JPS6353826B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Methods of blood purification and blood irrigation are well known. With few exceptions, the equipment used for these purposes has the ability to remove only substances in non-specialized ways. Removal of toxic or unsuitable species from the blood is based on molecular size by dialysis using semipermeable membranes (see U.S. Pat. No. 3,619,423) or by irrigation on ion exchange resins (see U.S. Pat. No. 3,794,584). , see specification No. 4031010)
or on the basis of its affinity for absorbers by irrigation on activated carbon. These techniques come with severe limitations caused by lack of specificity. Among the debris removed from the blood are hormones, nutrients, drugs, electrolytes, and other species, and their removal from the blood circulation often has an adverse effect on patients undergoing irrigation procedures. Patients with such treatments are overmedicated,
Due to kidney or liver damage, or other conditions that significantly reduce the patient's vitality, further imbalances in the patient's performance cannot be tolerated. A further drawback of the lack of specificity in blood perfusion devices is their limited capacity for the target species. Although the target species must be comparable to other materials for the effective binding surface of the absorber, such devices would be prohibitively large to ensure sufficient capacity for the target species.

In addition to the non-specificity problem mentioned above, these devices
This indicates that more complexities arise in terms of structure and flow properties. Disruption of blood constituent molecules and colloidal particle constituents, for example due to hemolysis, platelet aggregation, fimbril composition and destruction of leukocytes, is often observed when blood is exposed to abiotic surfaces or turbulence. The above-mentioned breakage prevention is effective only in a small proportion of patients during pepperin treatment. Blood irrigation devices with absorbers consisting of randomly dispersed individual microparticles exhibit a tendency to clog under flow conditions, resulting in excessive pressure drop and flow reduction in the device. Blood breakage increases under such conditions.

Many attempts have been made to solve these problems and for device designs with specificity and applicability, as well as for a wide range of molecular species, especially high molecular weight species. Certain synthetic matrices that have been tested exhibit special affinities for particular solutes. One such device uses fluorinated hydrocarbon plastics for the specific removal of bacterial endotoxins (see US Pat. No. 3,959,128).

Greater specificity is obtained by using bioactives coupled to insert organic or inorganic moieties into the blood perfusion system. An example of this format is: The affinity of bilirubin and thienodeoxychloric acid for serum albumin has been developed by several researchers and
Antibody interactions have also been used (Canadian Patent No. 957922). Immobile antigens include BSA, DNA,
It is irrigated with blood for HSA and ovalbumin, blood factors and antibodies against immunoglobulin debris _IgG and _InG for removal. Immobile antibodies (I _g G, I _g M) have been used in blood perfusion systems to reduce circulating amounts of drugs and endogenous species. Digoxin, DNA, BSA, lesion-associated antigens, and antibodies to donor kidney antigens and multiple myeloma proteins and low concentration riboproteins have been immobilized in extracorporeal tissues for various therapeutic purposes.

Among the enzymes, cell extracts and whole tissues that have been immobilized in vitro (Canadian Patent No. 957922) are urea, uricase, asparaginase, pancreatic cells, liver cells and liver microparticles, nucleases and catalase. The properties of materials and devices that are brought into contact with circulating biological fluids have been extensively studied. Weetall et al. have listed the following criteria as a check list for equipment design: According to Plenum Press, New York City, TMSChang.Ed.
In the biomedical applications of immobile enzymes and proteins, “some in vivo and in vitro studies of living molecules on organic matrices for potential therapeutic uses”, “(1) laminar flow, (2) velocity gradients. 350/sec or more, (3) the material that comes into contact with blood is relatively non-biochemical, (4) maintaining surface smoothness, and (5) at least approximately 100 um.
(6) avoidance of crushing or abrasive effects on the support. Two other criteria are of great importance: (1) the flow rate of activated blood that changes species per unit of loading; and (2) a minimum resistance to active contact between the species and the blood constituent molecules to be modified, i.e., contact requires a minimum amount of diffusion-controlled transport, and transport requires a minimum amount of resistance. This is something that should be done through objects.

