CN117899260A - Implantable device for compensating parenchymal tissue function - Google Patents
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Abstract
The present invention relates to an implantable device useful for the compensation of parenchymal tissue function, comprising: functionally compensating tissue for at least partially replacing an organ or tissue function of an animal; a housing for enclosing the functionally compensating tissue; an extension tube for passing through the functionally compensating tissue and the blood vessel in the animal body; the packaging material is used for integrating the functional compensation tissue, the shell and the external connection tube into a whole; the packaging material is responsive polydimethylsiloxane, and is prepared by reacting alkoxysilane with alkoxysilane containing a responsive group under an acidic condition. The implantable device of the present invention may be implanted in the body of a mouse or other mammal by direct vascular anastomosis.
Description
Technical Field
The invention relates to the technical field of biological materials and bionics, in particular to an implantable device for compensating the functions of parenchymal tissues, a preparation method and application thereof.
Background
The most widely accepted therapy at present for liver injury caused by acute or chronic liver disease or acute irritation is hepatectomy. Nevertheless, there are varying degrees of mortality following treatment by hepatectomy. In addition, the incidence of various complications such as infection, sepsis, hemorrhage, leakage or cardiopulmonary disease resulting from hepatectomy treatment is up to 45%. Among these, liver failure resulting from hepatectomy (post-hepatectomy liver failure, PHLF, refers to liver insufficiency occurring after partial hepatectomy, including worsening of the availability of one or more of synthesis, excretion or detoxification functions of the liver, involving hyperbilirubinemia, hypoalbuminemia, prolongation of prothrombin action time or international standardization rate, elevation of serum lactic acid and hepatic brain) is one of the serious complications.
Although many strategies have been employed to rescue PHLF patients, therapeutic success is still limited. Current therapeutic strategies can be largely divided into three categories: drug therapy, artificial liver support device therapy, and liver transplantation therapy. However, the above treatment methods have the disadvantages of different degrees, and the implantable liver tissue is manufactured by using new means to replace the resected part of the liver to perform functions.
Liver tissue engineering is to construct 3D liver tissue in vitro. The study of in vitro construction of 3D organ buds followed the general procedures of differentiation, assembly, in vivo transplantation. Studies have demonstrated that stem cells, hepatocytes, endothelial cells can be co-cultured to assemble into vascularized functional 3D liver buds, and studies have also been conducted to induce pluripotent stem cells to differentiate directionally into hepatocytes and endothelial cells, and then to assemble 3D liver buds on matrigel, which also suggests that mixed culture of various related cells is more favorable for formation of 3D organ buds. Compared with 2D culture, 3D culture is more favorable for maintaining the cell function and activity state, and even has more advantages in the in-vivo function exertion.
In recent years only a limited number of phenotypic and functional assays of the obtained organoids have been reported with regard to the in vitro reconstitution of liver organoids. Furthermore, the tissue engineered liver reconstructed in vitro is not related to a large scale, which may be one of the reasons why it is not possible to achieve a complete liver function afterwards.
Specifically, since the tissue engineering liver needs to have functions of secretion, metabolism, detoxification, synthesis and the like similar to those of the liver in vivo, the tissue engineering liver is required to be anastomosed with blood vessels of the liver in vivo, so that the tissue engineering liver is directly connected with metabolites in vivo. However, the current research has not yet reconstructed a liver integrating an ordered vascular circulatory structure, and has not achieved in situ/ex situ substitution of tissue engineered liver and in vivo liver circulatory system.
In general, although liver tissue engineering has been well developed at present, there are still many problems to be solved, which are mainly reflected in that the in vitro reconstruction of liver tissue has a pipeline structure which is not fine enough and cannot be well matched with the in vivo pipeline structure; the reconstructed liver tissue only completes tissue structure simulation but does not have complex physiological and biochemical functions and the like, so that the in vitro construction of the liver tissue has a long distance for clinical treatment.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides an implantable device for compensating a function of a parenchymal tissue, which can be used for in vivo transplantation of a mammal by direct vascular anastomosis. The implantable device comprises: functionally compensating tissue for at least partially replacing an organ or tissue function of an animal; a housing for enclosing the functionally compensating tissue; an extension tube for passing through the functionally compensating tissue and the blood vessel in the animal body; the packaging material is used for integrating the functional compensation tissue, the shell and the external connection tube into a whole;
The packaging material is responsive polydimethylsiloxane, and is prepared by reacting alkoxysilane with alkoxysilane containing a responsive group under an acidic condition.
