CN211512854U

CN211512854U - Bioartificial liver system

Info

Publication number: CN211512854U
Application number: CN201921234052.XU
Authority: CN
Inventors: 钟克波; 薛巍松; 李阳; 彭青; 廖曙光; 高毅
Original assignee: Southern Medical University Zhujiang Hospital
Current assignee: Southern Medical University Zhujiang Hospital
Priority date: 2019-07-31
Filing date: 2019-07-31
Publication date: 2020-09-18
Anticipated expiration: 2029-07-31

Abstract

The application provides a biological artificial liver system, at least includes following branch pipeline that connects gradually: the upstream end is set as the blood input branch pipeline of blood input end, includes the first plasma separator's of at least first branch thick liquid branch pipeline, includes the oxygen supply branch pipeline that the upstream is set as artificial blood access end at least, includes the biological purification branch pipeline of whole liver perfusion subassembly at least, and the downstream end is set as the return thick liquid branch pipeline of blood output end. The bioartificial liver system can fully oxygenate the external liver to exert the effects of decomposition, detoxification, biosynthesis and the like of the external liver, strive for enough time for the liver failure patient and the bridging patient to wait for the liver transplantation process, provide the opportunity of liver self-regeneration for the patient, avoid the immune reaction caused by direct contact of blood and the external liver, and overcome the problem of biocompatibility.

Description

Bioartificial liver system

[ technical field ] A method for producing a semiconductor device

The application relates to the technical field of artificial liver, in particular to a bioartificial liver system.

[ background of the invention ]

The artificial liver support system is a hot spot of current research as a method for 'bridge treatment' during waiting for liver failure for liver source or liver self-regeneration, and the current artificial liver support system mainly comprises a biological artificial liver support system, a non-biological artificial liver support system and a combined biological artificial liver support system, wherein the biological artificial liver is divided into two types, namely a hepatocyte type and a whole liver type according to different reactors.

The traditional bioreactor usually adopts whole blood or red blood cell perfusion oxygen supply and even dissolved oxygen supply, however, for the total liver type artificial liver system, the whole blood or red blood cell perfusion has not only the problem of biocompatibility, but also the dissolved oxygen can cause insufficient oxygen supply. Therefore, there is a need for a total liver type artificial liver system capable of sufficiently supplying oxygen while overcoming biocompatibility.

[ Utility model ] content

The present application aims to provide a bioartificial liver system capable of overcoming biocompatibility and sufficiently supplying oxygen.

In order to achieve the purpose, the technical scheme is as follows:

a bioartificial liver system at least comprises the following branch pipelines which are connected in sequence: the upstream end is set as the blood input branch pipeline of blood input end, includes the first plasma separator's of at least first branch thick liquid branch pipeline, includes the oxygen supply branch pipeline that the upstream is set as artificial blood access end at least, includes the biological purification branch pipeline of whole liver perfusion subassembly at least, and the downstream end is set as the return thick liquid branch pipeline of blood output end.

Preferably, the first slurry dividing line includes: the plasma separator comprises a first plasma separator provided with a blood inlet, a plasma outlet and a blood cell outlet, a plasma pump connected with the plasma outlet through a conduit, and a plasma branch extending from the plasma pump to the downstream.

Preferably, the oxygen supply branch pipeline comprises an artificial blood reservoir, an artificial blood access end and an oxygenator connected with the downstream of the artificial blood access end in sequence.

Preferably, the bioartificial liver system further comprises a second plasma separation line, the second plasma separation line at least comprises a second plasma separator provided with a second plasma inlet, a second plasma outlet and a cell outlet, the second plasma inlet is connected with the total liver perfusion assembly, and the second plasma outlet is connected with the oxygen supply line.

Preferably, the cell outlet is connected before the oxygenator.

Preferably, the biological purification branch pipeline comprises a whole liver, and a whole liver perfusion assembly of a hepatic artery connecting pipe, a portal vein connecting pipe, a inferior vena cava connecting pipe and a common bile duct connecting pipe, wherein one end of the hepatic artery connecting pipe, the portal vein connecting pipe, the inferior vena cava connecting pipe and the common bile duct connecting pipe are connected with the whole liver, the other ends of the hepatic artery connecting pipe and the portal vein connecting pipe are connected with the oxygen supply branch pipeline, and the other end of the inferior vena cava connecting pipe is connected with the second plasma inlet.

