CN1806774A - Artificial blood vessel scaffold and artificial organs - Google Patents

Artificial blood vessel scaffold and artificial organs Download PDF

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Publication number
CN1806774A
CN1806774A CNA2005100065172A CN200510006517A CN1806774A CN 1806774 A CN1806774 A CN 1806774A CN A2005100065172 A CNA2005100065172 A CN A2005100065172A CN 200510006517 A CN200510006517 A CN 200510006517A CN 1806774 A CN1806774 A CN 1806774A
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artificial
support
blood vessel
cell
heart
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CNA2005100065172A
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吉姆·V·西茨曼
欧根·V·西茨曼
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BIOARTTIS Inc
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BIOARTTIS Inc
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Priority to CNA2005100065172A priority Critical patent/CN1806774A/en
Publication of CN1806774A publication Critical patent/CN1806774A/en
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Abstract

The invention discloses an artificial blood vessel support, the artificial blood vessel is made from biological compatible materials, and can coat various selected cells. The invention also discloses various artificial organs made from biological compatible support material.

Description

Artificial blood vessel bracket and artificial organ
Technical field
The present invention relates to fields such as biomaterial, transplantable medical apparatus and cytobiology, specifically, the artificial organ that the present invention relates to a kind of artificial blood vessel bracket and its manufacture method and make thus.
Background technology
Naturally the blood vessel of Sheng Chenging is the constituting body of a complexity, describes with the simplest language, and tremulous pulse is exactly to be used for transmitting the pipe of blood to the whole body different parts.Blood vessel comprises tremulous pulse and vein, and every kind all has unique demand, and for example, it just stands high shear force and pressure when blood pump is crossed tremulous pulse.Blood vessel be one softish, have elasticity and flexible entity, it comprises the thin layer of smooth muscle cell and the internal layer of endotheliocyte.Their formation and form are different and different with environment of living in and vessel size and type.
People have paid the effort of many decades, seek can external manufacturing and its physiology characteristic and body in the similar permanent artificial blood vessel of natural blood vessel.Yet so far also without any a kind of single complete successful method, it can produce performance and reach requirement and can reach need of rapid production.Vein and biological artificial vein have been used to replace tremulous pulse, but their intensity and durability not insufficient are not suitable for the tremulous pulse environment of high shear force.
Ideally, should simulate the structure and the function of natural blood vessel as much as possible.For this reason, the NIUJIAO protoplasm is used as the backing substrate material, is covered with vascular smooth muscle cell and endotheliocyte in the above.This method is just developing into as carotid substitute.But the shortcoming of the method is the NIUJIAO protoplasm is not optimal material, because it costs an arm and a leg, must obtain on one's body from animal, and might cause the immunne response inflammation.
With the basis of synthetic support, it is advantageous that its simplicity, and can be complementary with natural demand as much as possible as blood vessel transplantation.Yet, create the trial of synthetic support, for example adopt the porous type polymer support, often confirm that this type of support is too hard, thereby As time goes on, cause the increase of hyperplasia and thrombosis occurrence frequency easily.About its best form and bendability or extensibility, its answer is not fully aware of.
Existing technology also once adopted weaving multifilament together, yet the pipeline tissue made of kind method lacks ideal cell and transmits the control in needed little porous (unified size and space) thus, also lacks elasticity and toughness that highly porous property is reached.
As seen, existing synthetic support can not reach ideal form and the bendability or the extensibility of natural blood vessel, and therefore, synthetic support need have the physiological property suitable with natural blood vessel, and similarly, specific cell also must be able to be inserted in the polymer support.The insertion of cell has increased the thickness of wall, and has eliminated that blood contacts with the direct of substrate under the high shear situation.Contact with the high shear of non-cellular matter and can cause disadvantageous long-term (surpassing some months) effect.
Except synthetic vessel had aforesaid shortcoming, present available artificial organ also had similar defective.Yet although the alternate demand of organ has far been surpassed obtainable transplant organ, the Prosthesis only obtains limited success and application.Except pollution problem and the infection problem that we were concerned about, the compatibility of tissue remains a problem, especially performs the operation for xenotransplantation.Therefore, except already present organ, the artificial organ with biocompatibility will play great role, and it can be used as substitute organ, perhaps wait for a permanent succedaneum or, can be used as a makeshift device by inserting the patient that succedaneum acquires strength for those.At last, these bio-compatible sexual organ must be able to obtain fast.Obtain a time at present, and in filed of organ transplantation, perhaps this delay is fatal with device several thoughtful several months of needs of complete function.
Summary of the invention
One object of the present invention just provides a kind of man-made support, and this support is durable, soft, can resist and use wearing and tearing, and have biocompatibility.
Another object of the present invention just provides and is placed in the intravital substitute organ of host, and the method and apparatus for preparing this substitute organ.The host can be any mammal, includes but are not limited to the mankind.
In the specific embodiment of the present invention, an artificial blood vessel bracket is provided, this support comprises supporting plate and many fibrae circulares of a plurality of prolongations, these supporting plates are settled with the side neighbouring relations, form tubular structure; Wherein, each prolongs supporting plate and all comprises the first parallel fiber bundle and the second parallel fiber bundle, and this first parallel fiber bundle is permanently connected together by the many perpendicular basically fibers that are connected with the second parallel fiber bundle; Fibrae circulares surrounds and is connected in regularly on the tubular structure, and tubular structure has defined internal diameter and external diameter.In addition, this specific embodiment can comprise further that also one deck sticks to the endotheliocyte on this artificial blood vessel bracket internal diameter and/or sticks to smooth muscle cell on the external diameter.The internal diameter of aforementioned artificial blood vessel bracket can be at 0.5cm between the 3.0cm.In addition, this specific embodiment can also optionally comprise the digestible substance of one deck in the internal diameter the inside, and attached on the artificial blood vessel bracket.
In the other specific embodiment of the present invention, a cell growth chamber also is provided, it comprises opening, port and environmental monitor on blood vessel, this blood vessel, wherein, opening on the blood vessel can allow the insertion of intravascular stent and shift out, and this opening can be airtight, and aforesaid port can be provided at the opening that allows the cell culture fluid turnover on the blood vessel, and environmental monitor then is used to monitor the inner case of blood vessel.In addition, this port can also comprise first port of being furnished with input pipe and second port of being furnished with outlet tube.The environmental monitor of present embodiment can be regulated environmental condition for the good cell growing state.
In the other specific embodiment of the present invention, the artificial blood vessel bracket that is coated with the cell growth substance also is provided, this support is positioned at previous described cell growth chamber.The artificial blood vessel bracket of a plurality of such coatings can constitute artificial organ.
In the other specific embodiment of the present invention, an artificial liver also is provided, it comprises a common input area, at least four independent input areas, at least four internal blood vessel, at least four independent output areas and a common output area; Wherein, common input area comprises a hollow cylindrical conduit with first end and second end; Independent input area also has first terminal and second end, and wherein first end closely is connected second end of common input area; Internal blood vessel has first terminal and second end equally, and wherein first end closely is connected second end of independent input area; Independent output area also has first terminal and second end, and wherein first end closely is connected second end of internal blood vessel; Common output area also comprises a hollow cylindrical conduit with first end and second end, and wherein first end closely is connected second end of independent output area; First terminal second end with common output area of common input area links to each other with the patient; Independent input area, internal blood vessel and independent output area are made of the man-made support with inner surface and outer surface, and wherein, internal layer is coated with vascular endothelial cell, outer coating hepatocyte.
In the other specific embodiment of the present invention, an inside or outside artificial liver also are provided, it comprises artificial liver, first pump and second pump in water-proof container; Wherein, this water-proof container has first terminal and second end, and first pump is positioned its first end, and second pump is positioned its second end, and first end is connected with patient's tremulous pulse and keeps liquid to exchange, and second end is connected with patient's vein and keeps liquid to exchange.
In the other specific embodiment of the present invention, an artificial pancreas also is provided, this artificial pancreas comprises at least two pancreas units, first connection tube and second connection tube; Each pancreas unit comprises a columniform intravenous injection support and a plurality of side branch, and has first terminal and second end; First end of first connection tube is fixedlyed connected with first end of artificial pancreas unit, and its second end is fixedlyed connected with the patient in the alternative mode of liquid; First end of second connection tube is fixedlyed connected with second end of artificial pancreas unit, and its second end is fixedly connected with the patient and keep liquid to exchange; Intravenous injection support and side branch include first terminal and second end, wherein, branched first end of side is fixedly connected with the intravenous injection support and keep liquid to exchange with it, branched second end of side is fixedly connected with the intravenous injection support and keep liquid to exchange with it, second end of the more close intravenous injection support of first end of the relative intravenous injection support of this junction point; Intravenous injection support and side branch are coated with the islet cells of secreting hormone.
