Multi-mode combined bioartificial liver system and control method

Abstract

The present application provides a multi-mode combined bioartificial liver system, comprising: a plasma separation pathway; a blood storage tank; a whole liver purification pathway, provided with a first valve; a non-whole liver purification pathway, provided with a second valve; an oxygen carrier recovery pathway, provided with a third valve; and a controller configured for controlling the flow rates of the first valve, the second valve, and the third valve according to an input instruction and feedback data. The present application further provides a control method for the multi-mode combined bioartificial liver system applied to the described multi-mode combined bioartificial liver system. The multi-mode combined bioartificial liver system and the control method of the present application, by using the blood storage tank as a transfer point of plasma, can control, according to the characteristics of blood purifiers based on different principles, the flow rates of the valves to reasonably allocate the purification pathways of plasma, thereby improving the blood purification efficiency of the bioartificial liver system of the present application.

Description

Multimodal bioartificial liver system and control method Technical Field

[0001] This application relates to the field of medical device technology, and more specifically, to a multi-mode bioartificial liver system and its control method. Background Technology

[0002] Bioartificial liver systems can temporarily replace some of the liver's functions, creating conditions for hepatocyte repair and regeneration in patients with liver failure, and also buying time while waiting for a liver transplant donor. However, due to the different types of bioreactors used, the plasma purification effect varies, and the purification efficiency needs to be improved.

[0003] Currently used bioreactors include hepatocyte bioreactors and whole-liver bioreactors. Hepatocyte bioreactors, depending on the carrier, include fluidized bed reactors, rotary flask reactors, microencapsulated reactors, and biochip reactors. Whole-liver bioreactors utilize whole livers preserved in vitro for blood purification. However, due to differences in the source of the whole liver, even livers from the same species, individual differences can affect the purification effect. In some application scenarios, bioartificial liver systems also require non-biological blood purifiers, such as dialyzers and bilirubin adsorbers. Existing technologies can configure corresponding pipelines and control methods to adapt to each type of bioreactor or blood purifier. However, when comprehensive use is required, multiple sets of pipelines and control schemes are needed, which leads to inconvenience in clinical applications. Summary of the Invention

[0004] This application addresses the shortcomings of existing methods by proposing a multi-mode bioartificial liver system and control method to solve the technical problems of insufficient compatibility, flexibility, and combinability in related technologies.

[0005] In a first aspect, this application provides a multi-modal bioartificial liver system, comprising:

[0006] The plasma separation pathway includes a plasma separator, an arterial conduit connecting the inlet of the plasma separator to the recipient artery, and a venous conduit connecting the cell outlet of the plasma separator to the recipient vein.

[0007] A blood storage tank, the inlet of which is connected to the plasma outlet of the plasma separator via a lead-in line, and the outlet of which is connected to the venous line via a return line;

[0008] The whole liver purification pathway includes a whole liver perfusion device, a pre-hepatic tubing connecting the inlet of the whole liver perfusion device to the outlet of the blood storage tank, a post-hepatic tubing 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 installed on the pre-hepatic tubing, and a second pressure sensor installed on the post-hepatic tubing.

[0009] The non-whole liver purification pathway includes 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 installed in the pre-reactor pipeline.

[0010] The oxygen carrier recovery path includes 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 installed in the pre-recovery pipeline.

[0011] The controller is used to control the flow of the first valve, the second valve, and the third valve based on input instructions and feedback data, wherein the feedback data includes data from various pressure sensors.

[0012] Alternatively, the purification reactor may include at least one purification element selected from hepatocyte bioreactor and non-biological blood purifier.

[0013] Alternatively, when the purification reactor comprises two or more purification units, the different purification units may be connected in parallel or in series.

[0014] Furthermore, the blood storage tank is equipped with a liquid level sensor, which is set at a preset upper liquid level position and a lower liquid level position, to generate a liquid level signal and send it to the controller.

[0015] Optionally, the reflux line, pre-liver line, pre-reactor line, and pre-recovery line are respectively connected to different outlets of the blood storage tank, and the first valve, second valve, and third valve are respectively configured.

[0016] Alternatively, 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, which performs the functions of the first valve, the second valve, and the third valve.

[0017] Alternatively, the blood inlet line, the post-hepatic line, the post-reactor line, and the post-recovery line may be connected to different inlets of the blood storage tank, or the blood inlet line, the post-hepatic line, the post-reactor line, and the post-recovery line may be connected to the same inlet of the blood storage tank.

[0018] Furthermore, at least one peristaltic pump is provided on each of the plasma separation pathway, whole liver purification pathway, non-whole liver purification pathway, and oxygen carrier recovery pathway.

