarbejdet til et 3-dimensionalt arrangement, 2) fibrene må være i alt væsentligt uopløselige under 35 neutrale vandige forhold, 3) fibrene skal have en glat, ikke-porøs overflade til formindskelse af blodbeskadigelse og til nedsættelse af ikke-specifik adsorption, 4) fibrene må ikke afgive toxiske substanser eller fragmenter til det vandige medium, der siver imellem dem, 5) fibersammensætningens biokompatibilitetsgrad skal stå i rimeligt forhold 151180 6 til den tilsigtede anvendelse. Ved langtidsanvendelse eller kronisk anvendelse til hæmoperfusion mi fibrene ikke bevirke irreversible, kumulative, skadelige ændringer af cirkulerende stofarters mængde eller vitale kapacitet. Ved korttidsanvendelse eller i nødstilfælde behøver 5 fibrene kun at tillade tilstrækkelig passage af hepariniseret eller pi anden mide antikoaguleret blod uden at der fremkommer thrombose eller hæmolyse, der ligger ud over grænserne for patientens vitale kapacitet.It is well known to attach biologically active molecules to insoluble materials. The specific insoluble materials useful in the present invention are determined by several criteria: 1) the material must be capable of being formed into fibers sufficiently strong to be processed into a 3-dimensional arrangement; ) the fibers must be substantially insoluble under 35 neutral aqueous conditions; 3) the fibers must have a smooth, non-porous surface to reduce blood damage and to reduce non-specific adsorption; 4) the fibers must not release toxic substances or fragments to 5) the biocompatibility degree of the fiber composition must be proportionate to its intended use. In long-term use or chronic use for hemoperfusion in the fibers, do not cause irreversible, cumulative, harmful changes in the amount or vital capacity of circulating substances. In short-term or emergency situations, the fibers need only allow sufficient passage of heparinized or otherwise anticoagulated blood without producing thrombosis or hemolysis beyond the limits of the patient's vital capacity.

6) De anvendte fibre mi udvise egenskaber, som vil muliggøre en ikke-reversibel fæstnelse eller indkapsling (eng: englobement) af de 10 aktive stoffer. De foretrukne fibre vil være sidanne, som har vist sig at være i alt væsentlig kompatible ved implantering i legemet. Sådanne fibre kan udvælges blandt en af følgende kategorier: 1) substanser af biologisk oprindelse eller produkter, der fremkommer herudfra, dvs. cellulose, perfluorethylcellulose, cellulosetriacetat, celluloseacetat, nitro-15 cellelulose, dextran, chitin, collagen, fibrin, elastin, keratin, tvær- bundne opløselige proteiner, polymeriserede opløselige organiske stoffer af biologisk oprindelse (po ly mælkesyre, polylysin, nukleinsyrer), silke, gummi, stivelse og hydroxyethyl stivelse, 2) syntetiske hetero- kædepolymerer, såsom polyamider, polyestere, polyethere, poly-20 urethaner, polycarbonater og siliconer, 3) carbonhydridpolymerer, såsom polyethylen, polypropylen, polyisoprener, polystyrener, polyacrylforbindelser, såsom polyacrylamid, polymethacrylat, vinyl polymerer, såsom polyvinylacetat, og halogeneret carbonhydrid-plast, såsom polyvinylchlorid, polyfluorcarboner, såsom Teflon, 25 fluorcarboncopolymerer og polychlortrifluorethylen, 4) uorganiske fibre, såsom fiberglas.6) The fibers used exhibit properties that will allow a non-reversible attachment or encapsulation of the 10 active substances. The preferred fibers will be lateral which have been found to be substantially compatible with implantation in the body. Such fibers may be selected from one of the following categories: 1) substances of biological origin or products derived therefrom, viz. cellulose, perfluoroethyl cellulose, cellulose triacetate, cellulose acetate, nitrocellulose, dextran, chitin, collagen, fibrin, elastin, keratin, cross-linked soluble proteins, polymerized soluble organics of biological origin (poly lactic acid, polylysine, rubber, starch, and hydroxyethyl starch; 2) synthetic hetero chain polymers such as polyamides, polyesters, polyethers, polyurethanes, polycarbonates and silicones; vinyl polymers such as polyvinyl acetate and halogenated hydrocarbon plastics such as polyvinyl chloride, polyfluorocarbons such as Teflon, fluorocarbon copolymers and polychlorotrifluoroethylene; 4) inorganic fibers such as fiberglass.

