Multi-mode combined bioartificial liver system and control method

Abstract

The invention provides a multi-mode combined bioartificial liver system. The multi-mode combined bioartificial liver system comprises a plasma separation channel; a blood storage tank; the whole liver purification passage is provided with a first valve; the non-whole liver purification passage is provided with a second valve; the oxygen carrier recovery passage is provided with a third valve; and the controller is used for controlling the flux of the first valve, the second valve and the third valve according to an input instruction and feedback data. The invention further provides a control method of the multi-mode combined bioartificial liver system. The control method is applied to the multi-mode combined bioartificial liver system. According to the multi-mode combined bioartificial liver system and the control method, the blood storage tank is used as a transfer point of plasma, a purification channel of the plasma can be reasonably distributed by controlling the flux of the control valve according to the characteristics of blood purifiers of different principles, and the blood purification efficiency of the bioartificial liver system is improved.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and more specifically, to a multi-mode combined bioartificial liver system and a control method. Background Art

[0002] The bioartificial liver system can temporarily replace some of the liver's functions, creating conditions for liver cell repair and regeneration in patients with liver failure, and also creating time for waiting for liver transplant donors. However, due to the different types of bioreactors used, the purification effect of plasma varies, and the purification efficiency needs to be improved.

[0003] The bioreactors currently used include hepatocyte bioreactors and whole-liver bioreactors. Among them, hepatocyte bioreactors also include fluidized bed reactors, rotating flask reactors, microencapsulation reactors and biochip reactors due to different carrier types; whole-liver bioreactors use whole livers preserved in vitro to achieve blood purification, but due to the different sources of whole livers, even livers from the same species will have different effects on the purification effect due to individual differences; in some usage scenarios, the bioartificial liver system also needs to use non-biological blood purifiers, such as dialyzers, bilirubin adsorbers, etc. In the existing technology, corresponding pipelines and control methods can be configured to adapt to each bioreactor or blood purifier, but when comprehensive use is required, multiple sets of pipelines and control schemes need to be configured, which will lead to inconvenience in clinical application. Summary of the invention

[0004] In view of the shortcomings of the existing methods, this application proposes a multi-mode combined bioartificial liver system and control method to solve the technical problems of insufficient compatibility, flexibility and combination of related technologies.

[0005] In a first aspect, the present application provides a multi-mode combined bioartificial liver system, comprising: The plasma separation passage comprises a plasma separator, an arterial line connecting the inlet of the plasma separator to the recipient artery, and a venous line connecting the cell outlet of the plasma separator to the recipient vein; A blood storage tank, the inlet of which is connected to the plasma outlet of the plasma separator through a blood inlet line, and the outlet of which is connected to the venous line through a return line; A whole liver purification pathway, comprising a whole liver perfusion device, a pre-hepatic pipeline connecting the inlet of the whole liver perfusion device to the outlet of the blood storage tank, a post-hepatic pipeline connecting the outlet of the whole liver perfusion device to the inlet of the blood storage tank, a first valve, a first pressure sensor and an oxygenator containing an oxygen carrier arranged on the pre-hepatic pipeline, and a second pressure sensor arranged on the post-hepatic pipeline; A non-whole liver purification pathway, comprising a purification reactor, a pre-reactor pipeline connecting the inlet of the purification reactor to the outlet of the blood storage tank, a post-reactor pipeline connecting the outlet of the purification reactor to the inlet of the blood storage tank, and a second valve and a third pressure sensor arranged in the pre-reactor pipeline; An oxygen carrier recovery passage, comprising an oxygen carrier recoverer, a pre-recovery pipeline connecting the inlet of the oxygen carrier recoverer to the outlet of the blood storage tank, a post-recovery pipeline connecting the outlet of the oxygen carrier recoverer to the inlet of the blood storage tank, and a third valve arranged on the pre-recovery pipeline; The controller is used to control the flux of the first valve, the second valve and the third valve according to the input instructions and the feedback data, wherein the feedback data includes the data from each pressure sensor.

[0006] Optionally, the purification reactor includes at least one purification body selected from the group consisting of a hepatocyte bioreactor and a non-biological blood purifier.

[0007] Further optionally, when the purification reactor includes two or more purification bodies, different purification bodies are connected in parallel or in series.

[0008] Furthermore, the blood storage tank is provided with a liquid level sensor, which is arranged at a preset upper limit position and a lower limit position of the liquid level, and is used to generate a liquid level signal and send it to the controller.

[0009] Optionally, the reflux line, the pre-liver line, the pre-reactor line and the pre-recovery line are respectively connected to different outlets of the blood storage tank, and the first valve, the second valve and the third valve are respectively configured.

[0010] Further optionally, the reflux line, pre-liver line, pre-reactor line and pre-recovery line are connected to the same outlet of the blood storage tank via a valve assembly, and the valve assembly performs the functions of the first valve, the second valve and the third valve.

[0011] Optionally, the blood guide line, post-hepatic line, post-reactor line and post-recovery line are respectively connected to different inlets of the blood storage tank, or the blood guide line, post-hepatic line, post-reactor line and post-recovery line are connected to the same inlet of the blood storage tank.

[0012] Furthermore, at least one peristaltic pump is respectively provided on the plasma separation passage, the whole liver purification passage, the non-whole liver purification passage and the oxygen carrier recovery passage.