[0019] Alternatively, the controller may include a control chip and a wireless transceiver module.

[0020] Furthermore, the whole-liver perfusion device includes a non-human liver and a perfusion support chamber, with the pre-hepatic and post-hepatic tubing connected to the non-human liver through the chamber.

[0021] Secondly, this application provides a control method for a multi-mode combined bioartificial liver system, applied to the multi-mode combined bioartificial liver system as described above, comprising the following steps:

[0022] After the current cycle receives the liquid input from the blood inlet line until the liquid level in the blood storage tank reaches the lower limit position, the whole liver purification pathway is opened in the debugging mode until the perfusion pressure of the whole liver reaches the preset value.

[0023] The non-full 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 achieve the full purification mode.

[0024] Before the current usage cycle ends, the whole liver purification pathway is closed first, followed by the non-whole liver purification pathway.

[0025] Optionally, if it is necessary to recover the oxygen carrier before the end of the current usage cycle, the following situations may occur:

[0026] Close the whole liver purification pathway, open the non-whole liver purification pathway and the oxygen carrier recovery pathway, and run several cycles.

[0027] Close the non-whole liver purification pathway and keep the oxygen carrier recovery pathway running for 1 to 2 cycles;

[0028] Close the oxygen carrier recovery pathway and end the current usage cycle.

[0029] Further optionally, it also includes a limited purification mode, including closing the whole-liver purification pathway and the second valve opening the non-whole-liver purification pathway at maximum flow.

[0030] Furthermore, the step of activating the whole liver purification pathway in debug mode until the perfusion pressure of the whole liver reaches a preset value includes: activating the first valve, closing the second valve and the third valve, wherein the flow rate of the first valve is adjusted according to the feedback data from the first pressure sensor and the second pressure sensor.

[0031] Alternatively, in the full purification mode, the third valve may remain closed or be intermittently opened.

[0032] Alternatively, in the full purification mode, the flow rate of the second valve is adjusted based on the liquid level in the blood storage tank and the feedback data from the third pressure sensor.

[0033] The beneficial technical effects of the technical solutions provided in this application include:

[0034] (1) The multi-mode combination bioartificial liver system and control method of this application, by using the blood storage tank as the plasma transfer point, can rationally allocate the plasma purification pathway by controlling the flow rate 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 this application.

[0035] (2) The multi-mode combination bioartificial liver system and control method of this application utilizes a blood storage tank and an adaptive adjustable first valve to prioritize the confirmation of the perfusion pressure of the whole liver in the debugging mode, which overcomes the problem that it is difficult to accurately match the perfusion pressure due to different recipient blood conditions and different in vitro liver conditions.

[0036] (3) The multi-mode combination bioartificial liver system and control method of this application, after confirming the perfusion pressure of the whole liver, can also be connected to different types of non-whole liver purification reactors, and multi-path synchronous circulation, which is conducive to accelerating the efficiency of blood purification.

[0037] (4) The multi-mode combination bioartificial liver system and control method of this application are also configured with an oxygen carrier recovery pathway, which can be selectively activated so as to select whether to intercept the oxygen carrier as needed.

[0038] Additional aspects and advantages of this application will be set forth in part in the description which follows, and will become apparent from the description or may be learned by practice of this application. Attached Figure Description

[0039] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the following description of the embodiments taken in conjunction with the accompanying drawings, wherein:

[0040] Figure 1 is a schematic diagram of a multi-mode combined bioartificial liver system provided in an embodiment of this application.

[0041] Figure 2 is a table showing the working modes and valve states of the multi-mode combined bioartificial liver system provided in the embodiments of this application. Detailed Implementation

[0042] The embodiments of this application are described below with reference to the accompanying drawings. It should be understood that the embodiments described below with reference to the accompanying drawings are exemplary descriptions for explaining the technical solutions of the embodiments of this application, and do not constitute a limitation on the technical solutions of the embodiments of this application.

[0043] Those skilled in the art will understand that, unless specifically stated otherwise, the terms "described" and "the" as used herein may also include plural forms. It should be further understood that the term "comprising" as used in the specification of this application means the presence of the stated features, integers, steps, operations, elements, and / or components, but does not exclude other features, information, data, steps, operations, elements, components, and / or combinations thereof supported by the art. The term "and / or" as used herein refers to at least one of the items defined by the term; for example, "A and / or B" can be implemented as "A," or as "B," or as "A and B."

[0044] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of this application will be described in further detail below with reference to the accompanying drawings.