To date, blood irrigation systems employing highly species-specific detoxification isolated within the device have employed one of the following: (1) Isolation of detoxified species from the blood being irrigated using a semipermeable membrane (e.g., U.S. Patent No.
3619423) or using hollow fiber tubes, (2) encapsulation with or attachment to special materials (e.g., U.S. Pat. No. 3,865,726), or (3) non-porous membranes of this type. or adhesion to other flat surfaces (e.g.
(US Pat. No. 3,959,128); or (4) adhesion to the interior surface of a polymeric tube through which blood is passed (e.g., Canadian Pat. No. 957,922).

None of these systems meet any of the above criteria. Semipermeable membranes and hollow fiber devices impose strong diffusion conditions for active incorporation of sequestering components, and they are also limited to activity for low molecular weight species in the blood. A device having a specific component,
Those in which the active species are minutely encapsulated or isolated within the pores of the support are subject to similar restrictions on diffusion resistance, and the flow resistance due to clogging is reduced to blood damage due to the abrasive action of specific motion. Similarly shown. Non-porous flat surfaces and polymeric tubes have a small surface area and therefore insufficient capacity for active ingredients.

Fiber-filled cartridges are used instead of these devices. Fibers have long been used in blood containment devices for collection and removal of blood components during irrigation (eg, US Pat. No. 3,462,361). cover each surface, and
Polymerized fibers with high-heat carbons arranged in arbitrary masses have been used as non-specific absorbers for blood irrigation (eg, US Pat. No. 3,972,818). Antibodies and other proteins have been incorporated into cellulose fibers by incorporation for applications in radioimmunoassays and for industrial use (eg, US Pat. No. 4,031,201). The antigen is attached to a nylon catheter and inserted into an artery to remove the antibody from the blood circulation.

In blood perfusion technology, there is limited success in designing devices for advanced specific modification of blood components and in employing storage fabrics. Hersh and Weetall (supra) used a cartridge containing bioactive molecules attached to optionally dispersed non-porous polyester fibers. Both enzymes and antibodies have been immobilized by both techniques described above. Although these devices represent a significant advance over prior blood irrigation systems in minimizing damage to blood components, several problems remain with this concept. Unfixed, arbitrarily dispersed fibers tend to become clogged under the required flow rate if there are sufficient fibers to provide the required amount of binding active species. Moreover, the inevitable channeling (unequal distribution of flow rate) in this fiber arrangement results in reduced efficiency of the device.

Antibodies attached to rigidly immobilized two-dimensional arrays have been described and used for the removal of whole cells from blood in vitro (eg, US Pat. No. 3,843,324).

Polymerized fibers having carbon particles encapsulated within the polymer and arranged in a manner within a blood irrigation cartridge have been described by Davis et al. (Trans. Amer. Soc. Artif. Int.
Org.20:353). Although limited in its application in non-specific absorption, this device exhibits excellent properties with respect to capacity, cost, flow characteristics, and also reduces damage to blood during irrigation.

According to the present invention, the above-mentioned problems can be solved by improving the three-dimensional arrangement of the fibers, the flow path diameter, and the meandering of the flow path in order to maximize the exposed fiber surface. It has a closed elongated container of impermeable material. The container has a plurality of axial ribs extending substantially the entire length thereof, an inlet provided in the one end plate, and a plurality of axial ribs formed in the interior thereof in a continuous manner in the radial direction. and an outlet provided in the end plate. An axially disposed impermeable spindle is provided within the container, and an axial groove is formed on the outer periphery of the impermeable spindle. A conical tip is formed at the other end of the impermeable spindle, and an annular gap is formed between the conical tip and the outlet. A conical opening communicating with the inlet and groove is fixed to one end of the spindle. The spindle is provided with a bobbin of fibers wound helically around the spindle so as to substantially fill the interior of the container up to the ribs. Attached to the spool of this fiber are specific active molecules that remove biogenic molecules of endogenous or exogenous sources from the blood. The blood flowing into the inlet flows along the groove of the spindle, passes through the fiber spool, flows along the inside of the container between the ribs, and flows out between the conical tip and the outlet. It's getting old.