De ovenfor nævnte eksempler på polymerer varierer meget i deres blod kompatibilitet. Der er imidlertid blevet beskrevet adskillige metoder til modificering af blodkompatibiliteten hos ellers uacceptable materialer; 30 blandt disse metoder er belægning af materialerne med mere kompatible substanser (f.eks. U.S.A. patent nr. 4.073.723) eller med antithrombo-gene substanser, såsom heparin.The above examples of polymers vary greatly in their blood compatibility. However, several methods have been described for modifying the blood compatibility of otherwise unacceptable materials; 30 of these methods are coating the materials with more compatible substances (e.g., U.S. Patent No. 4,073,723) or with antithromogenic substances such as heparin.

Fiberdimension og det specifikke 3-dimensionale fiberarrangement indeni filterindsatsen vil bestemme de af anordningen udviste 35 strømningsegenskaber, tilgængelig polymeroverfladeareal og prim- nings-volumen. De sidstnævnte 2 forhold vil være optimeret, når fiberdiameteren er minimal under frembringelse af tilstrækkelig styrke, og når fiberarrangementet vælges således, at der opnås et maximalt kompakt leje. Strømningsegenskaberne vil blive påvirket modsat i 7 151180 forhold til tilgængeligt overfladeareal og primningsvolumen. Disse forhold må derefter justeres således, at der opnås den optimale samlede effektivitet ved minimal blodbeskadigelse.Fiber dimension and the specific 3-dimensional fiber arrangement within the filter insert will determine the flow characteristics exhibited by the device, available polymer surface area, and priming volume. The latter two conditions will be optimized when the fiber diameter is minimal to produce sufficient strength and when the fiber arrangement is selected such that a maximum compact bed is obtained. The flow characteristics will be affected in contrast to available surface area and priming volume. These conditions must then be adjusted to achieve the optimum overall efficiency of minimal blood damage.

Anbringelsen af arrangementet af fikserede fibre mellem filter-5 indsatskappens til- og afgange kan vælges blandt utallige konfi gurationer. Blandt de mere hensigtsmæssige konfigurationer er følgende: 1) anbringelse af fibre ved vikling rundt om af- og tilgangsåbningen. Sådanne konfigurationer kan have cylindrisk symmetri omkring en rørformet åbning, der har midler til indstrømning eller 10 udstrømning af væsker langs rørets længde. I en anden konfiguration af viklede fibre, kan fibrene være viklet med sfærisk symmetri omkring en enkelt central åbning. 2) I filterindsatse, hvor væsken strømmer aksialt gennem filterindsatsen, kan fibrene være anbragt parallelt med strømretningen, idet de er fæstnet i hver ende af filterindsatsen. I en 15 anden konfiguration, der udnytter en filterindsats med aksiai strømning, kan fibrene være anbragt transversalt til blodstrømmen ved at fæstne fibrene til filterindsatsens sidedele. En kombination af parallel og transversal konfiguration kan også anvendes, ved hvilken kombination fibrene kan være fæstnet ved både ende- og sidedele af 20 filterindsatsen, og således anbragt på en sammenflettet måde.The arrangement of the arrangement of fixed fibers between the inputs and outlets of the filter insert can be selected from countless configurations. Among the more convenient configurations are the following: 1) placement of fibers by winding around the outlet and inlet apertures. Such configurations may have cylindrical symmetry around a tubular opening having means for inflowing or outflowing of fluids along the length of the tube. In another configuration of wound fibers, the fibers may be wound with spherical symmetry around a single central aperture. 2) In filter inserts where the fluid flows axially through the filter insert, the fibers may be arranged parallel to the flow direction, being attached to each end of the filter insert. In another configuration utilizing an axial flow filter insert, the fibers may be positioned transversely to the blood stream by attaching the fibers to the side portions of the filter insert. A combination of parallel and transverse configuration may also be used in which the combination of the fibers may be attached to both end and side portions of the filter insert, and thus arranged in an intertwined manner.

