Classifications

• • 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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
• • 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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
  • A61M1/3475—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate with filtrate treatment agent in the same enclosure as the membrane
• • 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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
  • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
• • 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
  • A61M1/3616—Batch-type treatment
• • 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
  • A61M1/3621—Extra-corporeal blood circuits
  • A61M1/3643—Priming, rinsing before or after use
• • 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
  • A61M1/3621—Extra-corporeal blood circuits
  • A61M1/3643—Priming, rinsing before or after use
  • A61M1/3644—Mode of operation
  • A61M1/365—Mode of operation through membranes, e.g. by inverted trans-membrane pressure [TMP]
• • 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
  • B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
  • B01D65/02—Membrane cleaning or sterilisation ; Membrane regeneration
• • 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
  • A61M2205/00—General characteristics of the apparatus
  • A61M2205/75—General characteristics of the apparatus with filters
  • A61M2205/7554—General characteristics of the apparatus with filters with means for unclogging or regenerating filters
• • 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
  • A61M2205/00—General characteristics of the apparatus
  • A61M2205/75—General characteristics of the apparatus with filters
  • A61M2205/7581—General characteristics of the apparatus with filters with means for switching over to a fresh filter on clogging or saturation
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D2313/00—Details relating to membrane modules or apparatus
  • B01D2313/32—Intermediate chambers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D2313/00—Details relating to membrane modules or apparatus
  • B01D2313/40—Adsorbents within the flow path
• • 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

Definitions

• the invention relates to a regenerable filter for the extracorporeal treatment of particle-containing liquids and their application.
• the field of application of the invention is medicine, in particular direct blood treatment
• Hemofiltration, hemodiafiltration, double filtration and plasma adsorption are milestones in the application of extracorporeal therapy (or therapeutic apheresis).
• plasma adsorption has been used to remove substances larger than albumin from the blood.
• Non-specific or specific factors are used to bind high molecular weight substances in the flowing blood or plasma.
• Electrostatic or hydrophobic interactions between the matrix and blood components routinely remove LDL, beta2-microglobulin, endotoxins, immunoglobulins, and circulating immune complexes from the blood.
• the specific affinity of protein A for the Fc receptor of IgG enabled the development of immunoadsorbents used, for example, for the depletion of IgG for the treatment of severe forms of rheumatoid arthritis (Prosorba®).
• Specific recognition sequences allow the removal of target structures with clearly defined specificity from the blood. You will u.a. used for the elimination of LDL (Therasorb®, LDL Lipopak®), Lp (a) (Lp (a) Lipopak®), acetylcholine receptor antibody (MedisorbaMG®), anti-ß1-adrenergic antibody (Corafin®) or Inflammatory mediators (EP 1163004).
• patient-specific, dissociated immune complex constituents as ligands for a patient-specific immunoadsorber (DE 19538641) is a special form on the way to increasingly targeted and personalized therapy.
• the filtrate flow in the primary separation is usually about 30% of the blood flow (plasma flow about 20-30 ml / min), depending on the indication usually one to two times the plasma volume of the patient is treated.
• plasma flow about 20-30 ml / min
• one or two patient plasma volumes assuming a single-compartment model without reperfusion, synthesis or catabolism
• a maximum reduction of the pathogen to 37% and 14% of baseline, respectively, can be achieved per treatment.
• these values are usually not realized in practice.
• Non-selective plasmapheresis plasma exchange
• the plasma in the extracorporeal circuit is separated from the blood cells by means of a membrane plasma separator or a centrifuge, the entire plasma is discarded and isovolemically substituted by an electrolyte solution plus human albumin or fresh plasma.
• the substitution solution is combined with the separated blood cells and re-infused to the patient.
• the advantage of unselective plasma exchange lies in the simple structure of the extracorporeal circulation, the general applicability of the method for all pathogens accessible to apheresis, the effectiveness in the case of an unknown pathogen structure (eg acetylcholine receptor antibody-negative myasthenia gravis) and the relatively small one extracorporeal volume. Disadvantages are the immunoglobulin and coagulation factor depletion, the risk of incompatibility of the substituted foreign protein and a hyperoncotic substitution and the potential risk of infection in the transmission of pathogens with the substitution solution.