Preferably, the whole liver is derived from animal liver.

Preferably, the whole liver perfusion assembly further comprises a perfusion cabin body, a supporting platform for supporting the whole liver, and a cabin cover arranged at the top of the perfusion cabin body.

Preferably, the bioartificial liver system further comprises a bile retrieval device connected to the common bile duct adapter.

Preferably, the slurry return branch pipeline at least comprises: the blood cell mixer is connected with the blood cell outlet and provided with a whole blood outlet, the bubble monitor is connected with the whole blood outlet, the bubble monitor is further connected with the blood output end, and the upstream end of the plasma return branch pipeline is connected with the second plasma outlet.

Compared with the prior art, the method has the following advantages:

1. the bioartificial liver system of this application is through introducing the oxygen suppliment branch pipeline for artificial blood through abundant oxygen suppliment mixes the back with plasma, perfuses external whole liver jointly, gives external liver abundant oxygenation in order to exert the effect such as decomposition, detoxification and biosynthesis of external liver, thereby for liver failure patient and bridging patient wait for the liver transplantation process to strive for sufficient time, provide the liver self-regeneration's opportunity for the patient simultaneously. Meanwhile, artificial blood is adopted to replace the traditional whole blood and red blood cells, so that the immunoreaction caused by direct contact of the blood and the liver in vitro can be avoided, and the problem of biocompatibility is solved.

2. The bioartificial liver system can provide sufficient oxygen for the whole liver by introducing artificial blood as an oxygen supply carrier so as to ensure that the whole liver continuously and stably plays a biological function in vitro.

3. The bioartificial liver system can isolate immune cells and prevent immunity from entering the liver circulation outside a human body through the first plasma separator; through the second plasma separator, the in-vitro liver exfoliated cells and cell fragments can be separated, and the exfoliated cells and the cell fragments are prevented from entering the body of a patient to cause anaphylactic reaction.

[ description of the drawings ]

Fig. 1 is a schematic structural diagram of an exemplary embodiment of a bioartificial liver system of the present application.

[ detailed description ] embodiments

The present application is further described with reference to the following drawings and exemplary embodiments, wherein like reference numerals are used to refer to like elements throughout. In addition, if a detailed description of the known art is not necessary to show the features of the present application, it is omitted.

Referring to fig. 1, the present application provides a bioartificial liver system, which at least comprises the following branch pipelines connected in sequence: a blood input branch line 11 with an upstream end set as a blood input end 111, a first plasma branch line 12 at least comprising a first plasma separator 121, an oxygen supply branch line 13 at least comprising an upstream set as an artificial blood access end 132, a biological purification branch line 14 at least comprising a total liver perfusion module 142, and a plasma return branch line 15 with a downstream end set as a blood output end 151.

In one embodiment of the present application, the bioartificial liver system is a whole liver type artificial liver system.

Specifically, in order to better control the blood input end 111 and the blood output end 151, an input end valve 111-1 for controlling the on-off of the blood input branch pipe 11 is arranged at the downstream of the catheter close to the blood input end 111, and an output end valve 151-1 for controlling the on-off of the plasma return branch pipe 15 is arranged at the downstream of the catheter close to the blood output end 151, so as to realize flow control. The input valve 111-1 and the output valve 151-1 may be pinch valves in this embodiment.

The first slurry distribution pipe 12 includes: a first plasma separator 121 provided with a blood inlet 121-1, a first plasma outlet 121-2, a blood cell outlet 121-3, a plasma pump 122 connected to the first plasma outlet 121-2 by a conduit, and a plasma branch 123 extending downstream from the plasma pump 122. The first plasma separator 121 is used for separating human plasma into the liver outside the human body, and the first plasma separator can also isolate immune cells and prevent the immunity from entering the liver circulation outside the human body.