[0013] Optionally, the controller includes a control chip and a wireless transceiver module.

[0014] Furthermore, the whole liver perfusion device includes a non-human liver and a cabin supporting perfusion, and the pre-hepatic pipeline and the post-hepatic pipeline are connected to the non-human liver through the cabin.

[0015] In a second aspect, the present application provides a control method for a multi-mode combined bioartificial liver system, which is applied to the multi-mode combined bioartificial liver system as described above, and comprises the following steps: After the liquid input from the blood drainage circuit is received in the current use round until the liquid level of the blood storage tank reaches the lower limit of the liquid level, the whole liver purification circuit is opened in the debugging mode until the perfusion pressure of the whole liver reaches a preset value; The non-whole liver purification pathway is opened so that the liquid level of the blood storage tank does not exceed the upper limit of the liquid level and does not fall below the lower limit of the liquid level, so as to realize the full purification mode; Before the current round of use ends, the whole liver purification pathway is closed first, and then the non-whole liver purification pathway is closed.

[0016] Optionally, before the current use cycle ends, the oxygen carrier needs to be recovered, including: Closing the whole liver purification pathway, opening the non-whole liver purification pathway and the oxygen carrier recovery pathway, and running several cycles; Closing the non-whole liver purification pathway and keeping the oxygen carrier recovery pathway running for 1-2 cycles; The oxygen carrier recovery passage is closed to end the current round of use.

[0017] Further optionally, a limited purification mode is included, including closing the whole liver purification path, and the second valve opens the non-whole liver purification path at a maximum flux.

[0018] Furthermore, the whole liver purification pathway is opened in the debugging mode until the perfusion pressure of the whole liver reaches a preset value, including: opening the first valve, closing the second valve and the third valve, and the flux of the first valve is adjusted according to feedback data from the first pressure sensor and the second pressure sensor.

[0019] Optionally, in the full purification mode, the third valve remains closed or is intermittently opened.

[0020] Further optionally, in the full purification mode, the flux of the second valve is adjusted according to the liquid level of the blood storage tank and feedback data from the third pressure sensor.

[0021] The beneficial technical effects brought about by the technical solution provided by the embodiment of the present application include: (1) The multi-mode combined bioartificial liver system and control method of the present application, by using a blood storage tank as a transfer point for plasma, can reasonably allocate the plasma purification path by controlling the flux of the control valve according to the characteristics of blood purifiers based on different principles, thereby improving the blood purification efficiency of the bioartificial liver system of the present application.

[0022] (2) The multi-mode bioartificial liver system and control method of the present application utilizes a blood storage tank and an adaptively adjustable first valve to prioritize the perfusion pressure of the whole liver in a debugging mode, thereby overcoming the problem of difficulty in accurately matching the perfusion pressure due to different blood states of the recipient and different states of the liver in vitro.

[0023] (3) The multi-mode combined bioartificial liver system and control method of the present application can, after confirming the perfusion pressure of the whole liver, also be connected to different types of non-whole liver purification reactors, with multi-channel synchronous circulation, which is conducive to accelerating the efficiency of blood purification.

[0024] (4) The multi-mode combined bioartificial liver system and control method of the present application are also equipped with an oxygen carrier recovery path, which can be selectively opened to facilitate the selection of whether to intercept the oxygen carrier as needed.

[0025] Additional aspects and advantages of the present application will be partially given in the following description, which will become apparent from the following description, or will be understood through the practice of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The above and / or additional aspects and advantages of the present application will become apparent and easily understood from the following description of the embodiments in conjunction with the accompanying drawings, in which: Figure 1 A schematic structural diagram of a multi-mode combined bioartificial liver system provided in an embodiment of the present application.

[0027] Figure 2 A corresponding table of working modes and valve states of the multi-mode combined bioartificial liver system provided in an embodiment of the present application. DETAILED DESCRIPTION

[0028] The embodiments of the present application are described below in conjunction with the drawings in the present application. It should be understood that the implementation methods described below in conjunction with the drawings are exemplary descriptions for explaining the technical solutions of the embodiments of the present application and do not constitute a limitation on the technical solutions of the embodiments of the present application.

[0029] Those skilled in the art will appreciate that, unless expressly stated, the "said" and "the" used herein may also include plural forms. It should be further understood that the term "including" used in the specification of the present application refers to the presence of the features, integers, steps, operations, elements and / or components, but does not exclude the implementation of other features, information, data, steps, operations, elements, components and / or combinations thereof supported by the technical field. The term "and / or" used herein refers to at least one of the items defined by the term, for example, "A and / or B" may be implemented as "A", or as "B", or as "A and B".

[0030] In order to make the objectives, technical solutions and advantages of the present application clearer, the implementation methods of the present application will be further described in detail below with reference to the accompanying drawings.

[0031] In the prior art, although the use of the whole liver as a bioreactor for plasma purification has the advantages of high throughput and high purification efficiency, it does not configure a suitable plasma perfusion pressure for the whole liver currently used. The prior art requires the adjustment of the plasma perfusion pressure of the whole liver in combination with the operator's experience and bile secretion, and the plasma perfusion pressure adjustment time may be too long. Furthermore, after the plasma perfusion pressure of the whole liver is confirmed, the surplus plasma in the blood storage tank can only wait to be filtered through the whole liver under the established perfusion pressure, and the efficiency of plasma purification cannot be further accelerated. Therefore, in order to overcome the shortcomings of the prior art, the present application proposes the following solution.