In some embodiments, the method of making the encapsulation material is characterized by one or more of the following:
1) The alkoxysilane is selected from dimethylsiloxane or diethylsiloxane, such as dimethyldiethoxysilane;
2) The responsive group-containing siloxane changes from a liquid state to a solid state in response to a particular form of stimulus, for example, the responsive group-containing siloxane is a photosensitive siloxane, the responsive group of which is preferably a mercapto group, such as mercaptopropyl methyl dimethoxy silane in particular;
3) The molar ratio of the alkoxysilane to the siloxane containing a responsive group is (5-20): 1, for example (10-20): 1, a step of;
4) The reaction temperature is 50-80 ℃, for example 60-70 ℃;
5) The reaction time is 1 hour to 24 hours, for example 2 hours to 10 hours, further for example 5 hours to 10 hours;
6) Adding water or buffer (such as phosphate buffer or HEPES buffer) with the molar quantity of 10-50 times of that of the alkoxy silane into the reaction system, for example 10-20 times;
7) Adding 0.1wt% to 5.0wt% HCl to provide the acidic condition, e.g., 1.0wt% to 2.0wt%;
8) After the reaction is completed, the method further comprises the steps of washing with an ethanol solution (such as 70-95% ethanol) and drying;
9) The thiol group-containing content is 0.05 to 0.5mol, for example 0.05 to 0.25mol, and further for example 0.05 to 0.125mol, per 100g of the encapsulating material.
In some embodiments, the organ is selected from the group consisting of liver, pancreas, brain, intestine, stomach, spinal cord, heart, lung, and kidney, preferably liver and pancreas.
In some embodiments, the animal is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, lagomorph, rodent (e.g., mouse or rat), non-human primate (e.g., cynomolgus monkey or cynomolgus monkey), and human; preferably a human.
In some embodiments, the functionally compensating tissue is a 3D printed hydrogel block containing the pourable tubing. The hydrogel is wrapped with human or animal liver cells, and is used for partially replacing liver function. After implantation, the hydrogel can withstand the pressure of the blood flow in the body and the tubing does not coagulate for a short period of time.
In some embodiments, the functionally compensating tissue comprises a matrix and one or more channels distributed inside the matrix, and two ports of at least one of the channels are respectively connected with the external connection tube.
In some embodiments, the channel format in the functionally compensating organization includes, but does not include, single channel, multi-branch channel, multi-layer channel, single-in single-out channel, multi-in multi-out channel, and any combination thereof.
The hydrogel external perfusion cavity can be used for packaging functional compensation tissues for subsequent external culture, and the preparation materials of the hydrogel external perfusion cavity comprise, but are not limited to, latex, butyronitrile, nylon, polyurethane, polymethoxy siloxane (PDMS), polyolefin, composite high polymer materials and the like. The hydrogel is wrapped with human or animal liver cells, and is used for partially replacing liver function cells. Cell printing forms include, but do not include, single cells, cell aggregates, and combinations of the two.
In some embodiments, the matrix is a hydrogel (e.g., a composite hydrogel (such as polyvinyl alcohol, polyacrylic acid, or polymethacrylic acid), a natural hydrogel, and derivatives thereof (such as methacrylated gelatin (GelMA), collagen, silk fibroin, fibronectin, gelatin, hyaluronic acid, chitosan, or sodium alginate), or a mixture of a composite hydrogel and a natural hydrogel and derivatives thereof); preferably, the matrix is a cross-linked methacrylated gelatin-fibrin matrix; preferably, the mass ratio of the methacrylic acid gelatin to the fibrin is (15-20): 1.