Therefore, the spool to which specific active molecules are attached adsorbs biofluid constituent molecules of endogenous or exogenous sources floating in the blood from the blood irrigated into the device by an immunochemical reaction. It can be removed by Therefore, unlike the case where particles in the blood are mechanically sieved and filtered, the distance between the fibers of the fiber winding frame can be made sufficiently larger than the particles in the blood. Therefore, it is possible to prevent the winding frame from being clogged with particles in the blood, and it is also possible to prevent uneven distribution and turbulence of the blood flow due to blood clog. Additionally, the spindle is axially grooved to ensure a constant, uniform flow through the fibers. Furthermore, the use of specific effective molecules can provide high specificity for altering blood composition. The use of wound fibers also overcomes the problems associated with the use of randomly distributed fibers rather than fixed ones.

Additionally, the device minimizes contact of blood with surfaces that do not contribute to the reaction and prevents prolonged contact of synthetic materials with blood and blood elements, thereby reducing potential damage to blood cells and clotting. The possibility of formation can be reduced.

The blood irrigation device of the present invention exhibits many of the features of the device described by Davis, but has been expanded and modified to make it applicable to highly specific modifications to biofluid components. Fiber cartridges employ fibers secured with an intentional three-dimensional arrangement of chemical components such that additional chemical species can be added to or encapsulated within the matrix surface of the fibers. The additional species are immobilized to allow efficient and highly specific modification of the biofluid infused through the cartridge. Another object of the present invention is to disclose the well-known formulation and manufacturing process by which the above-mentioned cartridges can be manufactured. Finally, it is an object of the present invention to remove chemical species contained in the raw fluid irrigated through said cartridge;
Applications of the above-mentioned cartridges that can be collected, degraded, or modified are disclosed.

The present invention generally consists of a fixed three-dimensional array of fibers contained in a container that maintains a steady flow of fluid through the container while maximizing fluid-to-fiber contact. In addition, a special feature of the device is that a special bioactive effective molecule is bound to the fiber, thereby allowing the effective molecule to come into contact with the target component of the fluid, thereby changing the composition of the fluid. .

Fibers, Required Properties, and Suitable Types Techniques for attaching bioactive molecules to insoluble materials are well known. The specific insoluble materials applicable to the present invention are defined by several criteria: (1) the material must be capable of forming fibers with sufficient strength to be processed into a three-dimensional array; (2) the fibers is essentially insoluble under neutral aqueous conditions; (3) the fiber has a smooth, non-porous surface to reduce blood breakage and reduce non-specific absorption; (4) ) the fibers do not release toxic substances or debris into the aqueous medium that permeates through them; (5)
The degree of biocompatibility of the fiber component shall be commensurate with the intended use. For long-term use in blood perfusion or phlegm, the fibers should not cause irreversible cumulative deleterious changes in the amount of circulating species or essential properties. For short-term or emergency use, the fibers only need to efficiently pass heparinized or otherwise anticoagulated blood without causing thrombosis or hemolysis that exceeds the patient's vital capacity. (6) The fiber used exhibits the property of not causing irreversible attachment or spherical encapsulation of active species. Preferably, the fibers have proven to be sufficiently compatible for implantation within the human body. Such fibers may be selected from one of the following types: (1) Biologically derived substances or products derived therefrom, i.e., cellulose, perfluoroethyl cellulose, cellulose triacetate, cellulose acetate, nitro Cellulose, dextran, chitin, collagen, fibrin, elastin, keratin, crosslinked soluble proteins, polymeric soluble organic species of biological origin (polylactic acid, polylysine, nucleic acids), silk, rubber, starch, and hydroxyethyl. (2) heterothiene synthetic polymers such as polyamides, polyesters, polyethers, polyurethanes, polycarbonates, and silicones; (3) polyethylene;
Hydrocarbon polymers like polypropylene, polyisoprene, polystyrene, polyacrylamide,
Polyacrylic acids such as polymethacrylate, vinyl polymers such as polyvinyl acetate, and halogenated hydrocarbon plastics such as polyvinyl chloride, Teflon, perfusate hydrocarbon copolymers, and polychlorotrifluoroethylene. (4) Inorganic fibers such as fiberglass.