[0032] refer to Figure 1 The multi-mode combined bioartificial liver system of the present application includes a plasma separation passage 2, a blood storage tank 3, a whole liver purification passage 4, a non-whole liver purification passage 5 and an oxygen carrier recovery passage 6 which are connected in sequence, and also includes a controller for overall control. Specifically: The plasma separation passage 2 includes a plasma separator 21, an arterial line 22 connecting the inlet of the plasma separator 21 to the artery of the recipient 1, an arterial line 22 connecting the plasma separator 21, and a venous line 23 connecting the cell outlet of the plasma separator 21 to the vein of the recipient 1. The core part of the plasma separator 21 is a separation chamber, which is usually equipped with a membrane with a microporous structure for physically separating blood cells and plasma. In this embodiment, after the arterial blood of the recipient 1 enters the plasma separator 21 through the arterial line 22, the blood cells and plasma are separated by the separation chamber, and the plasma is retained in other processing links through the blood guide line 31 below, and the intercepted blood cells flow back to the body of the recipient 1 through the venous line 23. In a possible implementation, the arterial line 22 includes an arterial line connected to a blood-drawing deep venous catheter preset in the receptor 1, a puncture head is provided at the end of the arterial line, and a blood pump and an arterial pot are provided on the arterial line. Correspondingly, a blood pump installation position for installing the blood pump is provided on the arterial line, and the arterial pot is provided with three interface connectors, one of which is used to connect a pressure sensor, and the remaining two interface connectors are used to connect the arterial line, so that the arterial line is connected through the arterial pot, and the role of the arterial pot here is mainly to prevent air from entering the subsequent circulation path. The venous line 23 includes a venous line connected to the vein of the receptor 1, and a venous pot with four connectors is provided on the venous line, two of which are used to connect the venous line, so that the venous pot is connected to the venous line; among the remaining two connectors, one connector is used to connect a pressure sensor, and the other connector is used to connect to the return line 32 of the blood storage tank 3 below. The role of the venous pot here is mainly to prevent air from entering the body of the receptor 1. The specific implementation of the above arterial line 22 and venous line 23 can be optimized and adjusted according to common knowledge, without affecting the essence of the invention of the present application.

[0033] The blood storage tank 3 is provided with a plurality of interfaces, some of which are used as inlets, and the rest are used as outlets. In this embodiment, the first inlet 33a is configured to be connected to the plasma outlet of the plasma separator 21 through the blood drainage line 31 to drain the separated plasma into the blood storage tank 3, and the first outlet 34a is configured to be connected to the venous line 23 through the return line 32 to form a path for returning to the receptor 1; further, the second inlet 33b and the second outlet 34b are configured to be connected to the whole liver purification path 4, the third inlet 33c and the third outlet 34c are configured to be connected to the non-whole liver purification path 5, and the fourth inlet 33d and the fourth outlet 34d are configured to be connected to the oxygen carrier recovery path 6. The present application sets up the blood storage tank 3 so that the whole liver purification path 4, the non-whole liver purification path 5 and the oxygen carrier recovery path 6 connected to the blood storage tank 3 form a parallel relationship to form three relatively independent circulation lines, thereby greatly improving the flow rate of the multi-mode combined bioartificial liver system of the present application and improving the working efficiency of the bioartificial liver system. Furthermore, the blood storage tank 3 is provided with a liquid level sensor 35, which is set at a suitable upper limit position and a lower limit position of the liquid level, and is used to generate a liquid level signal, and the controller can control the multi-mode combined bioartificial liver system of the present application according to the liquid level signal. The liquid level sensor 35 set at the upper limit position of the liquid level is used to prevent plasma from accumulating in the blood storage tank 3 and reducing the efficiency of plasma purification, and the liquid level sensor 35 set at the lower limit position of the liquid level is used to maintain the plasma outflow pressure of the liquid storage tank to facilitate pressure regulation of other pathways. In a possible implementation, the first inlet 33a, the second inlet 33b, the third inlet 33c and the fourth inlet 33d of the liquid storage tank can be respectively designated on different interfaces of the liquid storage tank, so that the various inlets can avoid mutual interference, or they can be connected to the same interface by configuring a diverter, so as to reduce the number of interfaces configured; the first outlet 34a, the second outlet 34b, the third outlet 34c and the fourth outlet 34d of the liquid storage tank can be respectively designated on different interfaces of the liquid storage tank, and valves or pressure sensors can be independently configured to achieve independent control, or they can be connected to the same interface by configuring a valve assembly, and a valve assembly performs the function of a separately configured valve. Adapting to the size and function of the bioartificial liver system of the present application, a valve assembly with a "five-way three-valve" control mode can be designed to adapt to the blood storage tank 3. When the blood storage tank 3 is placed vertically, the interface as the inlet is configured in the upper half of the blood storage tank 3, and the interface as the outlet is configured in the lower half of the blood storage tank 3, so that the upper limit of the liquid level is close to the interface as the inlet, and the lower limit of the liquid level is close to the interface as the outlet.