[0045] While existing technologies using whole liver as a bioreactor for plasma purification offer advantages such as high throughput and high purification efficiency, they do not specify suitable plasma perfusion pressures for the currently used whole liver. Adjusting the plasma perfusion pressure in existing technologies requires consideration of operator experience and bile secretion levels, potentially leading to excessively long adjustment times. Furthermore, once the whole liver plasma perfusion pressure is confirmed, any excess plasma in the storage tank can only wait to be filtered through the whole liver at the predetermined perfusion pressure, without further accelerating plasma purification efficiency. Therefore, this application proposes the following solution to overcome the shortcomings of existing technologies.

[0046] Referring to Figure 1, the multi-mode bioartificial liver system of this application includes a plasma collection pathway 2, a blood storage tank 3, a whole liver purification pathway 4, a non-whole liver purification pathway 5, and an oxygen carrier recovery pathway 6 connected in sequence, and also includes a controller for overall control. Specifically:

[0047] The plasma separation pathway 2 includes a plasma separator 21, an arterial conduit 22 connecting the inlet of the plasma separator 21 to the artery of recipient 1, an arterial conduit 22 connecting the plasma separator 21, and a venous conduit 23 connecting the cell outlet of the plasma separator 21 to the vein of recipient 1. The core part of the plasma separator 21 is the separation chamber, which is typically equipped with a membrane with a microporous structure for physically separating blood cells and plasma. In this embodiment, after the arterial blood of recipient 1 enters the plasma separator 21 through the arterial conduit 22, the blood cells and plasma are separated through the separation chamber. The plasma is retained for other processing stages through the drain conduit 31 (described below), while the intercepted blood cells are returned to recipient 1 through the venous conduit 23. In one possible implementation, the arterial conduit 22 includes an arterial catheter connected to a pre-installed deep vein catheter within the recipient 1. The arterial catheter has a puncture head at its end and is equipped with a blood pump and an arterial reservoir. Correspondingly, the arterial catheter has a blood pump mounting position for mounting the blood pump. The arterial reservoir has three connectors: one connector for connecting a pressure sensor, and the remaining two connectors for connecting the arterial catheter, allowing the arterial catheter to be connected via the reservoir. The reservoir's primary function is to prevent air from entering the subsequent circulatory pathway. The venous conduit 23 includes a venous catheter connected to a vein in the recipient 1. The venous catheter has a venous reservoir with four connectors: two connectors for connecting the venous catheter, allowing the reservoir to connect to the venous catheter; and of the remaining two connectors, one connector is for connecting a pressure sensor, and the other is for connecting to the return conduit 32 of the blood storage tank 3 (described below). The venous reservoir's primary function is to prevent air from entering the recipient 1. The specific implementations of the arterial conduit 22 and venous conduit 23 can be optimized and adjusted based on common knowledge without affecting the inventive essence of this application.

[0048] The blood storage tank 3 has multiple interfaces, some of which serve as inlets and others as outlets. In this embodiment, the first inlet 33a is connected to the plasma outlet of the plasma separator 21 via a drainage pipe 31 to drain the separated plasma into the blood storage tank 3. The first outlet 34a is connected to the venous pipe 23 via a return pipe 32 to form a pathway for returning to the receptor 1. Furthermore, the second inlet 33b and the second outlet 34b are configured to connect to the whole liver purification pathway 4, the third inlet 33c and the third outlet 34c are configured to connect to the non-whole liver purification pathway 5, and the fourth inlet 33d and the fourth outlet 34d are configured to connect to the oxygen carrier recovery pathway 6. By configuring the blood storage tank 3, this application enables the whole liver purification pathway 4, the non-whole liver purification pathway 5, and the oxygen carrier recovery pathway 6 connected to the blood storage tank 3 to form a parallel relationship, thereby constituting three relatively independent circulation pipelines. This significantly increases the flow rate of the multi-mode combined bioartificial liver system of this application and improves the working efficiency of the bioartificial liver system. Furthermore, the blood storage tank 3 is equipped with a level sensor 35, which is set at appropriate upper and lower liquid level positions to generate liquid level signals. The controller can control the multi-mode combined bioartificial liver system of this application based on the liquid level signals. The level sensor 35 set at the upper liquid level position is used to prevent plasma from accumulating in the blood storage tank 3 and reducing the efficiency of plasma purification. The level sensor 35 set at the lower liquid level position is used to maintain the plasma outflow pressure of the storage tank to facilitate pressure regulation in other channels. In one possible implementation, the first inlet 33a, second inlet 33b, third inlet 33c, and fourth inlet 33d of the storage tank can be designated on different interfaces of the storage tank, thus avoiding mutual interference between the inlets. Alternatively, a flow divider can be configured to connect to the same interface to reduce the number of interfaces. The first outlet 34a, second outlet 34b, third outlet 34c, and fourth outlet 34d of the storage tank can be designated on different interfaces of the storage tank and independently configured with valves or pressure sensors for independent control. Alternatively, a valve assembly can be configured to connect to the same interface, with one valve assembly performing the function of a individually configured valve. Adapting to the size and function of the bioartificial liver system of this application, a valve assembly with a "five-way three-valve" control method can be designed to fit the blood storage tank 3. When the blood storage tank 3 is placed vertically, the inlet interface is configured in the upper half of the blood storage tank 3, and the outlet interface 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 inlet interface, and the lower limit of the liquid level is close to the outlet interface.