The oxygen supply branch line 13 sequentially comprises an artificial blood reservoir 131, an artificial blood inlet 132, and an oxygenator 134 connected with the downstream of the artificial blood inlet 132. The artificial blood can replace hemoglobin for conveying oxygen in human blood, the hemoglobin in the artificial blood can play a role in carrying and supplying oxygen, the oxygenator 134 is an oxygen carrier, namely the oxygen supplying component for the artificial blood, and the artificial blood passing through the oxygenator 134 can provide sufficient oxygen for the whole liver 1421 so as to ensure that the whole liver 1421 continuously and stably plays a biological function in vitro. Preferably, the artificial blood is bovine-derived glutaraldehyde-polymerized hemoglobin. The oxygen suppliment branch pipeline 13 of this application is introducing artificial blood and is carrying oxygen, not only can provide sufficient oxygen for external whole liver 1421, adopts artificial blood to replace traditional whole blood, red blood cell moreover, can avoid the immunoreaction that blood and external liver direct contact lead to, can fully ensure patient's safety.

The bioartificial liver system further comprises a second plasma separation line 16, wherein the second plasma separation line 16 at least comprises a second plasma separator 161 provided with a second plasma inlet 161-1, a second plasma outlet 161-2 and a cell outlet 161-3, the second plasma inlet 161-1 is connected with the total liver perfusion assembly 142, and the second plasma outlet 161-2 is connected with the oxygen supply line 13. In the second plasma separator 161, the aperture of the second plasma outlet 161-2 is smaller than that of the human hemoglobin, so that the in-vitro liver exfoliated cells and cell fragments can be blocked, the exfoliated cells and cell fragments are prevented from entering the body of a patient to cause anaphylactic reaction, and the liver exfoliated cells and the human hemoglobin are both kept in the biological purification branch pipeline 14.

The cell outlet 161-3 is connected to the front of the oxygenator 134, so that the exfoliated liver cells and the artificial hemoglobin can be fully oxygenated by the oxygen supply branch line 13 and then re-enter the biological purification branch line 14. Preferably, the cell outlet 161-3 is connected between the artificial blood access 132 and the oxygenator 134, so as to ensure that the cell outlet 161-3 is arranged close to the circulation pump 141 in the biological purification branch 14, thereby realizing timely re-entry of the liver-shed cells and the artificial hemoglobin into the biological purification branch 14.

The biological decontamination branch line 14 includes: a recirculation pump 141 connected to the oxygenator 134 via conduits, a total liver perfusion assembly 142 connected to the recirculation pump 141, and a first slurry return pump 143 connected to the total liver perfusion assembly 142, extend from the first slurry return pump 143 to a downstream slurry return branch 144.

Specifically, the total liver perfusion assembly 142 includes a total liver 1421, a hepatic arterial junction (not shown), a portal venous junction (not shown), an inferior vena cava junction (not shown), and a common bile duct junction (not shown). The whole liver 1421 is derived from animal liver. Preferably, the whole liver 1421 is porcine liver. One end of the hepatic artery connecting tube is connected with a hepatic artery in the whole liver 1421, and the other end of the hepatic artery connecting tube is connected with the oxygen supply branch pipeline 13; one end of the portal vein connecting pipe is connected with a portal vein in the whole liver 1421, and the other end of the portal vein connecting pipe is connected with the oxygen supply branch pipe 13; the inferior vena cava adapter is connected with the inferior vena cava in the whole liver 1421, and the other end is connected with the second plasma inlet 161-1; one end of the common bile duct adapter is connected to the common bile duct in the whole liver 1421. In another embodiment of the present application, the bioartificial liver system further comprises a bile retrieval device (not shown) connected to the common bile duct junction to retrieve bile for parameter index detection. Flow meters and pressure gauges are arranged at the hepatic artery connecting pipe and the portal vein connecting pipe, so that the venous pressure and the arterial pressure can be monitored at any time in the clinical treatment process.

The whole liver perfusion assembly 142 further includes a perfusion chamber 1422, a support platform 1423 for supporting the whole liver 1421, and a cover 1424 disposed on the top of the perfusion chamber 1422. In this embodiment of the present invention, the pouring chamber 1422 and the lid 1424 are made at least partially of transparent materials for easy operation and observation of the pouring. Further, a temperature control device (not shown) is connected to the perfusion chamber 1422 to adjust the temperature inside the perfusion chamber 1422, so as to simulate the human body temperature for performing the experiment. The perfusion chamber 1422 provides a stable external environment for the whole liver 1421.