[0034] The whole liver purification passage 4 includes a whole liver perfusion device 41, a pre-liver pipeline 42 connecting the inlet of the whole liver perfusion device 41 to the outlet (second outlet 34b) of the blood storage tank 3, a post-liver pipeline 43 connecting the outlet of the whole liver perfusion device 41 to the inlet (second inlet 33b) of the blood storage tank 3, and a first valve 44, a first pressure sensor 45 and an oxygenator 47 containing an oxygen carrier arranged on the pre-liver pipeline 42, and a second pressure sensor 46 arranged on the post-liver pipeline 43. The whole liver perfusion device 41 includes a whole liver and a perfusion chamber for accommodating the whole liver, and in this embodiment, the whole liver is a non-human liver, preferably derived from an animal liver, and specifically a fresh pig whole liver can be used. It can be understood by those skilled in the art that the pig providing the whole liver can be a gene-edited pig, the organ size, structure and function of the pig are similar to those of humans, and the pig has a relatively stable breeding system. The gene-edited pig has knocked out the pathogens and allergens of pig origin, and the liver metabolic function can be further enhanced, making it more suitable for processing human plasma. The whole liver perfusion chamber is used, and the perfusion equipment used for organ preservation is used as a reference. A closed space with stable temperature and stable perfusion pressure is provided for the preservation and purification of the whole liver. In addition, the whole liver can be connected with the pre-liver pipeline 42 and the post-liver pipeline 43 by using the pipeline in the perfusion chamber. In order to monitor and adjust the perfusion pressure in time, pressure sensors (first pressure sensor 45 and second pressure sensor 46) are respectively configured in the perfusion passage (pre-liver pipeline 42) and the perfusion passage (post-liver pipeline 43) of the perfusion chamber. The data collected by these two pressure sensors are used to adaptively adjust the first valve 44 and the peristaltic pump 7 on the whole liver purification passage 4. In particular, when the bioartificial liver system of the present application is adapted to a new whole liver or a new patient, the perfusion pressure can be adjusted quickly, thereby completing the debugging mode. Preferably, in order to monitor the functional status of the whole liver, the perfusion chamber is equipped with a bile recovery and monitoring device connected to the whole liver to collect bile for liver-related physiological parameter index detection. The liver-related physiological parameters can also be integrated with the data collected by the pressure sensor to more finely control the flow of the first valve 44 and the flow rate controlled by the peristaltic pump 7.

[0035] Oxygenator containing oxygen carrier 47. In the blood purification system, oxygen carrier mainly involves artificial oxygen carrier, which can simulate the function of natural red blood cells and is used to provide oxygen to the patient in an emergency or when blood transfusion is difficult. The main oxygen carriers currently exist and their use methods are as follows: Perfluorocarbon (PFC) oxygen carrier; blood substitute used in the early stage, but due to its many limitations, the widespread clinical application of PFC has been greatly limited. Hemoglobin modified oxygen carrier; classified according to the preparation method as follows: First generation: mainly including intramolecular, intermolecular cross-linking, polymerization, and recombinant hemoglobin; Second generation: oxygen carrier characterized by cross-linking certain enzymes; Third generation: microencapsulated type; The first and second generation oxygen carriers have oxygen carrying-releasing functions close to natural red blood cells and have been used to a certain extent in clinical practice. However, due to its lack of cell membrane-like barriers, it has extremely high requirements for the purity of hemoglobin raw materials. Free hemoglobin is easy to interact with many active molecules in the blood, inducing a series of abnormal side reactions. Other blood substitutes; hemoglobin oxygen carriers (HBOC), including polymerized hemoglobin, genetically regulated hemoglobin, and polyethylene glycol (PEG) hemoglobin. These carriers have better stability, do not require blood typing and cross-matching, have a longer circulation half-life, and will not accumulate in related metabolic organs to produce toxicity. The use of the above artificial oxygen carriers can improve the oxygen supply effect of the whole liver, help maintain or activate the physiological activity of the whole liver, and help strengthen the purification effect of the whole liver.

[0036] Further, in order to adapt to the use of the aforementioned artificial oxygen carrier, the oxygen carrier recovery passage 6 is configured so as to selectively control whether the artificial oxygen carrier is input into the body of the recipient 1. Specifically, the oxygen carrier recovery passage 6 includes an oxygen carrier recovery device 61, a recovery front pipeline 62 connecting the inlet of the oxygen carrier recovery device 61 to the outlet (fourth outlet 34d) of the blood storage tank 3, a reactor post pipeline 53 connecting the outlet of the oxygen carrier recovery device 61 to the inlet (fourth inlet 33d) of the blood storage tank 3, and a third valve 64 arranged in the recovery front pipeline 62. In this embodiment, a separation chamber is provided inside the oxygen carrier recovery device 61, and a filter membrane is provided in the separation chamber. After the plasma containing the artificial oxygen carrier flows through the separation chamber of the oxygen carrier recovery device 61, the artificial oxygen carrier is intercepted by the filter membrane and retained in the oxygen carrier recovery device 61. After the plasma flows out of the oxygen carrier recovery device 61, there are two pathways for diversion, one of which is to return to the blood storage tank 3 through the recovery back pipeline 63 to continue the extracorporeal circulation, and the other is to return to the body circulation of the recipient 1 through the venous pipeline 23. The third valve 64 is used to control the connection and closing of the oxygen carrier recovery passage 6. When the third valve 64 is closed, the plasma containing the artificial oxygen carrier can directly flow into the body of the recipient 1 through the return line 32 connected to the venous line 23, thereby achieving the effect of supplementing the patient with artificial oxygen carriers, especially artificial hemoglobin.