[0049] The whole liver purification pathway 4 includes a whole liver perfusion device 41, a pre-hepatic conduit 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-hepatic conduit 43 connecting the outlet of the whole liver perfusion device 41 to the inlet (second inlet 33b) of the blood storage tank 3, a first valve 44, a first pressure sensor 45, and an oxygenator 47 containing an oxygen carrier disposed on the pre-hepatic conduit 42, and a second pressure sensor 46 disposed on the post-hepatic conduit 43. The whole liver perfusion device 41 includes a whole liver and a perfusion chamber for accommodating the whole liver. In this embodiment, the whole liver is a non-human liver, preferably derived from an animal liver, specifically a fresh pig whole liver. Those skilled in the art will understand that the pig providing the whole liver can be a gene-edited pig. The size, structure, and function of the pig's organs are similar to those of humans, and pigs have a relatively stable breeding system. Gene-edited pigs have had pathogens and allergens knocked out, and their liver metabolic function can be further enhanced, making them more suitable for processing human plasma. The perfusion chamber, inspired by perfusion equipment used for organ preservation, provides a temperature- and pressure-stable enclosed space for the preservation and purification of the whole liver. Furthermore, the tubing within the perfusion chamber connects the whole liver to the pre-hepatic tubing 42 and the post-hepatic tubing 43. To enable timely monitoring and adjustment of the perfusion pressure, pressure sensors (first pressure sensor 45 and second pressure sensor 46) are installed in the infusion pathway (pre-hepatic tubing 42) and the outfusion pathway (post-hepatic tubing 43) of the perfusion chamber. The data collected by these two pressure sensors is used to adaptively adjust the first valve 44 and the peristaltic pump 7 on the whole liver purification pathway 4. Especially when the bioartificial liver system of this application is adapted to a new whole liver or a new patient, it can quickly adjust the perfusion pressure, thereby completing the commissioning 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 the detection of liver-related physiological parameters. The liver-related physiological parameters can also be integrated with the data collected by the pressure sensor to more precisely control the flow rate of the first valve 44 and the flow rate controlled by the peristaltic pump 7.

[0050] Oxygenators 47 containing oxygen carriers are used in blood purification systems. Oxygen carriers primarily involve artificial oxygen carriers, which can mimic the function of natural red blood cells to provide oxygen to patients in emergency situations or when transfusion is difficult. Currently, several main oxygen carriers and their usage methods are as follows: Perfluorocarbon (PFC) oxygen carriers; early blood substitutes, but due to numerous limitations, the widespread clinical application of PFCs has been greatly restricted. Hemoglobin-modified oxygen carriers; classified according to preparation methods as follows: First generation: mainly including intramolecular and intermolecular cross-linking, polymerization, and recombinant hemoglobin; Second generation: oxygen carriers characterized by cross-linking with certain enzymes; Third generation: microencapsulated type; First and second generation oxygen carriers have oxygen-carrying and oxygen-releasing functions similar to natural red blood cells and have achieved some clinical application. However, due to their lack of a cell membrane-like barrier, the purity requirements for hemoglobin raw materials are extremely high. Free hemoglobin easily interacts with many active molecules in the blood, inducing a series of abnormal side reactions. Other blood substitutes include hemoglobin oxygen carriers (HBOCs), such as polymerized hemoglobin, genetically regulated hemoglobin, and PEGylated hemoglobin. These carriers offer better stability, do not require blood typing or crossmatching, have longer circulating half-lives, and do not accumulate in relevant metabolic organs to produce toxicity. The use of these artificial oxygen carriers can improve the oxygen supply to the whole liver, help maintain or activate its physiological activity, and enhance its overall purification effect.