In some embodiments, the matrix further comprises hepatocytes and/or aggregates of hepatocytes of human or animal origin. In some embodiments, the hepatocyte aggregates are HepG2 aggregates. In some embodiments, the aggregate of liver cells comprises liver cells and one or more of endothelial cells, pericytes, wherein the liver cells comprise one or more of liver cancer cells hepG2, hepRG, porcine primary liver cells, human primary liver cells, the endothelial cells comprise one or more of Human Umbilical Vein Endothelial Cells (HUVEC), porcine primary liver cells, and the pericytes comprise Mesenchymal Stem Cells (MSC), human Foreskin Fibroblasts (HFF), human lung fibroblasts (HNFL). In some embodiments, the HepG2 aggregates comprise 6x 10 5 per mL HepG2, 3x 10 5 per mL HUVEC, and 1x 10 5 per mL HFF.
In some embodiments, the outer tube is a two-piece flexible tube for connecting the functionally compensating tissue to the blood vessel in the body, thereby anastomosis with the blood vessel. The external tube outer diameter is matched with the function compensation tissue. After implantation, clotting does not occur in the short term in the extension tube.
In some embodiments, the material from which the extension tube is made is selected from the group consisting of latex, nitrile, nylon, polyurethane, polydimethylsiloxane (PDMS), polyolefin, and PLCL; preferably polyurethane.
In some embodiments, the housing is a resilient transparent (or translucent) housing that is not capped thereon for encasing the functionally compensating tissue and protecting the functionally compensating tissue in vivo. After implantation, the shell does not react or adhere to mucous membranes or the like in the body.
In some embodiments, the encapsulation material is a responsive transparent (or translucent) polymeric material that changes from a liquid state to a solid state in response to a particular form of stimulus and effectively bonds the outer hose, polymeric housing and hydrogel function compensating tissue together as a unit. Stimuli to which the material may respond include, but are not limited to, temperature, light, chemical and biochemical reactions, and the like.
In some embodiments, the material from which the shell is made is selected from the group consisting of latex, butyronitrile, nylon, polyurethane, polydimethylsiloxane (PDMS), polyolefin, and poly-L-lactide-caprolactone (PLCL); PDMS is preferred.
In some embodiments, the functionally compensating tissue, housing, and/or extension tube are obtained via a method of 3D bioprinting (e.g., extrusion bioprinting EBB).
In another aspect, the present invention provides a method of making the implantable device comprising the steps of:
3D bioprinting the functionally compensating tissue: printing and forming the matrix material, the inner bearing material and the core material by an extrusion type biological printer, overlapping the matrix material, performing responsive cross-linking curing, and finally removing the core material to form the channel;
Preparing the shell: casting a mould or preparing a material of the shell in a 3D printing mode, performing responsive crosslinking and curing, and punching to enable the external connection tube to penetrate through the shell and be connected with the function compensation tissue and the blood vessel in the animal body, so as to prepare the shell;
preparing the packaging material according to the method for preparing the packaging material;
and (3) assembling: placing the functional compensation tissue into the shell, inserting the external hose into a channel of the functional compensation tissue through a hole of the shell, pouring the packaging material into the shell, so that the packaging material is enabled to permeate through the functional compensation tissue and fill the interior of the shell, and curing in a responsive cross-linking manner;
Perfusion culture: the implantable device is obtained by connecting the outer tube to a perfusion device (e.g., an incubator containing peristaltic pump) for perfusion culture, wherein the culture medium comprises one or more of rat anticoagulated blood, endothelial cell culture medium (e.g., EGM 2), primary hepatocyte culture medium (e.g., HM) or basal serum culture medium (e.g., 10% fbs+90% dmem).
In some embodiments, the method is characterized by one or more of the following:
(1) The matrix material comprises 3% -5% of methacrylic gelatin, 0.25% -1% of fibrin and HepG2 aggregate; preferably, the HepG2 aggregates comprise 6X 10 5 pieces/mL HepG2, 3X 10 5 pieces/mL HUVEC and 1X 10 5 pieces/mL HFF;
(2) The inner bearing material is selected from 5% -10% of methacrylic acid gelatin;
(3) The core dissolving material is selected from 5% -10% gelatin.