[0037] The non-whole liver purification pathway 5 includes a purification reactor 51, a pre-reactor pipeline 52 connecting the inlet of the purification reactor 51 to the outlet (third outlet 34c) of the blood storage tank 3, a post-reaction pipeline connecting the outlet of the purification reactor 51 to the inlet (third inlet 33c) of the blood storage tank 3, and a second valve 54 and a third pressure sensor 55 arranged in the pre-reaction pipeline. The "non-whole liver purification pathway 5" is relative to the "whole liver purification pathway", and the present application means a pathway for purifying plasma by means other than the whole liver, including using a cell reactor as a pathway for the purification reactor 51, and / or including using physical adsorption as a pathway for the purification reactor 51. The cell reactor is used as the path of the purification reactor 51, and the in vitro expanded liver cells or mixed cells containing liver cells are used as the active part. In terms of form, the cell culture tank is used as the purification reactor 51. According to the cell culture method, the following methods can be used to achieve it: Fluidized Bed Reactors: The liver cells in this reactor are suspended in a flowing gas or liquid, so that the cells can be fully in contact with the nutrient solution as in the body, and maintain a suitable supply of oxygen and nutrients. Rotating Bottle Reactors: In this reactor, the liver cell culture solution is placed in a rotating bottle, which provides the necessary nutrients and oxygen through the rotating motion, and helps to remove waste. Microcapsulation Reactors: In this reactor, the liver cells are encapsulated in microcapsules to protect the cells and provide an environment suitable for their growth. Biochip Reactors: Using biochip technology, liver cells are densely cultured on microchips to increase cell density and reaction efficiency. By using physical adsorption as the pathway of the purification reactor 51, a module having the functions of filtering plasma, dialyzing plasma, replacing plasma or adsorbing plasma waste can be configured. When the non-whole liver purification pathway 5 includes two or more purification bodies constituting the purification reactor 51, different purification bodies can be connected in parallel, in series or in a mixed manner of parallel and series. The specific implementation method is based on the purification effect of plasma. One possible implementation method is to connect a hemodialysis module and a microencapsulated reactor of liver cells in series in sequence on the non-whole liver purification pathway 5. The working state of the second valve 54 is limited by the liquid level of the first valve 44 and the blood storage tank 3, and is also limited by the third pressure sensor 55.

[0038] At least one peristaltic pump 7 is respectively arranged on the plasma separation passage 2, the whole liver purification passage 4, the non-whole liver purification passage 5 and the oxygen carrier recovery passage 6 to drive the flow and circulation of plasma in the multi-mode combination bioartificial liver system of the present application. The peristaltic pump 7 can cooperate with each valve to adjust the flow rate and flow velocity of each passage. Each passage produces a differentiated flow rate and flow velocity, which can give full play to the advantages of each passage in plasma treatment and improve the efficiency of plasma purification.

[0039] The controller of the present application is used to control the flux of the aforementioned first valve 44, second valve 54 and third valve 64 according to the input instructions and feedback data, wherein the feedback data includes data from each pressure sensor, namely, from the first pressure sensor 45 and the second pressure sensor 46 located on the whole liver purification passage 4, the third pressure sensor 55 located on the non-whole liver purification passage 5, and can also be from other pressure sensors on other passages in the bioartificial liver system, and also include bile recovery and monitoring devices on the whole liver purification passage 4. In the implementation of the controller of the present application, a control chip and a wireless transceiver module can be included, and the wireless transceiver module of the adapter controller is preferably implemented wirelessly in the bioartificial liver system of the present application. In order to improve the interaction between the bioartificial liver system and the operator, an operation panel loaded with an interactive interface can also be provided. Furthermore, the controller can be integrated on the equipment of the bioartificial liver system, or the operation panel can be used in the form of an application on a computer or smart mobile terminal.

[0040] Based on the above-mentioned multi-mode combined bioartificial liver system of the present application, a control method of the bioartificial liver system is further proposed, which mainly controls the opening and closing of three valves in the four outlets of the blood storage tank 3 and the flux, and adjusts the working mode of the bioartificial liver system. The working mode of the bioartificial liver system of the present application can be divided into a debugging mode, a full purification mode, a limited purification mode and an end mode. Figure 2 The basic steps of the control method of this application under each working mode are as follows: S1, after the liquid input from the blood guide line 31 to the blood storage tank 3 reaches the lower limit of the liquid level in the current use round, the whole liver purification path 4 is opened in the debugging mode until the perfusion pressure of the whole liver reaches the preset value.

[0041] The current round of use can be understood as the entire process from the blood (or other liquid) of the recipient 1 starting to enter the multi-mode combined bioartificial liver system of the present application until all the blood in the system returns to the recipient 1. The recipient 1 may have used the bioartificial liver system of the present application before the current round of use, or may use the bioartificial liver system of the present application again after the current round of use. For a specific receptor 1, the usage data generated each time can be archived and called again to speed up the adjustment of the bioartificial liver system of the present application to the optimal state adapted to the specific receptor 1 as soon as possible.