[0051] Furthermore, to accommodate the aforementioned use of artificial oxygen carriers, the oxygen carrier recovery pathway 6 is configured to selectively control whether the artificial oxygen carrier is introduced into the recipient 1. Specifically, the oxygen carrier recovery pathway 6 includes an oxygen carrier recoverer 61, a pre-recovery pipeline 62 connecting the inlet of the oxygen carrier recoverer 61 to the outlet (fourth outlet 34d) of the blood storage tank 3, a post-reactor pipeline 53 connecting the outlet of the oxygen carrier recoverer 61 to the inlet (fourth inlet 33d) of the blood storage tank 3, and a third valve 64 disposed in the pre-recovery pipeline 62. In this embodiment, the oxygen carrier recoverer 61 has a separation chamber inside, and the separation chamber is equipped with a filter membrane. After the plasma containing artificial oxygen carriers flows through the separation chamber of the oxygen carrier recoverer 61, the artificial oxygen carriers are intercepted by the filter membrane and stored in the oxygen carrier recoverer 61. After the plasma flows out of the oxygen carrier recoverer 61, it is diverted through two pathways: one is to return to the blood storage tank 3 through the post-recovery pipeline 63 to continue extracorporeal circulation, and the other is to return to the recipient 1's in vivo circulation through the venous pipeline 23. The third valve 64 is used to control the opening and closing of the oxygen carrier recovery pathway 6. When the third valve 64 is closed, the plasma containing artificial oxygen carrier can be directly connected to the venous line 23 through the return line 32 and flow into the recipient 1, thereby achieving the effect of supplementing the patient with artificial oxygen carrier, especially artificial hemoglobin.

[0052] 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 installed in the pre-reaction pipeline. "Non-whole liver purification pathway 5" is used in contrast to "whole liver purification pathway." This application refers to a pathway that purifies plasma using methods other than whole liver purification, including using a cell reactor as the purification reactor 51, and / or using physical adsorption as the purification reactor 51. Using a cell reactor as the pathway for the purification reactor 51 involves using in vitro expanded hepatocytes or mixed cells containing hepatocytes as the active component. Formally, this means using a cell culture tank as the purification reactor 51. Depending on the cell culture method, the following methods can be employed: Fluidized Bed Reactors: In these reactors, hepatocytes are suspended in flowing gas or liquid, allowing for sufficient contact with the nutrient solution, similar to in vivo conditions, and maintaining a suitable supply of oxygen and nutrients. Rotating Bottle Reactors: In these reactors, the hepatocyte culture medium is placed in a rotating bottle, where rotation provides necessary nutrients and oxygen while aiding in waste removal. Microcapsulation Reactors: In these reactors, hepatocytes are encapsulated in microcapsules to protect the cells and provide a suitable environment for their growth. Biochip Reactors: Utilizing biochip technology, hepatocytes are densely cultured on microchips to increase cell density and reaction efficiency. Using physical adsorption as the pathway for the purification reactor 51, modules with functions of filtering plasma, dialysis plasma, replacing plasma, or adsorbing plasma waste can be configured. When the non-whole liver purification pathway 5 includes two or more purification entities constituting the purification reactor 51, the different purification entities can be connected in parallel, series, or a combination of parallel and series connections, depending on the plasma purification effect. One possible implementation is to connect a hemodialysis module and a microencapsulated reactor for hepatocytes in series on the non-whole liver purification pathway 5. The operating state of the second valve 54 is limited by the liquid level of the first valve 44 and the blood storage tank 3, and also by the third pressure sensor 55.

[0053] At least one peristaltic pump 7 is provided on each of the plasma separation pathway 2, whole liver purification pathway 4, non-whole liver purification pathway 5, and oxygen carrier recovery pathway 6 to drive the flow and circulation of plasma within the multi-mode combination bioartificial liver system of this application. The peristaltic pump 7 can cooperate with each valve to regulate the flow rate and velocity of each pathway. Different flow rates and velocities in each pathway can fully utilize the advantages of each pathway for plasma processing to improve plasma purification efficiency.

[0054] The controller of this application is used to control the flow rate of the aforementioned first valve 44, second valve 54, and third valve 64 according to input instructions and feedback data. The feedback data includes data from various pressure sensors, namely, the first pressure sensor 45 and second pressure sensor 46 located on the whole liver purification pathway 4, the third pressure sensor 55 located on the non-whole liver purification pathway 5, and other pressure sensors from other pathways in the bioartificial liver system. It also includes bile recovery and monitoring devices on the whole liver purification pathway 4. The controller of this application can be implemented using a control chip and a wireless transceiver module. Preferably, all control interaction links in the bioartificial liver system of this application are implemented wirelessly. To improve the interaction between the bioartificial liver system and the operator, an operation panel with an interactive interface can also be provided. Furthermore, the controller can be integrated into the bioartificial liver system device, or the operation panel can be used as an application on a computer or smart mobile terminal.