The slurry return branch pipe 15 at least includes: a blood cell mixer 152 connected with the blood cell outlet 121-3 and provided with a whole blood outlet 152-1, a bubble monitor 153 connected with the whole blood outlet 152-1, wherein the bubble monitor 153 is also connected with the blood output end 151, and the upstream end of the plasma return branch pipeline 15 is connected with the second plasma outlet 161-2.

In this embodiment, the blood input branch line 11 includes, in addition to the blood input end 111, a blood pump 112, a drug input device 113 connected in parallel to the blood input branch line 11, a blood mixer 114 connected in series in the blood input branch line 11, and a check valve 115 for preventing liquid from flowing backwards. In other possible embodiments, the drug injector 113 may select a quantitative or timed device such as a syringe to inject the drug into the blood inlet branch 11. In this embodiment, the drug input from the drug input device 113 may be an anticoagulant drug for preventing blood coagulation. More specifically, heparin is used as the anticoagulant in this embodiment, and in other possible embodiments, heparin, a natural anticoagulant such as hirudin, or at least one of potassium salts such as sodium citrate and potassium fluoride, and calcium ion chelating agents such as EDTA, may be used as the anticoagulant.

In other possible embodiments, the bioartificial liver system is further provided with a temperature regulator. Specifically, in the present embodiment, a first temperature regulator 134 is disposed at an outlet of the oxygenator 134, and a second temperature regulator 154 is disposed upstream of the slurry return branch line 15. The first temperature regulator 134 and the second temperature regulator 154 not only have a heating function, but also have a cooling function, and are mainly responsible for adjusting the fluid in the conduit to a proper reaction, a proper temperature range of a human body, or keeping the fluid in a stable and flowing state, and avoiding the change of the physical properties and chemical properties of the fluid caused by the change of temperature or extreme temperature. The temperature regulator can realize the refinement and regionalization temperature regulation of all or part of the area of the bioartificial liver system through the distribution quantity and the position change. In addition, under the condition of permission, the temperature can be adjusted by means of an auxiliary insulation box, a water bath constant temperature and the like. In the plasma return branch pipe 15, a plasma homogenizer is further provided between the second temperature regulator 154 and the cell mixer, physical properties and chemical properties of the plasma such as stratification, turbidity and precipitation are easy to change after the temperature of the plasma is regulated by the second temperature regulator 154, and the plasma homogenizer can be added to homogenize the plasma in advance before the whole blood is mixed, so that the quality of the whole blood mixture is improved.

Furthermore, in the bioartificial liver system, a blood flow detection device and a blood flow pressure detection device are introduced into each branch pipeline to monitor the state of the bioartificial liver system in real time and monitor the condition of a patient in real time.

The bioartificial liver system of the application oxygenates the artificial hemoglobin through the oxygenator 134 after the artificial blood is mixed with the plasma, perfuses the external liver together, and the oxygenated artificial blood fully oxygenate the external liver to play the roles of decomposition, detoxification, biosynthesis and the like of the external liver, can strive for enough time for liver failure patients and bridging patients to wait for the liver transplantation process, and provides the patients with the opportunity of liver self-regeneration. Meanwhile, artificial blood is adopted to replace the traditional whole blood and red blood cells, so that the immunoreaction caused by direct contact of the blood and the liver in vitro can be avoided, and the problem of biocompatibility is solved.

The operation of the bioartificial liver system is described in detail below:

under the power provided by the plasma separating pump 122, the blood passes through the first plasma separator 121, toxic plasma components and blood cells in the blood of the patient are separated respectively by the first plasma separator 121 in a mode plasma separation method, wherein the separated plasma flows out from the first plasma outlet 121-2 and enters the oxygen supply branch pipeline 13, and the blood cells enter the blood cell mixer 152 through the blood cell outlet 121-3; the separated plasma is mixed with the artificial blood in the oxygen supply branch line 13, and then hemoglobin in the artificial blood is oxygenated by the oxygenator 134; the oxygenated plasma is mixed with artificial blood and then enters the biological purification branch pipeline 14, and the plasma enters the whole liver perfusion component 142 under the power provided by the circulating pump 141.