[0042] The blood storage tank 3 is located at the intersection of various pathways in the bioartificial liver system of the present application. By setting the lower limit of the liquid level in the blood storage tank 3, the hydraulic pressure in at least one pathway can be guaranteed. In a preferred case, the liquid level in the blood storage tank 3 is maintained at the lower limit of the liquid level, so that the inflow of blood (or plasma) and the outflow to each circulation pathway maintain a dynamic balance, thereby improving the blood purification efficiency.

[0043] The perfusion pressure of the whole liver affects the physiological activity of the whole liver. The ex vivo liver will experience a short ischemic hypoxia state before reperfusion. If the ischemic hypoxia state lasts too long, a large number of liver cells will die, affecting the activity of the ex vivo liver. However, restoring the perfusion state as soon as possible can reverse the problems caused by ischemic hypoxia to a certain extent. Therefore, it is important to allow the ex vivo liver to reach the optimal perfusion pressure as soon as possible to maintain the activity of liver cells. Pressure sensors (first pressure sensor 45 and second pressure sensor 46) are respectively configured in the pre-liver pipeline 42 and the post-liver pipeline 43 of the whole liver purification passage 4, which can more accurately detect the dynamic changes of the perfusion pressure of the liver, so as to adjust the flux of the first valve 44 in the form of feedback. Those skilled in the art should understand that the physiological state of each ex vivo liver will be different, so the optimal perfusion pressure value of each liver is different. The controller can predict the specific value of the optimal perfusion pressure based on historical data to obtain a preset value, and in the debugging mode, the perfusion pressure is allowed to reach the preset value as soon as possible under controllable conditions to achieve activation of the whole liver. The first valve 44 is preferably an electric valve with stepless adjustment to more finely adjust the perfusion pressure of the whole liver purification passage 4 .

[0044] The debugging mode in the embodiment of the present application has the following characteristics: the first valve 44 is turned on, the second valve 54 and the third valve 64 are closed, the flux of the first valve 44 is adjusted according to the feedback data of the first pressure sensor 45 and the second pressure sensor 46, and when the second valve 54 and the third valve 64 are closed, the plasma flowing into the bioartificial liver system mainly flows into the whole liver purification passage 4, and part of it is connected to the venous line 23 through the return line 32 that is always turned on, thereby making it possible to use as much plasma as possible to make the perfusion pressure of the whole liver reach the optimal value as soon as possible, shortening the time of the debugging mode. If the recipient 1 has been used before the current round of use, and the same whole liver is used, the time of the debugging mode can be ignored if the historical data can be called.

[0045] S2, the non-whole liver purification passage 5 is turned on, so that the liquid level of the blood storage tank 3 does not exceed the upper limit of the liquid level and does not fall below the lower limit of the liquid level, so as to realize the full purification mode.

[0046] The full purification mode means that both the whole liver purification pathway 4 and the non-whole liver purification pathway 5 are turned on, and the plasma flowing into the bioartificial liver system of the present application can pass through the whole liver purification pathway 4 and / or the non-whole liver purification pathway 5. According to the foregoing description, the whole liver purification pathway 4 operates at the optimal perfusion pressure, and some plasma in the blood storage tank 3 fails to be purified in time and remains in the blood storage tank 3 for a short time, or the plasma that does not flow into the whole liver purification pathway 4 in time returns to the body of the receptor 1 through the reflux pipeline 32, and the toxins in the plasma affect the receptor 1 again. In order to avoid the aforementioned problems, a non-whole liver purification pathway 5 is set on the basis of the whole liver purification pathway 4. The non-whole liver purification pathway 5 has a compensatory and supporting effect on the whole liver purification pathway 4. The non-whole liver purification pathway 5 can select a purification subject that is functionally different from the whole liver to ensure the operational stability of the entire bioartificial liver system. It can also select a purification subject on the non-whole liver pathway according to the individual situation of the patient to achieve a multi-mode combination. The two pathways operate simultaneously, which can also greatly improve the blood purification efficiency, shorten the time of the current use cycle, and alleviate the patient's discomfort.

[0047] In the full purification mode, the third valve 64 located on the oxygen carrier recovery passage 6 remains closed, suspending the recovery link of the oxygen carrier, or the third valve 64 is intermittently turned on, so that the oxygen carriers on the circulation passage are partially updated. Furthermore, the flux of the second valve 54 located on the non-whole liver purification passage 5 is adjusted according to the liquid level of the blood storage tank 3 and the feedback data of the third pressure sensor 55. When a specific purification subject is selected, it may be required to operate under a specific hydraulic pressure. It is necessary to monitor the hydraulic pressure of the non-whole liver purification passage 5 using the third pressure sensor 55, and it is necessary to monitor the liquid level in the blood storage tank 3 to prevent the liquid level from exceeding the upper and lower limits of the liquid level to maintain the stability of the operation of the bioartificial liver system.

[0048] S3, before the current round of use ends, first close the whole liver purification pathway 4, and then close the non-whole liver purification pathway 5. Before the current round of use ends, if it is necessary to recover the oxygen carrier, after closing the whole liver purification pathway 4, conduct the non-whole liver purification pathway 5 and the oxygen carrier recovery pathway 6, and run several cycles; after closing the non-whole liver purification pathway 5, keep the oxygen carrier recovery pathway 6 running for 1~2 cycles; finally, close the oxygen carrier recovery pathway 6 and end the current round of use.