Fibrene kan anbringes som monofilamenter eller som multifilament-garn, og anordningen kan indeholde en kontinuerlig fiber eller adskillige fibre. Det kræves kun, at konfigurationen af hæmoperfu-sionshylsteret og fiberanbringelsen kan forenes med væskedynamikken, 25 er forenelig med minimal beskadigelse af formede væskekomponenter, der strømmer gennem anordningen. Disse restriktioner er velkendte for en fagmand.The fibers can be placed as monofilaments or as multifilament yarns and the device may contain a continuous fiber or several fibers. It is only required that the configuration of the hemoperfusion sheath and the fiber application be compatible with the fluid dynamics, 25 is compatible with minimal damage to shaped fluid components flowing through the device. These restrictions are well known to those skilled in the art.

De meget specifikke effektormolekyler, der har aktivitet over for biologiske væskekomponenter af endogen eller exogen oprindelse, og som 30 er fæstnet til fibrene indeni i anordningen, kan udvælges blandt en eller flere af følgende stofarter: et helt eller et fragment af en antistof, antigen, allergin, komplementfaktor, koagulationsfaktor, enzym, substrat af et enzym, celleoverfladereceptormolekyle, vaccine, enzyminhibitor, hormon, vævshomogenat, renset protein, toxin, 35 nukleinsyre, polysaccharid, lipid, intakt celle, mikrokapsel, liposom, polymer, antibiotika, kemoterapeutisk middel, terapeutisk medikament, organiske stofarter, der har stor affinitet over for en specifik komponent i en biologisk væske, eller et uorganisk stof, der har stor affinitet for en specifik komponent i en biologisk væske.The very specific effector molecules that have activity against biological fluid components of endogenous or exogenous origin, and which are attached to the fibers within the device, can be selected from one or more of the following species: a whole or a fragment of an antibody, antigen, allergy, complement factor, coagulation factor, enzyme, substrate of an enzyme, cell surface receptor molecule, vaccine, enzyme inhibitor, hormone, tissue homogenate, purified protein, toxin, 35 nucleic acid, polysaccharide, lipid, intact cell, microcapsule, liposome, polymer, antibiotic drug, organic matter species having high affinity for a specific component of a biological fluid, or an inorganic substance having high affinity for a specific component of a biological fluid.

8 1511808 151180

Det valgte effektormolekyle kan være bundet til anordningen ved hjælp af for fagmanden kendte midler, navnlig midler kendt til immobilisering af enzymer (f.eks. U.S.A. patent nr. 4.031.201), fra affinitetskromatografi (f.eks. U.S.A. patent nr. 3.652.761), fastfase 5 immunoanalyse (f.eks. U.S.A. patent nr. 4.059.685), bundet sta-tionær-fase kromatografihæmoperfusion (f.eks. U.S.A. patent nr. 3.865.726), enzymbundet immunsorbant-analyse, cellemærkning og separation samt fra hæmodialyse (f.eks. canadisk patent nr. 957.922).The effector molecule of choice may be attached to the device by means known to those skilled in the art, in particular agents known for the immobilization of enzymes (e.g., U.S. Patent No. 4,031,201), from affinity chromatography (e.g., U.S. Patent No. 3,652. 761), solid phase 5 immunoassay (e.g., U.S. Patent No. 4,059,685), stationary-phase chromatography hemoperfusion (e.g., U.S. Patent No. 3,865,726), enzyme-linked immunosorbant assay, cell labeling and separation, and from hemodialysis (e.g., Canadian Patent No. 957,922).