In the other specific embodiment of the present invention, a Cardiac valve prosthesis also is provided, it comprises an annulus and a plurality of lobule, each lobule has two substantially parallel and flat basically surfaces and centers on the edge of lobule periphery; Wherein, the first of leaflet edge is fixedly linked with annulus flexiblely, and the size of lobule makes the second portion relative with leaflet edge first roughly be positioned the center of annulus with shape; Annulus and lobule comprise the support described in first specific embodiment of the present invention.
In the other specific embodiment of the present invention, an artificial ventricle also is provided, it comprises columniform basically central area and a hemispheric base region of a hollow; Central area comprises a bottom and a top, and the bottom is wideer than the top; Fixedly connected with the bottom of central area in the base region; Wherein, central area and base region comprise the support described in first specific embodiment of the present invention.In addition, present embodiment can further include the sheath of a big envelope artificial ventricle, and this sheath closely is connected the top of central area.
In the other specific embodiment of the present invention, an artificial heart pump also is provided, it comprises that motor and columniform basically, compressible heart substitute unit (device); Motor links to each other with pump installation, and this pump installation comprises that at least one can substitute the wheel that unit rolls along heart, so that compression and decompression heart substitute unit.
In the other specific embodiment of the present invention, an artificial heart pump also is provided, it comprises that the motor and columniform basically, the compressible heart that link to each other with pump installation substitute unit; This heart substitutes unit and is positioned at a liquid unit of escapement inside, and keeps liquid to exchange with at least one conduit of deriving this liquid unit of escapement; Wherein, aforesaid pump installation comprises the liquid shift unit, and this device can raise or reduce the pressure in the liquid storage unit, can cause heart to substitute the compression or the decompression of unit and raise or reduce fluid pressure.
In the other specific embodiment of the present invention, an artificial cardiac devices also is provided, it comprises two artificial ventricle, a hemispheric base region and at least one aforesaid artificial heart pump; Each ventricle comprises the cylindrical central area of hollow, and this central area has a bottom and a top, and the bottom is wideer than the top; Fixedly connected with the bottom of central area in the base region; Heart pump is used for compressing and two artificial ventricle of reducing pressure.This device can also comprise a biocompatibility outer housing that is positioned at the cardiac devices outside, and this outer housing that contains cardiac devices places in patient's body.
The present invention relates to a novel support, this support can duplication of production, and can carry out cutting according to special requirement.This support can by some material for example porous film tubing make.Wherein, porous can be controlled by dissolving some composition in the tubing selectively.In an embodiment of the invention, can make tubing, then tubing be contacted with solvent, wherein a kind of polymer and/or other substance dissolves are fallen by two or more polymer coextrusion or molding.This design allows cell to grow in the aseptic experiment room environmental at first, subsequently this device is implanted in the host with fertile functioning cell.Up to now, in the multiple animal body of each cell type, finished the transplanting (quoted passage of face as follows) of similar device.This will make these have inventive device and organ is that goals of medicine is applied on the mammal and the person, with the succedaneum as blood vessel and other organ.
In an embodiment of the invention, porous polymeric material is built as a support, form one competent, can not have thrombotic device by rubber-like yet, wherein, cell can be grown on this support.This polymeric material can be a kind of porous thermoplastic tube, and suitable non-water-soluble polymer (as the compositions of nylon-11, thermoplastic polyurethane, polysiloxanes or its different proportion) is extruded or molding forms by mixing.The thickness of tube wall and diameter can have different sizes to select by selected extrusion die or injection molding decision.50 microns wall thickness is optimal blood vessel assembling basically.Can obtain the tubing of different-diameter by extruding the prescription that contains non-soluble polymer such as nylon-11 and water-soluble polymer such as polyethylene oxide.
The non-soluble polymer that the porous conduit is made in suitable can be used among the present invention comprises nylon-11, thermoplastic polyurethane, polysiloxanes and compositions thereof.Insoluble polymer can be a kind of high-molecular weight thermoplasticity or thermosetting resin.This insoluble polymer or resin have enough polarity, can adhere well on the cell, and must autoclavable, can sterilize and have durability and elasticity preferably.
The special example of the non-soluble polymer that adopts among the present invention comprises:
Product coding Kind The CAS number of registration
ORGASOL 1001UD NAT Nylon 12 [25038-74-8]
ORGASOL 1002D is natural Nylon 6 [25038-54-4]
ORGASOL 2001UD NAT Nylon 12 [25038-74-8]
ORGASOL 2001UD NAT Nylon 12 [25038-74-8]
ORGASOL 2002D NAT Nylon 12 [25038-74-8]
Nylon-11 has no swelling being particularly useful as stroma ground substance with in biological artificial organ manufacturing because compare it with other nylon.Nylon-11 has anti-high pressure, hydrolytic resistance, water-insoluble and ruggedness.The conjugate of nylon-11 and thermoplastic polyurethane (TPU ' s) and/or TPU be as non-soluble polymer, aspect the elasticity that strengthens the porous tubing also of great use.This discovery that can be used as the tubing of matrix scaffold (human cell is portion and outside growth within it) brings a brand-new biological reactivity device field.
This conduit of extruding can immerse in the suitable solvent subsequently, and leaching section or all water-soluble polymers obtain tubing porous, hot mechanicalness, and this tubing also can be flexible.The structural aperture of nylon tube is that polyethylene oxide is gone out the back generation by water logging.By changing water-insoluble and ratio water-soluble polymer, the porosity of tubing is controlled between 50% to 80%, mean pore size is controlled between 0.5 micron to 5 microns.
In order to obtain having more the porous mass of pliability and wearability, can use thermoplastic polyurethane instead of part or whole nylon.
The polymer matrix optimization that dissolves is the thermoplastic material of a kind of intermediate molecular weight, nonionic, for example polyethylene oxide (PEO).
Resulting tubing is plasticizer-containing, solvent or other undesirable or deleterious composition not.By changing water-insoluble and ratio water-soluble polymer, the porosity that makes tubing is between 50% to 80%.The controllable size in hole is built in about 0.5 micron to 5 microns.Typical conduit has 75% porosity, 2 microns of average cell size, 50 microns of wall thickness.
Be ready to just can insert required cell after this porous polymer support.This can optionally plant required cell by bioreactor and realize on artificial organ substrate.For example, artificial tremulous pulse can be by planting smooth muscle cell on the outer wall of porous conduit, and plant endotheliocyte on its inwall.This process utilizes cell to increase the thickness of tube wall, and has eliminated that blood contacts with the direct of substrate under high shear environment.Artificial blood vessel inside exists the level and smooth n cell of one deck of crucial importance, can produce secular side effect because the high shear force with the acellular material of some months contacts.
Cell enters the aperture of substrate and interconnects, and forms a uniform pantostrat in the outside of polymeric catheter.Because small structure allows cell closely to contact by the inner and outer wall of tubing, so cell is locked within the substrate.Poromeric polarity amide moieties density is lower, and it serves as the contact point of cell adhesion.The cell cover layer is separated polymeric catheter and host environment uniformly, has further strengthened the no thrombotic of device.The orifice size of substrate and high porosity can improve intercellular being in contact with one another, thereby reply in the body of enhancing to environmental stimulus.
Can be implanted into the artificial organ that replaces or strengthen depleted organ in the body by on porous polymer substrate, cultivating, can producing fully from various suitable organ cells.The artificial organ that is suitable for transplanting comprises blood vessel, liver, skeleton, tendon/ligament, skin etc.Similarly, by on porous polymer substrate, cultivating the cell of different endocrine gland, can produce the artificial endocrine gland that is suitable for transplanting.In this way the artificial body of gland of Zhi Zaoing comprises thyroid, parathyroid gland, pancreas, adrenal gland, hypophysis, testis and ovary.By on porous polymer substrate, cultivating the cell that to secrete different cell proteins or enzyme, can also produce the alternative graft of secreting desirable proteins or enzyme that implants.
Therefore the present invention can produce and multiplely can implant the intravital artificial apparatus of patient, as artificial organ, keeps the growth of kind of a group specificity (as the human or animal) cell, thereby Therapeutic Method required, that the race is specific, medical science is applicatory is provided.