[0055] Based on the multi-mode combination bioartificial liver system of this application, a control method for the bioartificial liver system is further proposed. This method mainly controls the opening and closing of three valves at the four outlets of the blood storage tank 3, as well as the flow rate, to adjust the working mode of the bioartificial liver system. The working modes of the bioartificial liver system of this application can be divided into debugging mode, full purification mode, limited purification mode, and termination mode. Referring to Figure 2, the basic steps of the control method of this application under the coordination of each working mode are as follows:

[0056] S1, in the current cycle, after the liquid input from the blood inlet line 31 reaches the lower limit of the liquid level in the blood storage tank 3, the whole liver purification pathway 4 is opened in the debugging mode until the perfusion pressure of the whole liver reaches the preset value.

[0057] The current usage cycle can be understood as the entire process from the beginning of the recipient 1's blood (or other fluid) entering the multi-mode combination bioartificial liver system of this application until all the blood in the system is returned to the recipient 1. The recipient 1 may have used the bioartificial liver system of this application before the current usage cycle, or may use the bioartificial liver system of this application again after the current usage cycle. For a specific recipient 1, the usage data generated each time can be archived and retrieved again to accelerate the adjustment of the bioartificial liver system of this application to the optimal state adapted to the specific recipient 1 as quickly as possible.

[0058] The blood storage tank 3 is located at the intersection of various pathways in the bioartificial liver system of this application. By setting a lower limit position for the liquid level in the blood storage tank 3, the hydraulic pressure in at least one pathway can be guaranteed. Preferably, the liquid level in the blood storage tank 3 is maintained at the lower limit position, so that the inflow of blood (or plasma) and the outflow to each circulatory pathway are kept in dynamic balance, thereby improving the blood purification efficiency.

[0059] The perfusion pressure of the whole liver affects its physiological activity. Before reperfusion, the isolated liver experiences a transient state of ischemic hypoxia. Prolonged ischemic hypoxia leads to the death of numerous hepatocytes, affecting the activity of the isolated liver. However, quickly restoring perfusion can reverse the problems caused by ischemic hypoxia to some extent. Therefore, achieving the optimal perfusion pressure in the isolated liver as soon as possible is crucial for maintaining hepatocyte activity. Pressure sensors (first pressure sensor 45 and second pressure sensor 46) are respectively installed in the pre-hepatic tubing 42 and post-hepatic tubing 43 of the whole liver purification pathway 4 to more accurately detect dynamic changes in liver perfusion pressure, allowing for feedback-based adjustment of the flow rate of the first valve 44. Those skilled in the art should understand that the physiological state of each isolated liver varies, therefore the optimal perfusion pressure value differs for each liver. The controller can predict the specific value of the optimal perfusion pressure based on historical data to obtain a preset value. In the debugging mode, the perfusion pressure is brought to the preset value as quickly as possible under controllable conditions, thereby activating the whole liver. The first valve 44 is preferably an infinitely adjustable electric valve to more precisely regulate the perfusion pressure of the whole liver purification pathway 4.

[0060] The debugging mode in this embodiment has the following characteristics: the first valve 44 is opened, and the second valve 54 and the third valve 64 are closed. The flow rate of the first valve 44 is adjusted according to the feedback data of the first pressure sensor 45 and the second pressure sensor 46. 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 pathway 4, and partly connects to the venous line 23 through the always-conducting return line 32. This allows the perfusion pressure of the whole liver to reach the optimal value as quickly as possible by utilizing as much plasma as possible, thus shortening the debugging mode time. If the recipient 1 has been used before the current round of use and the same whole liver was used, the debugging mode time can be ignored if historical data can be retrieved.

[0061] S2, activates the non-full liver purification pathway 5, ensuring that the liquid level in the blood storage tank 3 does not exceed the upper limit of the liquid level and is not lower than the lower limit of the liquid level, thereby achieving the full purification mode.

[0062] The full purification mode refers to the operation of both the whole liver purification pathway 4 and the non-whole liver purification pathway 5. Plasma flowing into the bioartificial liver system of this application can pass through both the whole liver purification pathway 4 and / or the non-whole liver purification pathway 5. As described above, when the whole liver purification pathway 4 operates at the optimal perfusion pressure, some plasma in the blood storage tank 3 may not be purified in time and may remain there temporarily. Alternatively, plasma that does not flow into the whole liver purification pathway 4 may return to the recipient 1 through the return tubing 32, causing toxins in the plasma to affect the recipient 1 again. To avoid the aforementioned problems, a non-whole liver purification pathway 5 is set up on top of the whole liver purification pathway 4. The non-whole liver purification pathway 5 compensates for and supports the whole liver purification pathway 4. The non-whole liver purification pathway 5 can be connected to a purification subject that differs functionally from the whole liver purification pathway, ensuring the operational stability of the entire bioartificial liver system. Furthermore, the purification subject on the non-whole liver pathway can be selected according to the individual patient's condition, achieving multi-mode combinations. Simultaneous operation of both pathways can also significantly improve blood purification efficiency, shorten the current usage cycle, and reduce patient discomfort.