Fastgørelse af effektormolekylet til fibrene kan udføres under 10 polymerfremstilling, fiberspinning, lige før fibrene anbringes i filterindsatsen eller efter at fibrene er anbragt i filterindsatsen.Attachment of the effector molecule to the fibers can be performed during polymer manufacturing, fiber spinning, just before the fibers are placed in the filter insert or after the fibers are placed in the filter insert.

Filterindsatse kan opbevares tørt efter frysetørring eller fyldes med en puffer, der indeholder antimikrobielle midler. Sterilisation af anordningen kan udføres før inkorporeringen af de aktive stoffer på 15 fibrene, idet alle efterfølgende trin udføres med sterile reagenser, eller sterilisering kan udføres efter inkorporeringen.Filter inserts can be stored dry after freeze drying or filled with a buffer containing antimicrobial agents. Sterilization of the device can be performed prior to the incorporation of the active substances on the fibers, all subsequent steps being performed with sterile reagents, or sterilization can be performed after the incorporation.

Den samlede filterindsats består af en glas- eller plastkappe 1, dækket i en ende af en cirkulær glas- eller plastskive 2 og i den anden ende af en lignende skive 2a. Skiven 2 har i sit center en cylindrisk 20 udgangsibning 3. Kappen og hætten har hævede elementer i form af ribber 4, der tillader uhindret aksial væskestrøm langs overfladen af kappen og hætten og tillader udtømningen heraf via åbningen. Indeni kappen er en fiberspole 5, viklet i spiralform omkring en glas- eller plastspindel 6. Spindelen og fibrene fylder hele kappevolumenet med 25 undtagelse af rummet mellem ribberne.The overall filter insert consists of a glass or plastic sheath 1, covered at one end by a circular glass or plastic disc 2 and at the other end by a similar disc 2a. The disc 2 has in its center a cylindrical exit opening 3. The sheath and cap have raised elements in the form of ribs 4 which allow unobstructed axial fluid flow along the surface of the sheath and cap and allow the discharge thereof via the opening. Inside the sheath is a fiber coil 5, wound in a spiral shape around a glass or plastic spindle 6. The spindle and fibers fill the entire sheath volume with the exception of the space between the ribs.

Figur 2 viser spindelen 6, som er en glas- eller plaststang, der har en konisk basis 7 og er forsynet med spalter i sin længderetning som ved 8. Stangen er ved sin top anbragt i en konisk åbning 10, der er fastgjort til en cirkulær spindelhætte 2a af lignende sammensætning.Figure 2 shows the spindle 6, which is a glass or plastic rod having a tapered base 7 and provided with slots in its longitudinal direction as at 8. The rod is placed at its top in a tapered opening 10 which is attached to a circular spindle cap 2a of similar composition.

30 Diameteren af hætten er valgt således, at hætten slutter tæt med kappen og danner en forseglet beholder, når spindelen indsættes i kappen. Til spindelhættens ydre overflade er der fastgjort en cylindrisk indgangsåbning 11, som ligger lige overfor den koniske åbning 10, og som har en indre diameter, der tillader adgang af væske, som passerer 35 gennem den, til spalterne 8 i spindelen 6. Spindelens koniske basis har ydermere sådanne dimensioner, at anbringelsen af spindelbasis i udgangsåbningen resulterer i, at spindelen kun har kontakt med kappehættens ribber 4. Dette tillader den væske, der akkumulerer mellem ribberne, at komme ud gennem hulrummet mellem den koniske 9 151180 basis 7 af spindelen 6 og afgangsibningen 3. Når spindelen er påviklet en fiber, strømmer væsker, der kommer gennem anordningen, således i den retning, som angives af pilene i figur 1.The diameter of the cap is selected such that the cap ends tightly with the sheath and forms a sealed container as the spindle is inserted into the sheath. To the outer surface of the spindle cap is attached a cylindrical inlet opening 11, which is just opposite the conical opening 10, and which has an inner diameter which allows access of liquid passing 35 through it to the slots 8 in the spindle 6. The spindle base of the spindle further have dimensions such that the placement of spindle base in the outlet opening results in the spindle having contact only with the sheath cap ribs 4. This allows the fluid that accumulates between the ribs to exit through the cavity between the tapered base 7 of the spindle 6 and The discharge sieve 3. When the spindle is wound on a fiber, fluids coming through the device flow in the direction indicated by the arrows in Figure 1.