Combine with becoming long cell by polymeric catheter, can produce the substitute of tremulous pulse flexible high hole.The device of gained can be done corresponding change by the cell type that changes above it or wherein grow.For example, select suitable cell can produce biological artificial liver with function.In addition, have the support that the change of the polymeric matrix of inorganic filler also can provide a kind of cell to grow thereon, to obtain being fit to serve as the device of skeleton or cartilage.
The characteristic of other purpose of the present invention, advantage and novelty is more obvious with what show in the detailed below description.
Description of drawings
It shown in Figure 1A the single-side stand plate; It shown in Figure 1B the double bracket plate.
It shown in Fig. 2 A the pentagon perspective views of supports according; Fig. 2 B is the cross-sectional view of pentagon support; Fig. 2 C is the cross-sectional view of octagon support.
Fig. 3 is the support cell growth chamber that scales off.
Fig. 4 is the support perspective view that has the conduit liner.
Fig. 5 has the support perspective view that cell applies.
Fig. 6 A is the sketch map that inner artificial liver organ medium-height trestle is arranged.
Fig. 6 B is shown in the sectional view at Fig. 6 A I-I place.
Fig. 6 C is the sketch map that inner artificial liver organ medium-height trestle is arranged.
Fig. 6 D is the perspective view that shows an inner artificial liver organ part.
Fig. 7 A is that inner artificial liver organ is common and independently input or output the sketch map in district.
Fig. 7 B is that inner artificial liver organ is common and independently input or output the sketch map in district.
Fig. 7 C is that inner artificial liver organ is common and independently input or output the sketch map in district.
Fig. 8 is the hepatic cell growth chamber figure that scales off.
Fig. 9 is the structural representation of outside artificial liver.
Figure 10 A is artificial pancreas sketch map.
Figure 10 B is the detailed sketch map of the part of artificial pancreas.
Figure 11 A is that artificial pancreas medium-height trestle is arranged sketch map.
Figure 11 B is that artificial pancreas medium-height trestle is arranged sketch map.
Figure 12 A is the sectional view that artificial pancreas inputs or outputs part.
Figure 12 B is the perspective view that artificial pancreas inputs or outputs part.
Figure 13 is the figure of pancreatic cell growth room that scales off.
Figure 14 A is the diagrammatic sketch of bowing of Cardiac valve prosthesis.
Figure 14 B is the side diagrammatic sketch of Cardiac valve prosthesis.
Figure 15 is the figure of cardiac valve growth room that scales off.
Figure 16 A is the perspective view that a kind of heart substitutes the chamber.
Figure 16 B is another perspective view that heart substitutes the chamber.
Figure 16 C is the side view that has the alternative chamber of heart of overcoat.
Figure 17 is the side view in flap valve and increase-volume zone.
Figure 18 is the figure of heart cell growth room that scales off.
Figure 19 is the sketch map that has the inside heart pump of runner.
Figure 20 is the sketch map that has the inside heart pump of liquid.
Figure 21 A is the sketch map of inner heart pump constituent.
Figure 21 B is the figure that is used in the increase of the binary timing wheel on the inner heart pump.
Figure 21 C is the sketch map of parts of inner heart pump.
Figure 22 is the sketch map of inner heart alternative system.
Figure 23 A is the sketch map of external heart pump.
Figure 23 B is the vertical view of external heart pump.
Figure 23 C is the enlarged drawing of external heart pump rotating part.
Figure 24 is the sketch map of artificial artery among the present invention.
The specific embodiment
To the specific embodiment of invention and the detailed description of specific embodiment, can more easily understand the present invention with reference to following.Term used herein only is in order to describe the specific specific embodiment, rather than limitation of the present invention.
Embodiment 1
Shown in Figure 1A, panel 10 is with two or more, preferably two or three parallel beams 11 and minimal elastic (as the #10 nylon fiber), short perpendicular fasciculus 12 link to each other and form, wherein, parallel beam 11 is materials of no adsorptivity, and preferably do not have immunity, perpendicular fasciculus 12 is identical with parallel beam 11 diameters.0.5-1.0 μ m at interval approximately between the perpendicular fasciculus 12, and roughly be 90 ° with parallel beam 11.The all fibres bundle gives fixedly connected with the method that is fit to its material, these methods are including, but not limited to heating and adhesion.For example, high temperature can be induced combination, and makes some fiber such as SILASTIC TMBecome tough; Perhaps use sealant such as silicones, polyurethane or the polyethylene of trace, it can for good and all connect these fibers, and the present invention is adopting said method then.
In the embodiment shown in Figure 1A, what panel was showed is a flat relatively shape, and this flat panel has a plurality of advantages, as is easy to make.In addition, can prepare the dual platen 13 shown in Figure 1B, the perpendicular fasciculus 12 that it has a common vertical bundle 14 and sets up by required interval.Perpendicular fasciculus 12 couples together common vertical bundle 14 and one or two parallel beams 11.Perpendicular fasciculus 12 can relative both sides attached to vertical bundle 14 on, shown in Figure 1B, perhaps alternately arrange 12 of roughly the same quantity along 14.Figure 1B shows that each bar perpendicular fasciculus 12 couples together 14 and parallel beams 11 of common vertically bundle, so is vertically coming two perpendicular fasciculuses in 14 places with regard to shape α in an angle.Can vertically between bundle 14 and the parallel beam 11 farthest additional parallel beam 11 be set, this can gain in strength, especially in big support.It is preparation ternary panel (not providing sketch map) that another one is selected.Foregoing panel is normally planar or the angle is arranged, and we can utilize the panel with warp architecture to come the circular configuration of better simulating nature blood vessel.
Shown in Fig. 2 A, preparation panel 10 and/or dual platen 13, and so be provided with, make the parallel beam 11 of each panel 10 or dual platen 13 parallel to each other, thereby form a cylindrical stent 20 roughly.Panel 10 or panel 13 are set, make the similar angle of maintenance between each counter plate, about 25 °-45 °, as can being 25 °, 30 °, 35 °, 40 ° or 45 °.Gap 21 is present between every cover panel 10 or the dual platen 13, and this does not comprise interconnective space between the panel.Gap 21 sizes approximately are 0.5-1.0 μ m.
In order to make panel keep basically cylindrical shape, being connected leaving position at interval along panel length of the panel that links to each other in abutting connection with longitudinal edge.In order to adapt to the change of internal blood vessel pressure, disjunct one section panel that guarantees the gained tubular structure of insertion can move crooked and mutually.Conversely, this also makes the artificial blood vessel can be as the slight stretching, extension of nature blood vessel under pressure, and can improve its durability and reliability.The junction point that staggers in each relative both sides of panel has unique effectiveness, and it can be avoided along the inextensible node of vascularization.
By SILASTIC TM(Dow Corning, Midland MI) or other is suitable, rubber-like, the best annulus 22 made of the fiber of no antigen, are attached to the outer surface of panel 10,13, with the face equipment of holding cylindrical.The 100-600 μ m of being separated by between a plurality of annulus 22.The purposes of blood vessel has determined external diameter, length etc. in it.All sizes conform to natural blood vessel and change with the purposes of expecting.
In construction process, panel 10,13 is toward a common core (not accompanying drawing), and this core can be conduit or infundibulate, is made by smooth and firm material.The effect of this core is to help to set up support 20, and can be easy after support 20 is finished and remove rapidly.With panel 10,13 place this core around after, they remain on the appropriate position of annulus 22, annulus 22 can mode be connected with the fiber of panel 10,13, but preferably and selected materials adapt.The number of panel 10,13 is different with purposes.Support 20 cross section two examples comprise the octagon shown in the pentagon shown in Fig. 1 D and Fig. 1 E.
Annulus 22 can be made by multiple known material, includes but not limited to SILASTIC TM, methacrylate, nylon, terylene, polydimethylsiloxane, polyurethane, polyethylene, big gram close, triangle fibre board (gore-tex), latex, rubber, elastomer, glass, pottery and plastic cement.Bundle bar in the panel 10,13 can be made by any known substance in this area, includes but not limited to SILASTIC TM, methacrylate, nylon, terylene, polydimethylsiloxane, polyurethane, polyethylene, big gram close, triangle fibre board, polypropylene, 2-octyl group-cyanoacrylate, polymethyl acrylate, metaradrine, polystyrene, poly-D-lysine, aluminum, copper, rustless steel and titanium.
The suitable core material that helps to build support 20 comprises latex, rubber, elastomer, glass, pottery, plastics, aluminum, copper, rustless steel and titanium.