In some embodiments, the method comprises the steps of:
(1) Manufacturing the shell: casting by 3D printing or other modes, pouring high polymer materials, curing to obtain the shell, and punching two ends of the shell; taking a 3D printing casting mould as an example, the mould can be printed by polylactic acid and other materials;
(2) Biological 3D printing the functionally compensating tissue: the functional compensation tissue is obtained through multi-material biological 3D printing, the materials are divided into matrix materials, inner bearing materials and core dissolving materials, the materials are sequentially printed and molded through an extrusion type biological printer and are overlapped layer by layer, crosslinking and curing are carried out according to the type of hydrogel, and finally the core dissolving materials are removed to form a pipeline; the matrix material consists of hydrogel and wrapped cells; the inner bearing material is formed by directly printing high-strength hydrogel or other methods for strengthening the surface of the pipe wall; the core-dissolving material is a responsive hydrogel material, and is printed at a preset pipeline position, and the material can be converted from solid state to liquid state under the conditions of temperature, illumination and the like and dissolved in aqueous solution.
(3) Functional compensation organization assembly: placing the function compensation tissue into the shell, respectively inserting the external connection tube into holes at two ends of the shell, and keeping the external connection tube in the hydrogel function compensation tissue pipeline; pouring the packaging material, so that the packaging material is not filled with the functional compensation tissue and is filled in the shell, and according to different packaging materials, using different modes to stimulate the packaging material to be solidified and molded;
(4) After assembly: after the packaging is completed, the external tube is connected with a perfusion device such as a peristaltic pump for perfusion culture, the device is free from leakage, and the internal hydrogel is free from damage.
In some embodiments, the invention provides the use of an implantable device as described above in organ or tissue transplantation thereof or in the preparation of a device (e.g., artificial liver) for repairing liver injury.
In some embodiments, the organ is selected from the group consisting of liver, pancreas, brain, intestine, stomach, spinal cord, heart, lung, and kidney, preferably liver and pancreas.
Advantageous effects of the invention
The present invention provides an implantable device useful for the functional compensation of parenchymal tissue, which for the first time enables direct vascular anastomosis for implantation in the body of a rat or other mammal. For SD rats losing 85% of liver tissue, the lifetime after hepatectomy was prolonged from 2 hours to more than 12 hours. In addition, the materials of each part of the portable device can be replaced according to the requirements, so that the portable device has higher flexibility and can be suitable for various application scenes. The implantable device of the present invention may also be used as an in vitro drug screening model, or to study the behavior of various cells within vascularized tissue.
Drawings
The accompanying drawings are included to provide a further understanding of the application, and are incorporated into and constitute a part of this specification, and are not to be construed as unduly limiting the application. In the drawings:
fig. 1 is a physical view of the housing of the implantable device of the present invention.
Fig. 2 is a schematic diagram of the encapsulating material of the implantable device of the present invention.
FIG. 3 is a physical view of the implantable device of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1: preparation of implantable device housing
Step 1: PDMS is mixed, placed on a mixing and defoaming stirrer, subjected to mixing and defoaming treatment for 30s at a speed of 2,000g, and repeated for 3 times;
Step 2: placing in a refrigerator at-20deg.C, and storing for 24 hr;
step 3: drawing and generating a model in an STL format by using Solidworks, and introducing Ultimaker S a printing die to manufacture a reverse die of the shell;
Step 4: sticking the printed counter mould at the center of a 10cm glass dish, pouring PDMS prepared in advance, and measuring the PDMS to be 1.2mm higher than the top end of the mould by using a graduated scale;
step 5: vacuum-pumping in a vacuum drying oven for 30min to remove bubbles;
Step 6: placing the mixture in a baking oven at 50 ℃ for curing for 12 hours;
Step 7: taking down the solidified PDMS by using blunt forceps, and cutting the PDMS to a proper size according to a preset edge line;
Step 8: punching at the preset hole line with a 2mm puncher to obtain the implantable device casing (shown in figure 1), cleaning, oven drying, and sterilizing.
Example 2: preparation of implantable device function compensating tissue
Step 1: adding 10-200mg GelMA into 1mL PBS containing 0.001-0.5% of photoinitiator LAP (phenyl (2, 4, 6-trimethyl benzoyl) lithium phosphate), dissolving at 10-80deg.C to obtain 1-20% GelMA, adding into a bio-printer charging barrel, and storing at 1-4deg.C for use.