The polymers listed as examples above differ greatly in their respective blood compatibility. Several techniques were described that modify the blood compatibility of otherwise unusable materials, some of which include more compatible substances (e.g., U.S. Pat. No. 4,073,723) or coat the material with antithrombodiic substances such as heparin.

Fiber Composition and Container Fiber Dimensions and Identification of Fibers in Cartridges 3
The dimensional configuration will determine the flow characteristics, effective polymer surface area, and loading that the device will exhibit. The latter two conditions are optimal when the fiber diameter is the minimum value that yields sufficient strength and when the fiber arrangement is chosen to provide a maximally dense bed. Flow properties are affected in the opposite manner to effective surface area and loading. These conditions must then be adjusted to minimize blood damage and optimize overall efficiency.

The arrangement of the fixed fiber rows between the inlet and outlet of the cartridge jacket can be selected from numerous configurations. Some of the more convenient configurations are: (1)The arrangement of fibers by wrapping them around an outlet or an inlet. Such an arrangement may have cylindrical symmetry around the tube-like mouth providing a means for fluid inflow or outflow along the length of the tube. In another potential fiber wrapping configuration, the fibers may be wrapped in spherical symmetry around one central opening. (2) In a cartridge in which fluid flows around the axis through the cartridge, fibers may be attached to both ends of the cartridge and arranged parallel to the flow direction. Another configuration using an axial flow cartridge is to have the fibers placed transversely to the blood flow by attaching the fibers to the lateral portions of the cartridge. A combination of parallel and crossed configurations may also be used, in which the fibers may be arranged in an interleaved fashion by attaching them to both ends and lateral portions of the cartridge.

The fibers may be arranged as single filaments or as bifilament yarns, and the device may contain a single continuous fiber or multiple fibers. In short,
All that is required is a cartridge container construction and fiber arrangement that is compatible with hydraulics and is suitable to minimize damage to the compositional fluid components being irrigated through the device. These limitations are well known to those skilled in the art.

Effective Molecules The highly specialized effective molecules that have an effect on biological fluid components of endogenous or exogenous origin and that are attached to the fibers within the device may be selected from one or more of the following genera: This molecule includes antibodies, antigens, allergic antigens, complement factors, coagulation factors, enzymes, enzyme substrates, cell receptor molecules, vaccines, enzyme inhibitors, hormones, tissue homogenates, purified proteins, toxins, nucleic acids, polysaccharides, and lipids. , completed cells, microcapsules, lipid droplets, polymers, antibiotics, chemotherapeutic agents, therapeutic agents, organic species with a high affinity for a particular biofluid component, or a high affinity for a particular biofluid component. It is an inorganic species with .

Method of attaching effective molecules to fibers The selected effective molecules are, in particular, immobilized enzymes (e.g.
U.S. Pat. No. 4,031,201), affinity chromatography (e.g., U.S. Pat. No. 3,652,761), solid-phase immunoassay (e.g., U.S. Pat. No. 4,059,685), bonded stationary phase chromatography blood irrigation (U.S. Pat. No. 3,865,726)
issue), enzyme-linked immunosorbent assay, cell classification and isolation,
and hemodialysis (e.g. Canadian Patent No. 957922)
can be coupled to the device in a manner well known to those skilled in the art.

Attachment of the active molecule to the fibers can occur during preparation of the polymer immediately prior to installation of the fibers into a cartridge, during spinning of the fibers, or subsequent to placement of the fibers into a cartridge.

The cartridge may be lyophilized followed by dry storage or filled with a buffer containing an antimicrobial agent. Disinfection of the device may be performed prior to binding of the active species to the fibers, with all subsequent measures taken with sterile reagents, or disinfection may occur after binding.