Embodiment 2
Before implanting aforesaid prosthese blood vessel, vascular endothelial cell and smooth muscle cell must be planted and be cultivated on a fixed structure.When this process starts from the artificial blood vessel bracket construction, can be the support 20 in the example I.Outer surface cultivation along support 20 has one deck smooth muscle cell, and the inner surface of support 20 is then cultivated one deck endotheliocyte.The interpolation of cellular layer can be accomplished by support 20 being placed vascular cell growth chamber 30 as shown in Figure 3, just forms a mistress 31 and inner room 32 thus in 30.Mistress 31 has been full of the culture fluid that contains vascular smooth muscle cell, and support 20 is hatched about 2 days so that cell is attached to its outer surface at this.
After okioplast adhered to, the culture fluid that contains endotheliocyte flowed into inner room 32.This can realize that culture fluid pumps into from first port 33 of 30 by following manner, flow out from second port 34, thereby the inner surface that allows endotheliocyte to attach to support 20 is also suitably arranged.Port 33,34 should be consistent with the diameter of support 20.The culture fluid that contains endotheliocyte should be abundant in the time of the support 20 of flowing through, as fortnight.Two confluent monolayer cells all adhered to finish after, support 20 just shifts out from cell growth chamber 30, transplants rapidly or stores 20-36 hour at 0-30 ℃.
Such cytoskeleton front was described, and smooth muscle cell can cover on the strand that forms support.Other cell growth forms net, and length has the solids conduit of smooth muscle cell to center on and be positioned at the inside of supporting structure on it then.Subsequently, the endepidermis cell culture fluid outer surface of flowing through has deposited the support of exocuticle cell, forms artificial blood vessel's inner liner, and along being formed centrally continuous path in this support.This process approaches the growth of vascular cell in the body most, and when is connected with new support finish after, just can form one and the extremely similar manually blood vessel of natural vessel properties.
Other features of vascular cell growth of the present invention chamber 30 comprise the part that some are independent, as first end 35, mid portion 36 and second end 37.The side port 38 that is positioned at mid portion 36 is importing and the output for the vascular smooth muscle cell culture fluid.These independent parts can be connected by watertightness interface or other proper tools.Preferably make up vascular cell growth chamber 30 with transparent cylindrical plastic material.The preferred size of vascular cell growth chamber 30 is length 8-20cm, diameter 0.6-4.0cm.Be appreciated that and the present invention includes known equivalent of above-mentioned chamber and the equivalent of developing in the future in this area.
Carry out cell migration or transhipment by the space in the support 20 if desired, so just can make up one as shown in Figure 4 interior pipe 40 and along the arrangement of support 20 inner surfacies.In pipe 40 constitute the carbohydrate or the polyglycine material that close, can absorb as big gram by digestible fibrous matter.Interior pipe 40 can make support 20 avoid compressing or subsiding after transplanting, and is distributed with the hole of a lot of consistent size on it, and its diameter arrives 150mM, for example 100mM between 50.
As shown in Figure 5, support 20 has become the support 50 that is coated with skin 51 and internal layer 52.According to the size of employed support 20 and the thickness of skin 51 and internal layer 52, most supports 50 or artificial blood vessel's device can be determined its size.The size of internal diameter can define by the cell that is grown on support 20 inwalls.But concrete size, for example internal diameter, external diameter, length etc. must be determined by the actual needs of artificial blood vessel.
Application scenario of the present invention comprises crown or heart arter, arteriovenous fistula, big (for example abdomen organ such as liver or kidney, cranium brain orientation, upper limb) tremulous pulse and large vein sub.For coronary artery substitute or graft, preferred internal diameter is 350-1000 μ m, and external diameter is 500-1200 μ m, wall thickness 200-300 μ m, length 9.6-12cm.
For arteriovenous fistula, its effect is to place the subcutaneous dialysis service (as artificial kidney support, artificial nutrition, artificial liver support) that percutaneous is provided, and the preferred internal diameter of this implant is 1-3cm, external diameter 1.5-3cm, wall thickness 250-400mm, length 12-20cm.
Most of tremulous pulse substitutes can be transplanted the substitute as carotid artery, upper limb (axillary artery or brachial artery) or abdominal artery, and its internal diameter is 2-2.5cm, external diameter 2.5-3cm, wall thickness 500-600mm, length 10-15cm.
Most of vein substitutes can be transplanted as jugular vein, upper limb (axillary vein or brachial plexus vein), abdomen organ or pylic substitute, its internal diameter is 2-3.5cm, external diameter 2.5-4cm, wall thickness 400-500 μ m, length is selected according to specific needs, and approximate size is 5-10cm.
The artificial blood vessel's internal diameter of prosthese that is used for arteriovenous fistula is between 0.75-1.10cm.Internal diameter is the succedaneum that the artificial blood vessel of 0.50-0.64cm mainly is used as heart arter, comprises the collateral branch of heart arter.So just blood vessel that can be traditional substitutes, as shank vein, preceding brachial artery or come from the tremulous pulse of thoracic wall.Than the Prosthesis of large diameter, internal diameter between 1.5cm to 3cm, 1.8cm for example, can be when liver or renal transplantation as the substitute of blood vessel.The blood vessel that the artificial blood vessel of maximum inner diameter is used for upper limb or lower limb forms again.
Embodiment 3
Fig. 6 A is the sketch map of an artificial inner liver unit 60.A common input port 61 in the artificial inner liver unit 60 is sewed up (not shown) with abdominal artery.61 internal diameter approximately is 2cm, and length approximately is 1-2cm.Relative with tremulous pulse what extend out is 2-20 independently input port 62 from 61, and wherein each diameter of 62 approximately is 80-100 μ m.Each is all lead first end of inner catheter 63 of input port 62 independently, and these inner catheters have 4-8, the about 30-50 μ of each internal diameter m, length 8-12cm.Rise from the inner catheter 63 of independent input port 62 and mostly their second end is linked to each other with independent output port 64,64 diameter is approximately 80-100 μ m.64 link together with common output port 65, and 65 internal diameter approximately is 2cm, length 2-4cm.65 sew up (not shown) with epigastric vein.Shown in Fig. 2 A, 62 and 64 is interlaced with the branch form.
Common input and output port can be made with any suitable tube material.Other parts of artificial organ comprise the artificial blood vessel in the example I, and its connection can realize by create a plurality of staggered openings around common input pipe.First of the independent input area of respective numbers terminal be connected in liquid mode with the opening of input pipe jointly and form sealing state.The another one example is exactly to form an end region in common input area, and it is a hemisphere that has a plurality of openings.First of independent input area terminal be connected in liquid mode with the opening of independent input area and form sealing state.Can utilize adhesion material, heat treatment and other obtainable method that the various piece of organ is linked together.
It shown in Fig. 6 B the cross section of in inner artificial liver unit 60, being done along the I-I line.Fig. 6 C is 60 perspective view.Fig. 6 D is the enlarged drawing of a part of 60, its shown common inlet 61 and lead in four independent inlets 62 of pipe 63.Except branched independent importation as shown in Figure 6, other arrangement modes of inner artificial liver unit 60 in Fig. 7 A, 7B and 7C, have been shown.These three figure have shown that respectively 10,12 and 20 independent importations 62,62 come the difference on the comfortable common inlet 61 respectively.A plurality of 62 modes with approximate vertical radiate from 61.Corresponding output area and above similar.
When preparing artificial inner liver, prepare a plurality of in advance as 10 or 20 artificial inner liver units 60.Typically, common importation 62 and output 64 comprise the solid fiber structure, can easily it be sewn onto (not shown) on the abdominal vascular.The other parts of artificial inner liver comprise the artificial blood vessel bracket in the example I.Each artificial inner liver can be coated with one deck biocompatibility, Nondegradable is weaved the material (not shown).These materials comprise dacron, triangle fibre board, polyurethane and polyethylene.They can extend to 64 since 62.As a rule, has the about 10-12cm of liver unit's 60 length of tunicle, diameter 5-8cm.
Because the artificial inner liver of assembling includes a plurality of supports, therefore before being applied to the patient, must make it be covered with cell.Each support in each artificial inner liver unit 60 all can be planted one deck liver cell at its outer surface, and its internal layer can be planted one or more layers endotheliocyte.The method of finishing this process is exactly the hepatic cell growth chamber 80 of using as shown in Figure 8.The artificial inner liver 81 that assembles is at first encased by a Nondegradable overcoat 82, places 80 then.Be full of the cell culture fluid that contains liver cell in 80, hatched about two angel's cell attachment to the outer surface of each support.