• Membrane plasma separators consist of hollow fiber modules with synthetic membranes (eg polyethylene or polysulfone). The surface is between 0.2-0.5 m 2 , the pore size 0.2-0.5 microns. To monitor the extracorporeal For this purpose, specially developed devices are used; Alternatively, the use of devices for hemoperfusion or hemofiltration is possible.
• synthetic membranes eg polyethylene or polysulfone
• the pathogen is removed from the plasma separated by a plasma filter (primary separation) in a secondary circuit either by a further filtration process (secondary separation) or by adsorption (immunological or physicochemical) or by precipitation, and the purified plasma is returned to the patient.
• a plasma filter primary separation
• secondary separation secondary separation
• adsorption immunological or physicochemical
• precipitation precipitation
• Double filtration cascade filtration, membrane differential filtration
• This method uses after separation of the plasma in a secondary circuit, a second filter smaller pore size (cut-off 25-40 nm).
• the aim is to recover albumin as quantitatively as possible, but to retain the higher molecular weight pathogenic protein in the secondary filter, which operates in the so-called "dead-end” mode (closure of the distal outlet of the hollow fibers).
• pathogens such as IgM, LDL, fibrinogen or a-2-macroglobulin
• indications include hyperviscosity syndrome, Waldenstrom, cryoglobulinemia and hypercholesterolaemia.
• rheopheresis The use of double-fibrillation plasmapheresis for the treatment of microcirculation disorders is called rheopheresis.
• LDL binding to anti-apoprotein B antibodies is also referred to as LDL immunoadsorption.
• the Liposorber® system (Kaneka, Osaka, Hospal, Planegg) is based on the adsorption of LDL and Lp (a) from the plasma on dextran sulfate / cellulose (DSC). The mechanism is based on an electrostatic interaction of the negatively charged sulfate groups of the dextran sulfate with the positively charged apo B of the two o.
• G. Lipoproteins. HDL, immunoglobulins and albumin are only slightly adsorbed.
• HELP ⁇ apheresis heparin-induced extracorporeal LDL precipitation, disposable product, Braun, Melsungen
• LDL, Lp (a) and fibrinogen are precipitated from the plasma at an acidic pH of 5.12 by means of heparin in an extracorporeal circulation and filtered off.
• Immunosorba ⁇ system (Fresenius HemoCare, St. Wendel) used as a ligand staphylococcal protein A with Sepharose as a carrier.
• Prosorba® system (Fresenius HemoCare, St. Wendel) used as a ligand staphylococcal protein A with a silica matrix as a carrier
• the Globaffin® (Fresenius HemoCare, St. Wendel) immobilizes the synthetic peptide GAM® as a ligand on Sepharose CL-4B.
• the binding properties correspond to those of protein A.
• Coraffin® (Fresenius HemoCare, St. Wendel) specifically removes autoantibodies against the ⁇ 1-adrenergic receptor of the heart muscle. This is an indication-specific procedure.
• the system Immusorba® (ASAHI / Diamed, Cologne) works with non-reusable adsorbents based on tryptophan (TR-350L) or phenylalanine ligands (PH-350L), which are bound to a polyvinylethanol gel matrix.
• cryofiltration In cryofiltration (Asahi Medical, Tokyo, Diamed, Cologne), the separated plasma is cooled to 4 ° C. in a membrane differential filtration method to precipitate cryoglobulins and, after removal of the precipitates, by means of a cryofilter after reheating to body temperature reinfused.
• adsorbing substances activated carbon, exchange resins
• the size of the Adsorber cartridge must ensure a sufficient exchange surface and contact time of the adsorbent.
• the direct adsorption of LDL and Lp (a) from whole blood is made possible by the DAL1® system (direct adsorption of lipoproteins from Fresenius HemoCare, St. Wendel).
• the disposable adsorbent cartridges consist of negatively charged polyacrylate ligands immobilized on polyacrylamide and electrostatically binding the atherogenic lipoproteins.