[0063] In full purification mode, the third valve 64 on the oxygen carrier recovery path 6 remains closed, suspending the oxygen carrier recovery process, or the third valve 64 is intermittently open, allowing partial renewal of the oxygen carrier in the circulation path. Furthermore, the flow rate of the second valve 54 on the non-whole liver purification path 5 is adjusted based on the liquid level in the blood storage tank 3 and feedback data from the third pressure sensor 55. When selecting a specific purification unit, operation under specific hydraulic pressure may be required. Therefore, monitoring the hydraulic pressure of the non-whole liver purification path 5 using the third pressure sensor 55 is necessary, as is monitoring the liquid level in the blood storage tank 3 to prevent the liquid level from exceeding the upper and lower limits, thus maintaining the stability of the bioartificial liver system.

[0064] S3, before the end of the current usage cycle, first close the whole liver purification pathway 4, then close the non-whole liver purification pathway 5. If oxygen carrier recovery is required before the end of the current usage cycle, after closing the whole liver purification pathway 4, open the non-whole liver purification pathway 5 and the oxygen carrier recovery pathway 6, and run for several cycles; after closing the non-whole liver purification pathway 5, keep the oxygen carrier recovery pathway 6 running for 1 to 2 cycles; finally, close the oxygen carrier recovery pathway 6 and end the current usage cycle.

[0065] Plasma circulates in multiple pathways. Before ending the current usage cycle, it is necessary to ensure that the plasma in each pathway has returned to the blood storage tank 3. The plasma is then collected in the blood storage tank 3 and returned to the recipient 1. According to the characteristics of each pathway, in this embodiment, the first valve 44 is used to close the whole liver purification pathway 4. Then, the second valve 54 is controlled to run the non-whole liver purification pathway 5 at maximum throughput. When it is necessary to open the oxygen carrier recovery pathway 6, the third valve 64 is controlled to run at maximum throughput, so that the plasma in the bioartificial liver can circulate several times to intercept immunogens or exogenous cell debris.

[0066] S4, in specific applications, also includes a limited purification mode, where plasma purification is achieved only by activating the non-whole liver purification pathway 5. Specifically, when the whole liver purification pathway 4 is closed, only the non-whole liver purification pathway 5 is activated, and the second valve 54 operates at maximum throughput. This mode can accommodate the temporary addition or discontinuation of the whole liver purification pathway 4, facilitating temporary adjustments to it. When patient needs are met, only the non-whole liver purification pathway 5 can be used. This further demonstrates the multi-mode combination feature of the bioartificial liver system of this application.

[0067] In summary, this application provides a multi-mode combined bioartificial liver system, comprising: a plasma separation pathway, including a plasma separator, an arterial conduit connecting the inlet of the plasma separator to the recipient artery, and a venous conduit 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 via a drainage conduit, and the outlet of which is connected to the venous conduit via a return conduit; a whole liver purification pathway, including a whole liver perfusion device, a pre-hepatic conduit connecting the inlet of the whole liver perfusion device to the outlet of the blood storage tank, a post-hepatic conduit connecting the outlet of the whole liver perfusion device to the inlet of the blood storage tank, and a first valve, a first pressure sensor, and an oxygenator containing an oxygen carrier disposed on the pre-hepatic conduit, and a second pressure sensor disposed on the post-hepatic conduit. Sensors; a non-whole liver purification pathway, including 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 disposed on the pre-reactor pipeline; an oxygen carrier recovery pathway, including 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 disposed on the pre-recovery pipeline; a controller, used to control the flow 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.

[0068] This application also provides a control method for a multi-mode combined bioartificial liver system, applied to the multi-mode combined bioartificial liver system as described above, comprising the following steps: after receiving fluid input from the inlet blood line in the current usage cycle until the liquid level in the blood storage tank reaches the lower limit position, the whole liver purification pathway is activated in the debugging mode until the perfusion pressure of the whole liver reaches a preset value; the non-whole liver purification pathway is activated so that the liquid level in the blood storage tank does not exceed the upper limit position and is not lower than the lower limit position, thereby realizing the full purification mode; before the end of the current usage cycle, the whole liver purification pathway is closed first, and then the non-whole liver purification pathway is closed.

[0069] The multi-mode combination bioartificial liver system and control method of this application, by using a blood storage tank as a plasma transfer point, can rationally allocate the plasma purification pathway by controlling the flow rate 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 this application.