After okioplast adheres to, the culture fluid that the contains endotheliocyte artificial inner liver 81 of flowing through.This can realize by following manner: culture fluid pumps into from first port 83 of hepatic cell growth chamber 80, flow out from its second port 84, thereby the internal layer that allows endotheliocyte to attach to support is also suitably arranged.Port 83,84 should be consistent with the diameter of common importation 61 and output 65.The culture fluid that contains endotheliocyte can have adequate time when flowing through hepatic cell growth chamber 80.Two confluent monolayer cells all adhered to finish after, 81 just shift out from cell growth chamber 80, transplant rapidly or store 20-36 hour at 0-30 ℃.
Other features of hepatic cell growth of the present invention chamber 80 comprise that side port 85,85 can allow to increase or remove hepatocyte solution.Finish and after cell applied, final length approximately was 10-12cm in artificial inner liver 81 combinations, inside the diameter of conduit be 350-450 μ m, wall thickness 100-200 μ m, the aperture 0.5-1 μ m on the wall.Gap between conduit and the liver overcoat 82 approximately is 350-600 μ m, for example 500 μ m.
Embodiment 4
Shown in Figure 9 is the brief configuration figure of outside artificial liver 90.Artificial inner liver among the embodiment 3 can be included in the artificial tubes tissue, if necessary, also can place external.Comprise a plurality of sealing chambers 91 through being placed on outside device after revising, its diameter approximately is 2-4cm, is preferably made by transparent plastic tube tissue.Each sealing chamber 91 comprises an artificial liver.
The diameter of the common input area 92 of outside artificial liver 90 is 0.5-1.0cm, and is connected with independent importation 93.Artificial liver independently enters the mouth and is included in the independent importation 93, and 93 are connected on the sealing chamber 91 that contains the artificial liver inner support.Externally a plurality of artificial livers make up in the mode of serial or parallel connection in the artificial liver 90, thereby needed surface area is provided.Independent output 94 allows to flow out in liquid each sealing chamber from 90.94 link to each other with common output 95, and 95 diameter is 0.5-1.0cm.Outside artificial liver 90 comprises 10-20 sealing chamber 91.
The first rotary pulse pump 96 can help blood flow to pass through sealing chamber 91,96 percutaneous to link to each other with the patient, by a polyethylene, plastics, ILASTIC TM, nylon or other flexible pipe thrust (not shown) in the tremulous pulse, and utilize suitable material to link to each other with common input area 92.The second optional rotary pulse pump 97 be positioned at 95 with the patient in the middle of and be connected with the two, be percutaneously advanced into (not shown) in the vein.Pump 96 (with 97) helps blood flow flow with 100-1000ml/ minute under the pressure of 25-100mm Hg to pass through this device, gets back in patient's body.
The present invention provides a kind of suitable substitute organ for any type of liver defective patient, and these patients often face the challenge of gangrenosum acne and hyperimmunity, and therefore the device of being made by the non-immunity material is that critical patient is needed.Be coated with that cell and avirulent material can suppress to repel, the activity of blood coagulation or cytokine, these factors can increase hepatic injury, disease or handicapped patient's burden abnormally.
Embodiment 5
Shown in Figure 10 A, artificial pancreas unit 100 is made up of intravenous injection support 101 and a plurality of side branch 102,101 cylindrical structurals normally, diameter is 0.5-1.5cm, length 8-24cm, 102 internal diameter approximately is 1/4 to 1/2 (0.125-0.75cm) of intravenous injection support, length 7-20cm.This support can be made of the material described in the example I.Side branch 102 is attached to 101 the first terminal and offside ground extension therefrom.Can form annulus 102 along 102 before being attached to 101 second end.A plurality of side branches 102 can be arranged on the intravenous injection support 101, approximately 10-20, for example 16.What Figure 10 B showed is wherein part perspective view altogether of artificial pancreas unit 100, and it has shown intravenous injection support 101 and side branch 102.
For clarity sake, Figure 11 A and 11B do not show side branch 102.Figure 11 A has described four artificial pancreas units 100 and has been bonded together and forms the first branch section 110 of biological artificial pancreas (whole organ does not show).The present invention can also choose wantonly is equipped with at interval 111,111 and links to each other with some or all of artificial pancreas units 100, thus between artificial pancreas unit needed space of maintenance.Figure 11 B shows that further three first branch sections 110 can be held together and form the 3rd branch section 112.More 110 along with increasing, just can obtain the artificial pancreas 111 of design specification.Finally the definite quantity of used branch section depends on patient's state, position and other factors of insertion.
Artificial pancreas has a common input area, its diameter 2-5cm, length 7-20cm.Artificial pancreas is made up of a plurality of artificial pancreas units 100, and these unit groupings form the branch section.The importation of each first branch section 110 (not shown) that links to each other with common input area.Can set out a plurality of independently input areas 113,113 from common input area and lead to each first branch section 110.At the relative other end, 100 polymerizations of artificial pancreas unit are that 115 among Figure 11 B is bonded together in 110 independently output 114,114 with common output area, and this can be understood as artificial pancreas and can comprise and being less than or more than three branch section.Common output 115 is suitable with common importation size.Figure 11 B has described the artificial pancreas unit 100 of 12 connections.According to the present invention, artificial the nearly 2-12 of pancreas artificial pancreas unit.
With a plurality of artificial pancreas units 100 with common input or output a kind of mode that the district couples together exactly with each artificial pancreas unit 100 as other branch with input or output that the district links up at a certain angle and to external radiation.For example, eight intravenous injection supports can be 45 ° and connect together mutually, that is to say, having the cylindrical artificial pancreas unit 100 that inputs or outputs the district can be at 0 °, 45 °, 90 °, 135 °, 180 °, 225 °, 270 ° and 315 ° of bifurcated.And 12 intravenous injection supports can be 30 ° of arrangements, that is to say, at 0 °, 30 °, 60 °, 90 °, 120 °, 150 °, 180 °, 210 °, 240 °, 270 °, 300 ° and 330 ° of bifurcateds.The cross section shown in Figure 12 A is seen in this configuration.It shown in Figure 12 B the perspective view of 16 apparatus derivatoriuses.18 intravenous injection supports can link together when separating with 20 °.
Arrange good branch and should be contained in the container 54 biocompatibility, that be essentially cylinder, the about 1-2cm of diameter, length 2-4cm are held in inputing or outputing of this cylindrical unit.
After being ready to artificial pancreas 111, repopulating cell therein just.A method finishing cell seeding is exactly by utilizing pancreatic cell growth room 130 shown in Figure 13.Input area 131 comprises an input pipe 132 that cell is flowed into.Excess liquid and/or cells are collected in output area 133, and by outlet tube 134 they are removed.The artificial pancreas unit 100 that has side branch 102 places pancreatic cell growth room 130.Randomly, can also be configured to re-use pancreatic cell growth room 130 after the shape that needs and the size in a plurality of artificial pancreas units 100.
The inner surface of artificial pancreas unit 100 and the islet cells that outer surface all is covered with secreting hormone.Islet cells and islet cell (cell that for example comes from pig, sheep or goat) preferably is divided into independent cell, as digestibility or enzymatic activity cell and islets of langerhans or hormone cell.Islets of langerhans or hormone cell can stick in the artificial pancreas unit 100 by pancreatic cell growth room 130.If end user's pancreatic cell should make donor and receptor's blood antigen (A+, A-, B+ etc.) be complementary, thereby minimizing is repelled or the occurrence probability of complication.
In case artificial pancreas 111 is made and is finished, and can be placed on certain acra of patient, for example for the mankind, consider to be easy to insert and local anesthesia, preferably be placed on forearm or lower limb place, be sewn to again on tremulous pulse or the vein.
Embodiment 6
It shown in Figure 14 A the vertical view of Cardiac valve prosthesis 140.Cardiac valve prosthesis 140 is made up of the circular flap valve ring 141 and a plurality of lobule 142 that serve as fixed position.Preferably two or three lobules are attached on 141 and to the center and extend, and form two leaves (Bicuspid valve) or SANYE (Tricuspid valve) valve.Lobule 142 also is made of the timbering material in the example I.It shown in Figure 14 B the side view of valve.
The diameter of valve approximately is 2-4cm.Valve 140 be in case can open to first direction under the blood flow effect after forming, thereby forces 142 to move to same direction, opens 140 center so that liquid passes through, and this center is defined by circular flap valve ring 141.Valve 140 will be closed with the opposite flow direction.The Push And Release of the pressure control valve of blood flow.