In the whole liver perfusion module 142, the whole liver 1421 performs functions of detoxification, transformation, synthesis, etc. on the toxic plasma, and the detoxified plasma flows out through the second plasma separator 161 and flows to the plasma return line 15 through the second plasma outlet 161-2.

After entering the plasma return branch line 15, the plasma after biological purification is mixed with blood cells from the blood cell outlet 121-3 in the blood cell mixer 152 to form whole blood, which is detected by the bubble detector 153 and then returned to the outside through the blood output port 151. The blood is subjected to the above process to complete the biological purification process.

In the biological purification process, the oxygenated human hemoglobin can provide full oxygenation to the in vitro whole liver 1421 to ensure that the in vitro whole liver 1421 fully exerts the decomposition, detoxification, biosynthesis and other effects, thereby effectively eliminating various metabolic toxins and pathogenic factors in the body of a patient and achieving the purpose of treatment.

Although a few exemplary embodiments of the present application have been shown and described, it would be appreciated by those skilled in the art that changes may be made in these exemplary embodiments without departing from the principles and spirit of the application, the scope of which is defined in the claims and their equivalents.

Claims

1. A bioartificial liver system is characterized by at least comprising the following branch pipelines which are connected in sequence: the upstream end is set as the blood input branch pipeline of blood input end, includes the first plasma separator's of at least first branch thick liquid branch pipeline, includes the oxygen supply branch pipeline that the upstream is set as artificial blood access end at least, includes the biological purification branch pipeline of whole liver perfusion subassembly at least, and the downstream end is set as the return thick liquid branch pipeline of blood output end.

2. The bioartificial liver system of claim 1, wherein the first slurry distribution manifold comprises: the plasma separator comprises a first plasma separator provided with a blood inlet, a plasma outlet and a blood cell outlet, a plasma pump connected with the plasma outlet through a conduit, and a plasma branch extending from the plasma pump to the downstream.

3. The bioartificial liver system of claim 2, wherein: the oxygen supply branch pipeline sequentially comprises an artificial blood storage, an artificial blood access end and an oxygenator connected with the downstream of the artificial blood access end.

4. The bioartificial liver system of claim 3, wherein: the bioartificial liver system further comprises a second plasma separation pipeline, the second plasma separation pipeline at least comprises a second plasma separator provided with a second plasma inlet, a second plasma outlet and a cell outlet, the second plasma inlet is connected with the whole liver perfusion assembly, and the second plasma outlet is connected with the oxygen supply separation pipeline.

5. The bioartificial liver system of claim 4, wherein: the cell outlet is connected before the oxygenator.

6. The bioartificial liver system of claim 5, wherein: biological purification divides the pipeline including being equipped with the whole liver to and wherein one end with the liver artery that the whole liver is connected is taken over, the portal vein is taken over, the inferior vena cava is taken over and the whole liver that the common bile duct was taken over fills the subassembly, the liver artery take over with the other end that the portal vein was taken over with the branch pipeline of oxygen suppliment is connected, the other end that the inferior vena cava was taken over with second plasma entry linkage.

7. The bioartificial liver system of claim 6, wherein: the whole liver is derived from animal liver.

8. The bioartificial liver system of claim 6, wherein: the whole liver perfusion assembly further comprises a perfusion cabin body, a bearing platform for bearing the whole liver and a cabin cover arranged at the top of the perfusion cabin body.

9. The bioartificial liver system of claim 6, wherein: the bioartificial liver system also comprises a bile recovery device connected with the common bile duct connecting pipe.

10. The bioartificial liver system of claim 9, wherein: the slurry return branch pipeline at least comprises: the blood cell mixer is connected with the blood cell outlet and provided with a whole blood outlet, the bubble monitor is connected with the whole blood outlet, the bubble monitor is further connected with the blood output end, and the upstream end of the plasma return branch pipeline is connected with the second plasma outlet.