[0049] Plasma circulates in multiple pathways. Before ending the current round of use, it is necessary to ensure that the plasma in each pathway has returned to the blood storage tank 3, and then returned to the recipient 1 through the collection of the blood storage tank 3. According to the characteristics of each pathway, in this embodiment, the first valve 44 is first used to close the whole liver purification pathway 4, and then the second valve 54 is controlled to operate the non-whole liver purification pathway 5 at maximum flux. When the oxygen carrier recovery pathway 6 needs to be opened, the third valve 64 is controlled to operate at maximum flux, so that the plasma in the bioartificial liver can circulate several times to intercept immunogens or exogenous cell fragments.

[0050] S4, in a specific use case, also includes a limited purification mode, that is, only the non-whole liver purification pathway 5 is turned on to achieve plasma purification, and the specific characteristics are: when the whole liver purification pathway 4 is closed, only the non-whole liver purification pathway 5 is turned on, and the second valve 54 operates at the maximum flux. This mode can cope with the temporary addition or temporary deactivation of the whole liver purification pathway 4, so as to facilitate temporary adjustment of the whole liver purification pathway 4. In the case of meeting the needs of the patient, only the non-whole liver purification pathway 5 can also be used. This further reflects the characteristics of the multi-mode combination of the bioartificial liver system of the present application.

[0051] In summary, the present application provides a multi-mode combined bioartificial liver system, which includes: a plasma separation pathway, including a plasma separator, an arterial pipeline connecting the inlet of the plasma separator to the recipient artery, and a venous pipeline connecting the cell outlet of the plasma separator to the recipient vein; a blood storage tank, whose inlet is connected to the plasma outlet of the plasma separator through a blood guide line, and whose outlet is connected to the venous pipeline through a return line; a whole liver purification pathway, including a whole liver perfusion device, a pre-hepatic pipeline connecting the inlet of the whole liver perfusion device to the outlet of the blood storage tank, a post-hepatic pipeline connecting the outlet of the whole liver perfusion device to the inlet of the blood storage tank, a first valve, a first pressure sensor and an oxygenator containing an oxygen carrier arranged on the pre-hepatic pipeline, and a second pressure sensor arranged on the post-hepatic pipeline. A sensor; a non-whole liver purification pathway, comprising a purification reactor, a pre-reactor pipeline connecting the inlet of the purification reactor to the outlet of the blood storage tank, a post-reactor pipeline connecting the outlet of the purification reactor to the inlet of the blood storage tank, and a second valve and a third pressure sensor arranged in the pre-reactor pipeline; an oxygen carrier recovery pathway, comprising an oxygen carrier recoverer, a pre-recovery pipeline connecting the inlet of the oxygen carrier recoverer to the outlet of the blood storage tank, a post-recovery pipeline connecting the outlet of the oxygen carrier recoverer to the inlet of the blood storage tank, and a third valve arranged in the pre-recovery pipeline; a controller, for controlling the flux of the first valve, the second valve and the third valve according to input instructions and feedback data, wherein the feedback data includes data from each pressure sensor.

[0052] The present application also provides a control method for a multi-mode combined bioartificial liver system, which is applied to the multi-mode combined bioartificial liver system as described above, and comprises the following steps: after the liquid input from the blood guide line is received in the current use round and the liquid level in the blood storage tank reaches the lower limit of the liquid level, the whole liver purification pathway is opened in a debugging mode until the perfusion pressure of the whole liver reaches a preset value; the non-whole liver purification pathway is opened so that the liquid level in the blood storage tank does not exceed the upper limit of the liquid level and is not lower than the lower limit of the liquid level, so as to realize the full purification mode; before the end of the current use round, the whole liver purification pathway is closed first, and then the non-whole liver purification pathway is closed.

[0053] The multi-mode combined bioartificial liver system and control method of the present application, using a blood storage tank as a transfer point for plasma, can reasonably allocate the purification pathway for plasma by controlling the flux of a control valve according to the characteristics of blood purifiers based on different principles, thereby improving the blood purification efficiency of the bioartificial liver system of the present application.

[0054] Those skilled in the art will appreciate that the various operations, methods, steps, measures, and schemes in the processes discussed in this application may be alternated, changed, combined, or deleted. Furthermore, other steps, measures, and schemes in the various operations, methods, and processes discussed in this application may also be alternated, changed, rearranged, decomposed, combined, or deleted. Furthermore, steps, measures, and schemes in the related art that are similar to those disclosed in this application may also be alternated, changed, rearranged, decomposed, combined, or deleted.

[0055] In the description of the present application, the directions or positional relationships indicated by words such as "center", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" are based on the exemplary directions or positional relationships shown in the accompanying drawings. They are for the convenience of describing or simplifying the description of the embodiments of the present application, and do not indicate or imply that the referred device or component must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be understood as limitations on the present application.

[0056] The terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of this application, unless otherwise specified, "plurality" means two or more.

[0057] In the description of this application, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected", and "connected" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a direct connection, or an indirect connection through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in this application can be understood according to specific circumstances.

[0058] In the description of this specification, specific features, structures, materials or characteristics may be combined in an appropriate manner in any one or more embodiments or examples.

[0059] The above is only a partial implementation method of the present application. It should be pointed out that for ordinary technicians in this technical field, without departing from the technical concept of the scheme of the present application, other similar implementation methods based on the technical ideas of the present application are also within the protection scope of the embodiments of the present application.