• Matson, et al. (US 6,287,516) describes a hemofiltration system consisting of a blood filter with downstream adsorber.
• the ultrafiltrate from the filter (exclusion MW # 50,000 daltons) is pumped via a tubing system into an adsorber unit where the sepsis mediators are bound.
• the ultrafiltrate thus treated can be combined with the primary filtered blood by another pump-tube valve system and reinfused into the patient:
• EP 0139949 describes an apparatus for blood purification which contains both the plasma-filtering hollow fibers in one housing and an adsorption matrix in the plasma space Shettigar (WO 93/02777) describes a very similar device: both of them have in common that the adsorbing matrix can not be regenerated .
• the possibility of regeneration is expressly provided in US 6497675B1
• the disadvantage here is that the adsorber unit integrated in the plasma filter does indeed lively can be neriert, but must be removed from the housing. This manipulation complicates the procedure and increases the risk of confusion and thus the risk of transmission of diseases.
• the regenerated Adsorber GmbH is screwed in a further step in a new plasma filter housing.
• the aim of the invention is a whole blood treatment unit, which is characterized by a simple system structure, so by eliminating pumps and additional hose connections, and combines the advantages of membranes and particles in itself.
• the whole blood treatment unit according to the invention should enable higher blood flows (up to 160 ml / min), shorten the treatment time and above all be regenerable.
• the objective is achieved by introducing conventional plasma filters (membrane hollow tubes) with the usual pore diameter of 0.2-0.5 ⁇ m into a self-contained housing made of biocompatible material (see Fig. 1 and Fig. 1a).
• the membrane material used may be cellulose derivatives or synthetic materials such as polysulfones or polyamides.
• the housing also serves as a receptacle for the functionalized particles. Polysulfone, polyacrylonitrile, polymethyl methacrylate, polyvinyl alcohol, polyamides, polycarbonates and cellulose derivatives can be used as the material for the particles.
• the plasma passes through the membrane according to the pressure gradient and the pore size.
• the plasma now flows through the adsorber gel, consisting of non-specific or specifically functionalized micro-particles with a diameter above the pore diameter of the membrane.
• the plasma so specifically purified of certain bioactive substances is combined in the housing with the intra-luminal plasma filter blood stream and reinfused into the patient as purified whole blood.
• a system of filters prevents micro particles from entering the bloodstream.
• Essential to the invention is that in the filter system three-way valves are arranged so that a pumping of liquids into the particle space and an outflow from the inlet opening is made possible (see Fig. 2 and Fig. 2a). By operating these three-way valves, the blood / plasma stream in the outlet of the housing is suppressed after exhaustion of the adsorption potential.
• the regeneration takes place via the particle reservoir with conventional buffers.
• the regeneration buffer passes through the pores of the plasma filter into the inside of the lumen of the filter membrane and frees the surface from the biofilm so that the filter for the next treatment cycle is available after the end of the respective rinsing program.
• the treatment system can also consist of two or more filters, so that during the regeneration of an adsorber unit the treatment is continued with another and in this way a continuous blood treatment can take place.
• the inventive arrangement of the three-way valves allows for the first time a regeneration of the functionalized particles, without the adsorber unit must be removed from the housing. In this way, the regeneration step can be performed faster and with less technical effort.
• the use of devices according to the invention can significantly reduce the cost of therapy compared with disposable products requiring extracorporeal treatment lasting several days.
• Embodiment 1 The invention will be explained in more detail by exemplary embodiments.
• Embodiment 1 The invention will be explained in more detail by exemplary embodiments.
• the experimentally used device for the removal of antigens from whole blood consists of a hollow-fiber plasma separator (A) whose lower housing part has been replaced by an inserted cylinder (B) in which the adsorber gel surrounds the hollow fibers.
• A hollow-fiber plasma separator
• B inserted cylinder
• the blood plasma released by the transmembrane pressure must pass through the adsorber and is thereby freed from the target substances.
• the plasma separation module consisted of a 0.4 m 2 hollow fiber filter (A).