Step 2: adding 10-200mg gelatin into 1mL PBS, dissolving completely at 10-80deg.C to obtain 1% -20% gelatin, adding into a bio-printer charging barrel 3, and preserving at 4deg.C for use.
Step 3: the hepatocyte lines were cultured and expanded to 1X 10 5/ml to 1X 10 7/ml.
Step 4: and designing a 3D model by using CAD software to obtain the stl file. Slicing is carried out by using slicing software, and the G-code file is obtained.
Step 5: heating 1% -20% GelMA to 10-80deg.C for dissolving, mixing hepatocyte suspension with GelMA solution at a ratio of 1:1, adding into barrel 2 of biological printer, and standing at 4deg.C for use.
Step 6: loading the G-code obtained in the step4 into a biological printer, and loading the cartridges 1,2 and 3 transferred in the steps 1,2 and 5 into an extrusion biological printer.
Step 7: printing the loaded G-code file to obtain a hydrogel block.
Step 8: and (3) after printing, placing the obtained hydrogel block under an ultraviolet light source, and adjusting the illumination intensity to 1-100mW/cm 2 for 1-20 minutes.
Step 9: placing the hydrogel block obtained in the step 8 into PBS at 37 ℃, and incubating for 10-90 minutes to obtain the hydrogel function compensating tissue containing the pipeline.
Example 3: preparation of implantable device packaging materials
Step 1: DMDESi (80.55 g,0.67 mol) and MPDMSi (12.08 g,0.067 mol) were mixed with H 2 O (26.53 g,1.47 mol) and 1.0wt% HCl in a round bottom flask and placed on a heatable magnetic stirrer.
Step 2: after the step 1 mixture was kept at 70℃for 5 hours, PDMS-SH was isolated and washed with 75wt% ethanol.
Step 3: PDMS-SH was dried in vacuo at 130℃to give a clear viscous liquid, as shown in FIG. 2. The thiol group content was determined to be 0.125mol/100g PDMS-SH using dioxane as an internal standard.
Example 4: preparation of implantable devices
Step 1: the hydrogel function compensation tissue is placed in a high polymer elastic shell, and an external hose is inserted from the pipeline at two ends.
Step 2: pouring packaging materials into the high polymer elastic shell, performing photocrosslinking by using a surface light source ultraviolet lamp, setting the wavelength to 365nm and the power to 10mW/cm 2, placing the assembled tissue at the center of the ultraviolet lamp, and irradiating for 2min for photocrosslinking;
Step 3: the external hose is connected with an external perfusion device, and the culture solution is introduced for perfusion culture for 2-48 hours.
Step 4: resuspension HUVECs at a cell density of 5X 10 6/mL, and gently blow mixing;
Step 5: pouring the cell suspension into a printing forming pipeline of vascularized liver tissue, culturing for 1-90 minutes at 37 ℃, and turning over to enable the cells to be uniformly attached to the inner wall of a circular pipeline; further incubation is carried out for 1-90 minutes. After the non-adhered cells are discharged out of the pipeline through perfusion, the device is connected with a perfusion device for continuous culture for 1-7 days. A liver tissue device is obtained which can be used for surgical vascular anastomosis or suturing, as shown in fig. 3.