Claims

1. A multi-mode combined bioartificial liver system, characterized in that: include: The plasma separation passage comprises a plasma separator, an arterial line connecting the inlet of the plasma separator to the recipient artery, and a venous line connecting the cell outlet of the plasma separator to the recipient vein; A blood storage tank, the inlet of which is connected to the plasma outlet of the plasma separator through a blood inlet line, and the outlet of which is connected to the venous line through a return line; A whole liver purification pathway, comprising a whole liver perfusion device, a pre-hepatic pipeline connecting the inlet of the whole liver perfusion device to the outlet of the blood storage tank, a post-hepatic pipeline connecting the outlet of the whole liver perfusion device to the inlet of the blood storage tank, a first valve, a first pressure sensor and an oxygenator containing an oxygen carrier arranged on the pre-hepatic pipeline, and a second pressure sensor arranged on the post-hepatic pipeline; A non-whole liver purification pathway, comprising a purification reactor, a pre-reactor pipeline connecting the inlet of the purification reactor to the outlet of the blood storage tank, a post-reactor pipeline connecting the outlet of the purification reactor to the inlet of the blood storage tank, and a second valve and a third pressure sensor arranged in the pre-reactor pipeline; An oxygen carrier recovery passage, comprising an oxygen carrier recoverer, a pre-recovery pipeline connecting the inlet of the oxygen carrier recoverer to the outlet of the blood storage tank, a post-recovery pipeline connecting the outlet of the oxygen carrier recoverer to the inlet of the blood storage tank, and a third valve arranged on the pre-recovery pipeline; The controller is used to control the flux of the first valve, the second valve and the third valve according to the input instructions and the feedback data, wherein the feedback data includes the data from each pressure sensor.

2. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The purification reactor includes at least one purification body selected from the group consisting of a hepatocyte bioreactor and a non-biological blood purifier.

3. The multi-mode combined bioartificial liver system according to claim 2, characterized in that: When the purification reactor comprises two or more purification bodies, different purification bodies are connected in parallel or in series.

4. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The blood storage tank is provided with a liquid level sensor, which is arranged at a preset liquid level upper limit position and a liquid level lower limit position, and is used to generate a liquid level signal and send it to the controller.

5. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The reflux pipeline, the pre-liver pipeline, the pre-reactor pipeline and the pre-recovery pipeline are respectively connected to different outlets of the blood storage tank, and the first valve, the second valve and the third valve are respectively configured.

6. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The reflux pipeline, the pre-liver pipeline, the pre-reactor pipeline and the pre-recovery pipeline are connected to the same outlet of the blood storage tank through a valve assembly, and the valve assembly performs the functions of the first valve, the second valve and the third valve.

7. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The blood guide line, post-hepatic line, post-reactor line and post-recovery line are respectively connected to different inlets of the blood storage tank, or the blood guide line, post-hepatic line, post-reactor line and post-recovery line are connected to the same inlet of the blood storage tank.

8. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: At least one peristaltic pump is respectively arranged on the plasma separation passage, the whole liver purification passage, the non-whole liver purification passage and the oxygen carrier recovery passage.

9. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The controller includes a control chip and a wireless transceiver module.

10. The multi-mode combined bioartificial liver system according to claim 1, characterized in that: The whole liver perfusion device comprises a non-human liver and a cabin supporting perfusion, and the pre-hepatic pipeline and the post-hepatic pipeline are connected to the non-human liver through the cabin.

11. A control method for a multi-mode combined bioartificial liver system, characterized in that: A bioartificial liver system with a multi-mode combination as claimed in any one of claims 1 to 10, comprising the following steps: After the liquid input from the blood drainage circuit is received in the current use round until the liquid level of the blood storage tank reaches the lower limit of the liquid level, the whole liver purification circuit is opened in the debugging mode until the perfusion pressure of the whole liver reaches a preset value; The non-whole liver purification pathway is opened so that the liquid level of the blood storage tank does not exceed the upper limit of the liquid level and does not fall below the lower limit of the liquid level, so as to realize the full purification mode; Before the current round of use ends, the whole liver purification pathway is closed first, and then the non-whole liver purification pathway is closed.

12. The method according to claim 11, characterized in that Before the end of the current use cycle, the oxygen carrier needs to be recovered, including: Closing the whole liver purification pathway, opening the non-whole liver purification pathway and the oxygen carrier recovery pathway, and running several cycles; Closing the non-whole liver purification pathway and keeping the oxygen carrier recovery pathway running for 1-2 cycles; The oxygen carrier recovery passage is closed to end the current round of use.

13. The method according to claim 11, characterized in that It also includes a limited purification mode, including closing the whole liver purification path, and the second valve opens the non-whole liver purification path at a maximum flux.

14. The method according to claim 11, characterized in that The method of opening the whole liver purification pathway in the debugging mode until the perfusion pressure of the whole liver reaches a preset value includes: opening the first valve, closing the second valve and the third valve, and adjusting the flux of the first valve according to feedback data from the first pressure sensor and the second pressure sensor.

15. The method according to claim 11, characterized in that In the full purification mode, the third valve remains closed or is intermittently turned on.

16. The method according to claim 11, characterized in that In the full purification mode, the flux of the second valve is adjusted according to the liquid level of the blood storage tank and the feedback data of the third pressure sensor.

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