For the lobule support that provides to be coated with cell, valve 140 can place a heart valve cell growth room 150 before in being transplanted to patient's body, as shown in figure 15.After placing 150 treatment region 151 with 140, the solution that contains fibroblast and/or chondrocyte will cross and surround 140 by pump.This pump is inhaled process and is finished by a pump and fountain 152.Cell culture fluid is entered in the treatment region 151 by conduit 153 by pump and 152.The situation that has shown two conduits 153 among the figure; Two conduits 153 of preferred use, it can simulate the direction of blood flow better.
In addition, after fibroblast and/or the chondrocyte growth, also can be to valve 140 with endothelial cell seeding.After cell seeding was intact, circular valve annulus 141 just can be sewn onto on in-vivo tissue or the artificial heart's device.
Circular valve annulus 141 can be made of any suitable material, for example SILASTIC TM, proline, methacrylate, nylon, terylene, polydimethylsiloxane, polyurethane, polyethylene, big gram close, triangle fibre board, polypropylene, 2-octyl group-cyanoacrylate, polymethyl acrylate, polyactide, metaradrine, polystyrene, poly-D-lysine, latex, rubber, elastomer, glass, pottery, plastics, aluminum, copper, rustless steel and titanium.140 holder part can be made of following material: SILASTIC TM, proline, methacrylate, nylon, terylene, polydimethylsiloxane, polyurethane, polyethylene, big gram close, triangle fibre board, polypropylene, 2-octyl group-cyanoacrylate, polymethyl acrylate, polyactide, metaradrine, polystyrene, poly-D-lysine, aluminum, copper, rustless steel and titanium, or other similar material.Conduit 53 can be made by any required material, but preferably by those can adherent cell material constitute.
Embodiment 7
The further application of the man-made support in the example I is to make artificial ventricle 160, shown in Figure 16 A.Artificial ventricle 160 is made of cylindrical stent 161, and links to each other with a hemispherical substrate 162.Cylindrical stent 161 is wide than top 163 near 162 place, bottom, top 163 be opening and can be attached on the valve described in the embodiment 6.The donor valve of transplanting or the artificial valve of any type all can be used as required.It shown in Figure 16 B the schematic drawing of artificial ventricle 160.The ventricle top is unipolarity and is opposite direction mutually with two valves.One of them valve allows liquid to flow into ventricle, and another then allows liquid to flow out ventricle.Form independent chamber although can be bonded together at inner two valves of ventricle, they remain separately in the ventricle outside, and are connected on the different blood vessel or cardiac structure.
Shown in Figure 16 C, artificial ventricle 160 is encased by a ventricle peplos 164.Ventricle peplos 164 can protect 160 to avoid some potential damages, and these damages may be to inhale active material or mechanical being caused by being used for creating pump.Figure 17 has shown an additional zone of 160, comprises a valve area 165.Two valves of 165 usefulness are illustrated that it can be attached to (not shown) in the artificial ventricle, and 165 diameter approximately is 2.5cm, length 0.5cm.Can see an optional two-way valve extension 166 and two unidirectional valve extensions 167 among the figure.166,167 length are approximately 2-3cm, can be used for prolonging additional areas, and this zone is to be used for linking on the intravital tubing of patient or directly linking to each other with the patient 165.
The valve area is made of prosthetic material, for example terylene, triangle fibre board, polyethylene or polyurethane.No matter be nature or artificial, cardiac valve all can be attached on the valve area by suitable material.The material of valve extension can be made of the same material of making the valve area, or other material, as the timbering material among the present invention, this timbering material has the serving of the coating of one deck impermeability cell or one deck encapsulant, these encapsulants such as terylene, silicone rubber, polyethylene, polyurethane or triangle fibre board.Valve and ventricle optional comprise the valve extension, are adhered to the form of similar stitching with fiber or with fabric technology.The another one method is attached to valve and extension on the ventricle with adhesive material exactly, and the two is sticked together mutually.A plurality of materials of mentioning among the present invention all are fit to adhere to, as proline, nylon, rustless steel and methacrylic resin.
After artificial ventricle 160 made and finishes and place in the heart peplos 164, this device must apply a confluent monolayer cells.The method that cell seeding gets on is utilized ventricle cell growth chamber 180 exactly, as shown in figure 18.Artificial ventricle 160 is placed in the ventricle cell growth chamber 180, and the cell culture fluid that contains myocardial cell flows into ventricle cell growth chamber 180 by side port one 81.This process allows myocardial cell to be attached in the artificial ventricle 160.
Ventricle cell growth chamber 180 can comprise that also an input area 182,182 is connected on the top 163 of artificial ventricle 160.By input area 182, the culture fluid that contains endotheliocyte is by 160 inside and endotheliocyte is attached on its inner support.
The material that is fit to artificial ventricle's support comprises SILASTIC TM, proline, methacrylate, nylon, terylene, polydimethylsiloxane, polyurethane, polyethylene, big gram close, triangle fibre board, polypropylene, 2-octyl group-cyanoacrylate, polymethyl acrylate, polyactide, metaradrine, polystyrene, poly-D-lysine, aluminum, copper, rustless steel and titanium.The material that is suitable for overcoat comprises latex, rubber, elastomer, pottery and plastics.These materials are yielding and can resist pump suction activity and hydraulic effect, and the two can make the object compression.
Embodiment 8
As shown in figure 19, pump 190 is used for making the artificial ventricle among liquid inflow or the outflow embodiment 7.190 are connected in (not shown) on the driver, and this driver can make 192 rotations around the axle center of crank wheel or driving wheel 191.The motion of driving wheel 191 can cause the reciprocating motion of drive rod 193.Thereby drive rod 193 makes 196 motions of a pitman that a pair of ventricle compression wheel 194 is rotated in turn.Ventricle compression wheel 194 moves along wheel guide rod 195, the compression and the decompression activity that make artificial ventricle 160 produce rhythmicity.The inner normal pump suction activity of compression simulation organism of this rhythmicity.Details about time and pressure can be regulated according to the needs of organism.The driver of friction speed also is provided at the pump characteristics that can adjust.
It is enough firm that wheel 194 preferably makes up, thereby produce compression, yet 194 also should how many band point flexibility and flatness.194 preferably cover the similar or identical material to the clad material of artificial ventricle 160 of one deck.Guide rod 195 can apply lubricant, for example, and a kind of oil based on silicones.Lubricant needn't contact with artificial ventricle 160, because 195 wrap up or are included in the valve jacket.
Embodiment 9
Make artificial ventricle's 160 generation rhythmicity compressions and simulation normal heart pump inhale an active alternative method and be to use fluid clutch 200, as shown in figure 20.Fluid clutch operates by raising or reducing fluid pressure, rather than manual compression as described in example 8 above.
Fluid clutch 200 is driven by a motor (not shown), and this motor is connected on the live axle 201, and driving wheel 202 is rotated.202 are connected on the drive rod 203, make 203 to produce reciprocating motion when 202 rotate.203 activity makes piston 204 produce corresponding motion.Fluid clutch is included in the pump receptacle 205, and 205 have an outlet 206.204 form a fluid-tight capping in 205, liquid containing is in the zone between 204 and 206, and 204 reciprocating motion makes the liquid in 205 be forced out or suck.
One other component of this cover pump desorption system is that the container 207,207 of cardiac devices is connected with liquid with pump receptacle 205 by port 206.Artificial ventricle 160 and some liquid are arranged in 207.Extrude by outlet 206 from 205 when fluid clutch 200 makes liquid, liquid enters in 207.The size of liquid volume and container 205,207 is through adjustment, so the pressure that increases in 207 enough makes liquid discharge by flap valve 140 from artificial ventricle.When piston 204 to 202 whens motion, liquid just leaves 207, is inhaled in 205.The motion of liquid causes 160 internal pressures to reduce accordingly, thereby liquid enters 160.
Other constituent of pump among the embodiment 8 and 9 is shown in Figure 21 A, B, C.Figure 21 A shows is one and links two pumps and inhale independent driving wheels 210 on the zone 211.Pei Zhi pump can compress two artificial ventricle simultaneously in view of the above, and the compression rhythm and pace of moving things is identical.What Figure 21 B showed is an independent live axle 212 of linking two driving wheels 210.What Figure 21 C showed is another kind of arrangement, and two driving wheels 210 adjoin mutually exactly, have live axle 212 separately, and each driving wheel 210 is connected single pump and inhales on the zone 211.By two drive rods are out of phase linked on the driving device with 180 °, just can finish a mutual pump suction activity.