Den fiber, der vikles omkring spindelen, er et monofilament, der 5 har en diameter i området fra 0,05 til 2,0 mm. Den består af hydroxy-ethylcellulose (HEC). Efter inkorporeringen af den beviklede spindel i hylsteret, forsegles anordningen, og den fyldes med dioxan indeholdende 20% hexamethylendiisocyanat. Fibrene får lov til at stå i 48 timer ved stuetemperatur og vaskes derefter med destilleret vand. Denne 10 operation frembringer en fiberspiral, der har covalent bundne primære aminer på sin overflade. Det destillerede vand erstattes derefter af en vandig opløsning indeholdende 0,25% IgG (immunoglobulin G) og 1% vandopløselig carbodiimid, pH 5,5. IgG'et kan være acyleret til eliminering af endogene primære aminer. Efter 24 timers eksponering 15 med denne opløsning vaskes anordningen grundigt med destilleret vand og steriliseres til brug for in vivo perfusion.The fiber wound around the spindle is a monofilament having a diameter in the range of 0.05 to 2.0 mm. It consists of hydroxyethyl cellulose (HEC). After incorporation of the wound spindle into the casing, the device is sealed and filled with dioxane containing 20% hexamethylene diisocyanate. The fibers are allowed to stand for 48 hours at room temperature and then washed with distilled water. This operation produces a fiber coil having covalently bonded primary amines on its surface. The distilled water is then replaced by an aqueous solution containing 0.25% IgG (immunoglobulin G) and 1% water-soluble carbodiimide, pH 5.5. The IgG may be acylated to eliminate endogenous primary amines. After 24 hours of exposure 15 with this solution, the device is thoroughly washed with distilled water and sterilized for in vivo perfusion.

Claims

151180 Patent Claims.

A hemoperfusion apparatus comprising an elongate housing (1) of an impermeable material, said housing at its ends closed by 5 impermeable end plates (2, 2a) with a supply opening in one of the end plates (2a) and a discharge sieve ( 3) has a plurality of axially extending ribs (4) on the other of the end plates (2) and on the inside thereof which extend substantially throughout the length of the housing and extend radially on the latter of the end plates (2), characterized in that an impermeable spindle (6) is arranged axially in the housing and is provided with axially extending grooves (8) in its circumference and has a tapered portion (10) attached to one end of the spindle (6) and in connection with the insertion opening (11) in the end pad (2a) and with the grooves (8), the spindle (6) terminates at its other end in a conical tip (7) which is arranged axially with respect to the outlet opening (3) with an annular space therebetween that a fiber is wound in coil on the spindle (6) to form e of a coil (5) which substantially fills the interior of the housing (1) out to the ribs (4) so that blood introduced through the feed opening flows along the spindle grooves (8), passes through the fiber coil (5) flowing along the inside of the housing (1) between the ribs (4) and then between the tapered tip (7) and the outlet opening (3) and attaching to the fiber specific effector molecules with activity to remove biological fluid components of endogenous or exogenous origin from blood flowing through the apparatus.

A hemoperfusion apparatus according to claim 1, characterized in that the fiber is a monofilament having a diameter of between approx. 0.05 mm and approx. 2.0 mm.

A hemoperfusion apparatus according to claim 2, characterized in that the fiber consists of hydroxyethyl cellulose.