• the adsorbent container contained 60 ml Sepharose, to which 5 mg IgY (vitellin antibodies from the eggs of chickens inoculated with IL6) were covalently bound per ml Sepharose.
• the binding capacity of the adsorber was 72 ⁇ g IL6.
• the blood flow rate was set to about 120 ml / min.
• the module can be operated easily.
• the treated amount of plasma was 1, 5 I.
• Buffer A 0.5 M NaCl in 0.2 M carbonate buffer, pH 8.5
• Buffer B 0.5 M NaCl in 0.1 M acetate buffer pH 4.5
• Buffer C PBS pH 7.4
• Sepharose 4 FF (Amersham / GE)
• vitellin antibody (IgY), specific to human IL-6, dissolved in PBS, pH 8.5
• the aspirated Sepharose is transferred to a suitable vessel and suspended in 8 ml of acetone 6: 4.
• the activation determination is then carried out according to (Kohn J, Wilchek M. A colorimetric method for monitoring activation of Sepharose by cyanogen bromide, Biochem Biophys Res Commun., 1978; 84 (1): 7-14.), In which the concentration of the cynate ester groups on the Sepharose is detected.
• the gel is then subjected to a multiple wash with the buffers in the order A, C, B.
• the loading of Sepharose with IgY is then determined in a modified micro BCA method.
• the control takes place via the UV-protein measurement of the washing liquids.
• the upper connection piece receives a three-way valve (V1), which serves for the blood inflow or the regeneration outflow.
• the lower side port is provided with a three-way valve (V2), which serves for the drainage of the treated plasma or the inflow of regeneration and washing solutions.
• V2 three-way valve
• the lower connector receives the three-way valve (V3), which serves to bring together the treated plasma with the corpuscular blood components to the treated whole blood or after its closure prevents the penetration of regeneration fluids into the whole blood.
• V3 three-way valve
• the IL-6 content of the blood was determined time-dependent by ELISA
• V1 three-way valve
• This liquid (T) passes through part B of the device AB, which contains particles that allow a specific adsorption of solutes (details see Fig. 1a).
• the purified liquid (T) and the particulate concentrate (K) are combined.
• the original liquid (F) is freed from dissolved, unwanted constituents.
• the treatment can be discontinuous and continuous.
• Fig. 1a Adsorption - details
• the regeneration of the filter is carried out by promoting a suitable washing solution opposite to the working direction of the filter.
• the adsorber module must be regenerated for repeated use.
• a suitable liquid (Reg) via the valve (V2) is directed opposite to the normal working direction in the adsorber.
• desorptive reactivation of the adsorber particles takes place.
• the membrane (a) is flowed through opposite and thereby freed of deposits in or on the pores. Filtration and adsorption capacity of the adsorber module are restored.
• the process according to the circuit of the three-way valves (V1-3) prevents contamination of the liquid supply with (Reg) or (W).

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• Health & Medical Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Hematology (AREA)
• Anesthesiology (AREA)
• Animal Behavior & Ethology (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Biodiversity & Conservation Biology (AREA)
• Cell Biology (AREA)
• Molecular Biology (AREA)
• External Artificial Organs (AREA)
• Separation Using Semi-Permeable Membranes (AREA)

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• 2006
  • 2006-03-14 DE DE102006012024A patent/DE102006012024A1/de not_active Withdrawn
• 2007
  • 2007-03-14 CN CN2007800094083A patent/CN101420992B/zh not_active Expired - Fee Related
  • 2007-03-14 DE DE112007001195T patent/DE112007001195A5/de not_active Withdrawn
  • 2007-03-14 US US12/282,407 patent/US8771513B2/en not_active Expired - Fee Related
  • 2007-03-14 JP JP2008558632A patent/JP2009529386A/ja active Pending
  • 2007-03-14 WO PCT/DE2007/000476 patent/WO2007104298A2/de not_active Ceased
  • 2007-03-14 EP EP07722047.3A patent/EP1993631B1/de not_active Not-in-force
  • 2007-03-14 CA CA2644732A patent/CA2644732C/en not_active Expired - Fee Related

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