Embodiment 10
Figure 22 has described an inner cardiac devices 220.220 inhale device 221 and connecting device 222 is formed by a pair of artificial ventricle 160, pump, and wherein, pump is inhaled device 221 and is used for making 160 to produce the rhythmicity compression, connecting device 222 160 and patient between set up the liquid connection.
221 can produce compression and decompression by any suitable mode, for example, and according to the mode in embodiment 8 or 9.In the time of 160 compressions, liquid wherein just is forced out 223, enters (not shown) in patient's body by efferent artery 224.Next 221 can make 160 decompressions, pass through 225 from inlet vein 226 imbititions.226 link to each other with patient's vein (not shown).
Motor or other are used for ordering about that pump inhales that the device (comprising any power resources) of device 221 can be positioned in patient's body or external.Can decide only source, size and position location by the people who in those scope of the invention this field comparatively is familiar with.For example, the pump of variable-ratio is inhaled device can provide energy by being positioned the subcutaneous battery of patient.One cover external device (ED) can remain near the position of subcutaneous battery and be its charging.
Embodiment 11
Shown in Figure 23 A, when the part of patient's heart 231 loses function, can use an external heart device 230.230 comprise one to embodiment 7 in the equal opening in two ends of the similar cylindrical cardiac devices 232,232 described.232 can be formed by the support of the lining cell among the embodiment as previously described.Valve 233 no matter be synthetical or donor is transplanted, is positioned at each end of artificial heart device 232.
Artificial heart device 232 is contained in pump and inhales in the district 234, has a pump to inhale device in 234 and can oppress liquid by 232.Figure 23 B has shown a kind of configuring condition of 234, and it has a pair of wheel that rotates along 232 length directions.Figure 23 C has shown the another kind of embodiment of pump suction device, and the one side along 232 can rotate and produce the roller bearing wheel of compression.Pump is inhaled device can comprise a storage pond (not shown), and this storage pond can replenish aseptic liquid, for example blood plasma for the zone between 232 and 234 overcoats.
No matter pump is inhaled the final selection of device, external heart device 230 can be linked on patient's the heart 231 by first connection tube 235 and second connection tube 236.235 first ends are connected in 231 defective zone, for example rights ventricle.235 second ends are connected on 232 the flap valve 233.236 first ends are connected on 232 another flap valves 233, and its second end is connected on patient's tremulous pulse 237, for example aorta.230 can be made of above mentioned material material, or known suitable material in the current field.External heart device 230 can by professional decision be used in patient's body temporarily or as one permanent use basic device.Connection tube 235,236 is made of material impervious to water, and for example apply terylene, polyethylene, the polyurethane of heparin or have the triangle fibre board of heparin, or the stable sealant or the external container of the glucosan of bound drug and flexibility.
Embodiment 12
Porous polymer material is made as support, and smooth muscle cell and endotheliocyte are grown thereon, form one and have durability, elasticity and non-thrombogenic device, and this device is suitable for as the substitute of tremulous pulse or graft.
Prepare microporous flexible pipe.Novel many micropores flexible pipe is by nylon-11 ,-[(CH 2) 10CONH]-(molecular weight about 200,000) make.Porosity is approximately 70%, and it is of a size of 2 microns (being determined by scanning electron microscopy (SEM)), can not expand in water, does not contain additive and plasticizer, has intensity and fastness preferably.The conduit of different-diameter can be realized by the complex of extruding nylon-11 and water-soluble poly oxirane.Poly(ethylene oxide) (PEO) has common structure division-(OCH 2CH 2) n-OH.Following table has provided a concrete mode of the artificial blood vessel of the present invention.
Table 1
Composition Nylon-11, wt% 1 PolyOx 2 CaCO 3 Total
Weight % 0.185 0.457 0.358 1.00
Volume % 0.225 0.57 0.175 1.00
Weight (g) 148 365.6 286.4 800
1Nylon-11 is from Elf Atochem;
2PolyOx is from Union Carbide
After forming conduit, it is immersed in the water.Poly(ethylene oxide) is dissolved in water and is removed from conduit, and they enter in the water by the structural aperture of nylon tube.The porosity of hole size and nylon tube tissue is different and different with extrusion condition and prescription.Can obtain the aperture of about 50-80% under controlled condition preferably, aperture size is controlled at the 0.5-5 micron.
Nylon-11 is a timbering material preferably of making biological artificial tissue, because it is water insoluble, and additive-free or plasticizer, and have good durability.On the contrary, use nylon-6 or nylon-6 widely, 6 can expand in water, and compare with nylon-11, and it sums up hot mechanical elasticity can not make the people satisfied under long term.
Use bioreactor, selectivity plantation smooth muscle cell and endotheliocyte on multiholed catheter, thus making tremulous pulse with function, Figure 24 is gained artificial artery's a simple sketch map.The outside of polymer support wall is covered with the layer of even vascular smooth muscle cell, and inside is covered with the monolayer vascular endothelial cell.What arrow was indicated is that cell culture fluid flows to.The outside of support tube contacts with the culture fluid that contains vascular smooth muscle cell, and inside contacts with the culture fluid that contains vascular endothelial cell.The nature cell of plantation and the polymer pipe gang of highly porous property just can be formed an artificial apparatus, and this device can be used as the organ substitute, as tremulous pulse.
After the multiholed catheter sterilization, place a box, this box is divided into two chambers by the porous polymer pipe holder.The mistress directly contacts with the outer wall of polymerization pipe, and contacts with the culture fluid that contains vascular smooth muscle cell (VSMC ' s).Inner room (in porous support inside) has been full of the culture fluid that contains endotheliocyte.After conduit is hatched fortnight, impose vertically mobile at inner room.After two weeks, conduit shifts out.The outer surface of scaffold tube comprises one deck vascular smooth muscle cell, and inner surface is lined with endotheliocyte.Endotheliocyte will be through suitably collimation adjustment.
The artificial blood vessel who makes can utilize present known technology to transplant, and these technology also can be used for the transplanting of similar device.
Embodiment 13
(as poly(ethylene oxide), POLYOX  water-soluble resin, the water-soluble poly of nonionic (oxirane) polymer, its common structure that has is-(OCH to use water solublity coextrusion thermoplastic 2CH 2) n-OH) and water-insoluble thermoplastic material (as nylon or TPU), can be used for controlling porosity.In addition, after the process of embodiment 12, can replace water to extract poly(ethylene oxide) with ethanol.Change the solvent of extraction,, comprise the change of pH, can make skilled skilled worker control porosity by selecting different dissolubility no matter be single or associating.So fine tuning can make support and composition material thereof have higher form resolution.The solvent that easily is mixed in water comprises anhydrous isopropyl alcohol, 1,2 ethylene glycol, propylene glycol, dehydrated alcohol, glycerol, ethylene glycol, carbitol and/or inorganic salt solution.
The kind that can be used for polymeric material of the present invention has been widened in the use of other types solvent.The Hildebrand solubility parameter is one and optimizes dissolubility standard preferably.Can make final products to the high selectivity of type of solvent is that the porosity of intravascular stent is controlled better.
Add some solubility filler at polymeric blends and also can strengthen control the brace aperture rate.For example, in order to improve intensity and to reduce elasticity, can use the lower inorganic filler of water solublity.Such timbering material can be used for manufacture of intraocular skeleton or cartilage.Can in extrusion step or molding step, add polymeric material to as the water miscible calcium carbonate of part, be dissolved then, to adjust the porosity of support.
Although perhaps nylon-11 is not suitable for all tremulous pulsies (for example nylon-11 perhaps too rigidity), it is very useful as the core support in the manufacture of intraocular liver.For more soft and porous material rubber-like, available heat plastic polyurethane (TPU) substitutes some or all nylon.

Claims (30)

1, a kind of artificial blood vessel bracket, it comprises:
A plurality of frame plates of drawing money on credit, it is arranged in tubular structure with the adjacent neighbour of side; And a plurality of circular fibers;
Wherein, described each frame plate of drawing money on credit includes the first parallel fiber bundle and the second parallel fiber bundle, and it is together fixedly connected by a plurality of connection fibers, and described connection fiber is perpendicular with the described first parallel fiber bundle and the second parallel fiber bundle basically; Described circular fiber centers on and is fixedly connected on described tubular structure; Described tubular structure has defined an internal diameter and an external diameter.