Cartridge The assembled cartridge consists of an outer shell 1 capped at one end by a circular glass or plastic disc 2 and at the other end by a similar disc 2a. Disk 2
has a cylindrical outlet 3 in its center. The jacket and lid have raised ribs 4 which allow the fluid to freely flow axially along the surface of the jacket and lid and its outflow through the outlet. Inside the jacket is a spool 5 of fibers wound helically around a glass or plastic mandrel 6. The mandrel and fibers fill the entire volume of the jacket except for the spaces between the ribs.

FIG. 2 has a conical shape at its base 7;
Also shown at 8 is a mandrel 6 of glass or plastic rod with grooves cut in its longitudinal direction.
This rod is fixed with its head in a conical mouth 10 which is attached to a circular mandrel cap such as the structure of 2a. The diameter of this lid is selected such that it fits tightly with the outer shell and forms a sealed container when the mandrel is inserted into the outer shell. The outer surface of the mandrel cap has a cylindrical inlet 11 mounted thereon opposite the conical opening 10 and having an inner diameter that allows the fluid passing therethrough to reach the groove 8 of the mandrel 6. The conical base of the mandrel is also dimensioned to allow the mandrel to be placed at the outlet such that it is in contact only with the ribs 4 of the overcap. This causes the fluid that accumulates between the ribs to flow out through the lumen between the conical base 7 of the mandrel 6 and the outlet 3. Thus, when the mandrel is wound with fibers, the flow of fluid through the device will be as indicated by the arrows in FIG.

The fibers wound around the mandrel are single filaments with diameters ranging from 0.05 to 2.0 mm. It consists of hydroxyethyl cellulose (HEC).
Following installation of the wrapped mandrel into the container, the device is sealed and filled with dioxane containing 20% hexamethylene diisocyanate. The fibers are left at room temperature for 48 hours and then washed with distilled water. This operation results in a fiber coil with covalent primary amines appearing on its surface. Therefore, this distilled water
0.25% I _g G and 1% water-soluble carbodiimide with pH 5.5
Replace with an aqueous solution containing The _IgG may be acylated to remove endogenous primary amines. After 24 hours of exposure to this solution, the device is thoroughly rinsed with distilled water and disinfected for use in in vivo perfusion applications.

[Brief explanation of the drawing]

FIG. 1 is a cutaway perspective view of an assembled blood irrigation cartridge, and FIG. 2 is a perspective view of the mandrel for the cartridge. 1...Outer cover, 2...Glass or plastic disc, 2a...Glass or plastic disc,
3... Cylindrical outlet, 4... Rib, 5... Fiber bobbin, 6... Plastic mandrel, 7... Conical base, 8... Groove, 10... Conical mouth, 11... Cylindrical shape Inlet.

Claims (1)

Claims: 1. A blood irrigation device comprising an elongated container of impermeable material closed at both ends by impermeable end plates, said container having a plurality of containers therein extending substantially over its length. an axial rib in the container, an inlet on one side of said end plate, an outlet on the other side of said end plate with said ribs being radially continuous; and has a groove arranged in the axial direction on its outer periphery, and the other end is formed into a conical tip arranged in the axial direction with an annular gap between it and the outlet. an impermeable spindle fixed to one end of the spindle and communicating with the inlet and the groove; and a conical opening fixed to one end of the spindle and extending around the spindle so as to substantially fill the interior of the container up to the ribs. a helically wound fibrous spool, said fibrous spool having specific effective molecules attached thereto for removing biofluid constituent molecules of endogenous or exogenous sources from blood. blood irrigation equipment. 2 The fiber is a single fiber and has a diameter of about 0.05 to about 2.0.
mm in diameter and characterized by the fact that effective molecules can be immobilized in such a way that they are chemically free to react with factors in the blood, thereby removing such factors from the blood. A blood perfusion device according to claim 1. 3. The blood perfusion device according to claim 2, wherein the fibers are made of hydroxyethyl cellulose.