Example 5: treatment of acute liver injury rats using implantable devices
Step 1: transplanting when the liver transplanting device cultures to the 7 th day;
step 2: taking 250-300 g SD male rats, weighing, injecting pentobarbital into the abdominal cavity of the rats according to the dosage of 1mL/100g, and starting the following steps after anesthesia;
step 3: skin preparation treatment is carried out on the abdomen and the neck of the rat by using an epilator, and an operation area is wiped by using iodophor to be disinfected;
step 4: separating the epidermis layer and fascia layer with blunt forceps at the opening of the abdomen epidermis layer with scissors for 3cm, and then opening the abdomen fascia layer with scissors for 3cm;
Step 5: modeling of liver injury for 85% acute hepatectomy: finding left lobe (including left outer lobe and left inner lobe) of liver in abdominal cavity, separating fascia with blunt forceps to separate liver lobes, clamping liver lobes with hemostatic forceps, and ligating root of liver lobe with 5-0 suture;
Step 6: cutting off the corresponding liver lobe at the ligature part, and observing whether blood seeps or not;
step 7: sequentially sewing the fascia layer and the epidermis layer by 3-0 with needle suture;
Step 8: injecting 125U/mL heparin sodium solution into a liver transplantation device pipeline;
step 9: the opening of the neck epidermis is 1cm by scissors, blunt separation is carried out by blunt forceps, and the common carotid artery and the jugular vein are found;
Step 10: clamping artery with artery clamp, ligating distal end with 3-0 suture thread, separating nerve, opening near distal end, inserting artificial blood vessel connected to tissue, lightly binding two knots with 3-0 suture thread, and fixing with 3M glue again;
Step 11: clamping vein with artery clamp, ligating distal end with 3-0 suture thread, separating nerve, opening near distal end, inserting the other end of artificial blood vessel connected to tissue, lightly binding two knots with 3-0 suture thread, and fixing with 3M glue again;
Step 12: loosening the arterial clamp, and observing the flow of blood in tissues, whether leakage exists or not and the like;
step 13: suturing the neck epidermis layer with 3-0 needled suture;
step 14: the rats were observed for survival by feeding with 10% dextrose in normal saline.
The results showed that for SD rats losing 85% of liver tissue, the lifetime after hepatectomy was prolonged from 2 hours to more than 12 hours.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. An implantable device, comprising: functionally compensating tissue for at least partially replacing an organ or tissue function of an animal; a housing for enclosing the functionally compensating tissue; an extension tube for passing through the functionally compensating tissue and the blood vessel in the animal body; the packaging material is used for integrating the functional compensation tissue, the shell and the external connection tube into a whole;
The packaging material is responsive polydimethylsiloxane, and is prepared by reacting alkoxysilane with alkoxysilane containing a responsive group under an acidic condition.
2. The implantable device of claim 1, wherein the method of preparing the encapsulation material is characterized by one or more of the following:
1) The alkoxysilane is selected from dimethylsiloxane or diethylsiloxane, such as dimethyldiethoxysilane;
2) The responsive group-containing siloxane changes from a liquid state to a solid state in response to a particular form of stimulus, for example, the responsive group-containing siloxane is a photosensitive siloxane, the responsive group of which is preferably a mercapto group, such as mercaptopropyl methyl dimethoxy silane in particular;
3) The molar ratio of the alkoxysilane to the siloxane containing a responsive group is (5-20): 1, for example (10-20): 1, a step of;
4) The reaction temperature is 50-80 ℃, for example 60-70 ℃;
5) The reaction time is 1 hour to 24 hours, for example 2 hours to 10 hours, further for example 5 hours to 10 hours;
6) Adding water or buffer (such as phosphate buffer or HEPES buffer) with the molar quantity of 10-50 times of that of the alkoxy silane into the reaction system, for example 10-20 times;
7) Adding 0.1wt% to 5.0wt% HCl to provide the acidic condition, e.g., 1.0wt% to 2.0wt%;
8) After the reaction is completed, the method further comprises the steps of washing with an ethanol solution (such as 70-95% ethanol) and drying;
9) The thiol group-containing content is 0.05 to 0.5mol, for example 0.05 to 0.25mol, and further for example 0.05 to 0.125mol, per 100g of the encapsulating material.
3. The implantable device of claim 1 or 2, wherein the organ is selected from the group consisting of liver, pancreas, brain, intestine, stomach, spinal cord, heart, lung and kidney, preferably liver and pancreas;
preferably, the animal is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, lagomorph, rodent (e.g., mouse or rat), non-human primate (e.g., cynomolgus monkey or cynomolgus monkey), and a human; preferably a human.