2, artificial blood vessel bracket as claimed in claim 1, it comprises that further one deck is attached to the endotheliocyte on the described artificial blood vessel bracket inner surface.
3, artificial blood vessel bracket as claimed in claim 2, it comprises that further one deck is attached to the smooth muscle cell on the described artificial blood vessel bracket outer surface.
4, artificial blood vessel bracket as claimed in claim 3 is characterized in that, described internal diameter is 0.5-3.0cm.
5, artificial blood vessel bracket as claimed in claim 1, but it comprises that further one deck is inner and be attached to digesting material on this support at described artificial blood vessel bracket.
6, a kind of cell growth chamber, it comprises:
, a blood vessel;
Opening on described blood vessel, this opening allows the insertion of intravascular stent and shifts out, and this opening can be airtight;
A sealable port, this port provide an opening for described blood vessel and allow the turnover of cell culture fluid; And
The environmental control that can monitor described internal blood vessel environmental condition.
7, cell growth chamber as claimed in claim 6 is characterized in that, described sealable port comprises first port that has input pipe and second port that has outlet tube.
8, a kind of artificial organ, it comprises a plurality of artificial blood vessel brackets as claimed in claim 1.
9, artificial organ as claimed in claim 8 is characterized in that, described artificial blood vessel bracket has applied cell in device as claimed in claim 6.
10, artificial liver, it comprises:
A common input area, this input area comprises the cylindrical tube of a hollow, and has first terminal and second end;
At least four input areas independently, its each all have first terminal and second end, wherein, this input area first end is fixedly connected on second end of described common input area;
Article at least four, internal blood vessel, its each bar all have first terminal and second end, and wherein, first end of described internal blood vessel is fixedly connected on second end of described independent input area;
At least four output areas independently, its each all have first terminal and second end, wherein, first end of described independent output area is fixedly connected on second end of described internal blood vessel; And
A common output area, this output area comprises the cylindrical tube of a hollow, and has first terminal and second end, wherein, first end of described common output area is fixedly connected on second end of described independent output area;
Wherein, first of described common input area second end terminal and described common output area is fixedly connected on the patient; Described independent input area, internal blood vessel and independent output area comprise the man-made support with inner surface and outer surface; The inner surface of described man-made support is coated with vascular endothelial cell, and the outer surface of described man-made support is coated with hepatocyte.
11, artificial liver as claimed in claim 10, this artificial liver can be used as outside artificial liver or inner artificial liver, and are arranged in the water-proof container with first end and second end; It is characterized in that this artificial liver also comprises: first pump that is positioned at described container first end; And second pump that is positioned at described container second end;
Wherein, first of the described water-proof container end is connected in the alternative mode of liquid with patient's tremulous pulse; Second end of described water-proof container is connected in the alternative mode of liquid with patient's vein.
12, a kind of artificial pancreas, it comprises:
At least two artificial pancreas units, each unit comprise a cylindrical intravenous injection support and a plurality of side branch, and have first terminal and second end;
First connection tube, first end of this connection tube is fixedlyed connected with first end of described artificial pancreas unit, and second end of this connection tube is fixedlyed connected in the alternative mode of liquid with the patient; And
Second connection tube, first end of this connection tube is fixedlyed connected with second end of described artificial pancreas unit, and second end of this connection tube is fixedlyed connected in the alternative mode of liquid with the patient;
Wherein, described intravenous injection support has first terminal and second end; Described side branch has first terminal and second end; Ramose first end of described side is fixedlyed connected with described intravenous injection support in the alternative mode of liquid, and compares second end of the more close described intravenous injection support in the position of junction point with described intravenous injection support first end; Described intravenous injection support and described side branch are coated with the islet cells of secreting hormone.
13, a kind of Cardiac valve prosthesis, it comprises an annulus and a plurality of lobule, each lobule has two substantially parallel flat surfaces and the edge that centers on this lobule periphery;
Wherein, the first of described leaflet edge is fixed and flexible being connected on the described annulus; Described lobule has so size and shape, makes the second portion relative with the first of described leaflet edge be located substantially on the position of described circle ring center; Described annulus and described lobule comprise support as claimed in claim 1.
14, a kind of artificial ventricle, it comprises:
Basically the columniform central area of a hollow, it has a bottom and a top, and more described top, described bottom is wide; And
A hemispheric basal area, it is fixedly connected on the bottom of described central area;
Wherein, described central area and described basal area comprise support as claimed in claim 1.
15, as the artificial ventricle of claim 14, it further comprises a described artificial ventricle of parcel and is fixedly connected on the vertical shell of described central area.
16, a kind of heart pump, it comprises:
A motor that is connected with pump suction device; And
Basically a columniform compressible heart substitutes unit;
Wherein, described pump is inhaled device and is comprised that at least one can substitute the wheel that unit rolls along described heart, with compression or the alternative unit of the described heart of decompress(ion).
17, a kind of heart pump, it comprises:
A motor that is connected with pump suction device; And
Basically columniform compressible heart substitutes unit, and it is positioned at the inside of a fluid exchange unit, and carries out liquid with at least one conduit that stretches out this fluid exchange unit outside and be connected;
Wherein, described pump is inhaled device and is comprised fluid exchange apparatus, and described fluid exchange apparatus can improve or reduce the fluid pressure in the described liquid container unit; The rising of described fluid pressure or reduction can cause that described heart substitutes the compression or the decompression of unit.
18, a kind of artificial heart device, it comprises:
Two artificial ventricle, each ventricle comprises the columniform basically central area of a hollow, it has a bottom and a top, and more described top, described bottom is wide;
A hemispherical basal area, this basal area is fixedly connected on the bottom of described central area; And
At least one is as the heart pump in claim 19 or 20, and it is used for compressing or described two artificial ventricle of reducing pressure.
19, as the artificial heart device in the claim 18, it further comprises:
A biocompatibility shell, this shell holds the external boundary of described cardiac devices; The wherein said shell that contains cardiac devices is planted in patient's body.
20, a kind of artificial organ support, it comprises:
A kind of porous polymer material, this porous polymer material comprise at least a non-soluble polymer and at least a water-soluble polymer;
Wherein, the porosity of described support is about 50-80%, the about 0.5-5.0 micron in aperture.
21, artificial organ support as claimed in claim 20 is characterized in that, described non-soluble polymer comprises nylon-11.
22, artificial organ support as claimed in claim 20 is characterized in that, described non-soluble polymer comprises nylon-11, and described water-soluble polymer comprises poly(ethylene oxide).
23, artificial organ support as claimed in claim 22, it further comprises calcium carbonate.
24, artificial organ support as claimed in claim 23 is characterized in that, nylon-11 is 0.26 weight %, and poly(ethylene oxide) is 0.57 weight %, and calcium carbonate is 0.18 weight %.
25, a kind of artificial organ, it comprises:
A kind of porous polymer material, this porous polymer material comprise at least a non-soluble polymer and at least a water-soluble polymer, and form a support with catheter shape of an inner surface and an outer surface;
Wherein, the porosity of described support is about 50-80%, the about 0.5-5.0 micron in aperture; Have a kind of cellular layer on the described support at least, described cellular layer is attached on the described support and forms artificial organ.
26, artificial organ as claimed in claim 25 is characterized in that, described at least a cellular layer comprises endotheliocyte.
27, artificial organ as claimed in claim 26 is characterized in that, described at least a cellular layer also comprises smooth muscle cell.
28, artificial organ as claimed in claim 27 is characterized in that, described endotheliocyte is attached to the inner surface of described conduit, and described smooth muscle cell is attached to the outer surface of described conduit.
29, a kind of method for preparing artificial organ, it comprises:
Select a kind of porous polymer material, described porous polymer material comprises at least a non-soluble polymer and at least a water-soluble polymer at first;
Described porous polymer material is formed the support with catheter shape of an inner surface and an outer surface, the porosity of described support is about 50-80%, the about 0.5-5.0 micron in aperture, and the aperture on the described support forms by selective dissolution;
Described is placed in the bioreactor;
At least one deck smooth muscle cell and endotheliocyte add in the described bioreactor; And
Described cell is cultivated in described bioreactor, formed a confluent monolayer cells up to each surface at described support.
30, method as claimed in claim 29 is characterized in that, described artificial organ is a blood vessel.
CNA2005100065172A 2005-01-19 2005-01-19 Artificial blood vessel scaffold and artificial organs Pending CN1806774A (en)

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