4. The implantable device of any one of claims 1-3, wherein the functionally compensating tissue comprises a matrix and one or more channels distributed inside the matrix, and two ports of at least one of the channels are respectively connected with the external tube;
Preferably, the matrix is a hydrogel (e.g., a composite hydrogel (such as polyvinyl alcohol, polyacrylic acid, or polymethacrylic acid), a natural hydrogel, and derivatives thereof (such as methacrylated gelatin (GelMA), collagen, silk fibroin, fibronectin, gelatin, hyaluronic acid, chitosan, or sodium alginate), or a mixture of a composite hydrogel and a natural hydrogel and derivatives thereof); preferably, the matrix is a cross-linked methacrylated gelatin-fibrin matrix; preferably, the mass ratio of the methacrylic acid gelatin to the fibrin is (15-20): 1, a step of;
Preferably, the matrix also contains liver cells and/or liver cell aggregates of human or animal origin; preferably, the hepatocyte aggregates are HepG2 aggregates; preferably, the liver cell aggregate contains one or more of liver cells and endothelial cells and pericytes, wherein the liver cells comprise one or more of liver cancer cells hepG2, hepRG, porcine primary liver cells and human primary liver cells, the endothelial cells comprise one or more of Human Umbilical Vein Endothelial Cells (HUVEC), porcine primary liver cells and pericytes comprise Mesenchymal Stem Cells (MSC), human Foreskin Fibroblasts (HFF) and human lung fibroblasts (HNFL); preferably, the HepG2 aggregates comprise 6X 10 5 pieces/mL HepG2, 3X 10 5 pieces/mL HUVEC and 1X 10 5 pieces/mL HFF;
Preferably, the channels are selected from the group consisting of single channel, multiple branch channels, multiple layer channels, single in single out channels, multiple in multiple out channels, and any combination thereof.
5. The implantable device of any one of claims 1-4, wherein the material from which the housing is made is selected from the group consisting of latex, nitrile, nylon, polyurethane, polydimethylsiloxane (PDMS), polyolefin, and poly-L-lactide-caprolactone (PLCL); PDMS is preferred.
6. The implantable device of any one of claims 1-5, wherein the material from which the extension tube is made is selected from the group consisting of latex, nitrile, nylon, polyurethane, polydimethylsiloxane (PDMS), polyolefin, and PLCL; preferably polyurethane.
7. The implantable device of any one of claims 1-6, wherein the functionally compensating tissue, housing, and/or extension tube is obtained via a 3D bioprinting (e.g., extrusion bioprinting EBB) process.
8. A method of making the implantable device of any one of claims 1-7, comprising the steps of:
3D bioprinting the functionally compensating tissue: printing and forming the matrix material, the inner bearing material and the core material by an extrusion type biological printer, overlapping the matrix material, performing responsive cross-linking curing, and finally removing the core material to form the channel;
Preparing the shell: casting a mould or preparing a material of the shell in a 3D printing mode, performing responsive crosslinking and curing, and punching to enable the external connection tube to penetrate through the shell and be connected with the function compensation tissue and the blood vessel in the animal body, so as to prepare the shell;
Preparing the encapsulation material according to the method for preparing the encapsulation material according to claim 1 or 2;
and (3) assembling: placing the functional compensation tissue into the shell, inserting the external hose into a channel of the functional compensation tissue through a hole of the shell, pouring the packaging material into the shell, so that the packaging material is enabled to permeate through the functional compensation tissue and fill the interior of the shell, and curing in a responsive cross-linking manner;
Perfusion culture: the implantable device is obtained by connecting the outer tube to a perfusion device (e.g., an incubator containing peristaltic pump) for perfusion culture, wherein the culture medium comprises one or more of rat anticoagulated blood, endothelial cell culture medium (e.g., EGM 2), primary hepatocyte culture medium (e.g., HM) or basal serum culture medium (e.g., 10% fbs+90% dmem).
9. The method of claim 8, wherein one or more of the following:
(1) The matrix material comprises 3% -5% of methacrylic gelatin, 0.25% -1% of fibrin and HepG2 aggregate; preferably, the HepG2 aggregates comprise 6X 10 5 pieces/mL HepG2, 3X 10 5 pieces/mL HUVEC and 1X 10 5 pieces/mL HFF;
(2) The inner bearing material is selected from 5% -10% of methacrylic acid gelatin;
(3) The core dissolving material is selected from 5% -10% gelatin.
10. Use of the implantable device of any one of claims 1-7 in organ or tissue transplantation or preparation of a device (e.g. artificial liver) for repairing liver injury;
Preferably, the organ is selected from the group consisting of liver, pancreas, brain, intestine, stomach, spinal cord, heart, lung and kidney, preferably liver and pancreas.
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