[0070] Those skilled in the art will understand that the steps, measures, and solutions in the various operations, methods, and processes discussed in this application can be alternated, modified, combined, or deleted. Furthermore, other steps, measures, and solutions in the various operations, methods, and processes discussed in this application can also be alternated, modified, rearranged, decomposed, combined, or deleted. Furthermore, steps, measures, and solutions in related technologies that are similar to those disclosed in this application can also be alternated, modified, rearranged, decomposed, combined, or deleted.

[0071] In the description of this application, the terms "center," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," and "outer," etc., indicate directions or positional relationships based on the exemplary directions or positional relationships shown in the accompanying drawings. They are used to facilitate the description or simplification of the embodiments of this application and are not intended to indicate or imply that the device or component referred to must have a specific orientation or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this application.

[0072] The terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this application, unless otherwise stated, "a plurality of" means two or more.

[0073] In the description of this application, it should be noted that, unless otherwise expressly specified and limited, the terms "installation," "connection," and "joining" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal communication between two components. Those skilled in the art can understand the specific meaning of the above terms in this application based on the specific circumstances.

[0074] In the description of this specification, specific features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples.

[0075] The above description is only a partial embodiment of this application. It should be noted that for those skilled in the art, other similar implementation methods based on the technical concept of this application, without departing from the technical concept of this application, also fall within the protection scope of the embodiments of this application.

Claims

1. A multi-modal bioartificial liver system, characterized in that, include: The plasma separation pathway includes a plasma separator, an arterial conduit connecting the inlet of the plasma separator to the recipient artery, and a venous conduit 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 via a lead-in line, and the outlet of which is connected to the venous line via a return line; The whole liver purification pathway includes a whole liver perfusion device, a pre-hepatic tubing connecting the inlet of the whole liver perfusion device to the outlet of the blood storage tank, a post-hepatic tubing 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 installed on the pre-hepatic tubing, and a second pressure sensor installed on the post-hepatic tubing. The non-whole liver purification pathway includes 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 installed in the pre-reactor pipeline. The oxygen carrier recovery path includes 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 installed in the pre-recovery pipeline. The controller is used to control the flow of the first valve, the second valve, and the third valve based on input instructions and feedback data, wherein the feedback data includes data from various pressure sensors.

2. The multi-mode combined bioartificial liver system as described in claim 1, characterized in that, The purification reactor includes at least one purification element among hepatocyte bioreactor and non-biological blood purifier.

3. The multi-mode combined bioartificial liver system as described in claim 2, characterized in that, When the purification reactor includes two or more purification units, the different purification units are connected in parallel or in series.

4. The multi-mode combined bioartificial liver system as described in claim 1, characterized in that, The blood storage tank is equipped with a liquid level sensor, which is set at a preset upper and lower liquid level position to generate a liquid level signal and send it to the controller.

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

6. The multi-mode combined bioartificial liver system as described in claim 1, characterized in that, 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, which performs the functions of the first valve, the second valve, and the third valve.

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

8. The multi-mode combined bioartificial liver system as described in claim 1, characterized in that, At least one peristaltic pump is installed on each of the plasma separation pathway, whole liver purification pathway, non-whole liver purification pathway, and oxygen carrier recovery pathway.

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

10. The multi-mode combined bioartificial liver system as described in claim 1, characterized in that, The whole-liver perfusion device includes a non-human liver and a perfusion support chamber, with the pre-hepatic and post-hepatic tubing connected to the non-human liver through the chamber.

11. A control method for a multi-mode combined bioartificial liver system, characterized in that, The bioartificial liver system applied to the multimodal combination as described in any one of claims 1 to 10 includes the following steps: After the current cycle receives the liquid input from the blood inlet line until the liquid level in the blood storage tank reaches the lower limit position, the whole liver purification pathway is opened in the debugging mode until the perfusion pressure of the whole liver reaches the preset value. The non-full 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 achieve the full purification mode. Before the current usage cycle ends, the whole liver purification pathway is closed first, followed by the non-whole liver purification pathway.

12. The method as described in claim 11, characterized in that, In cases where oxygen carrier recovery is required before the end of the current usage cycle, including: Close the whole liver purification pathway, open the non-whole liver purification pathway and the oxygen carrier recovery pathway, and run several cycles. Close the non-whole liver purification pathway and keep the oxygen carrier recovery pathway running for 1 to 2 cycles; Close the oxygen carrier recovery pathway and end the current usage cycle.

13. The method as described in claim 11, characterized in that, It also includes a limited purification mode, which includes closing the whole liver purification pathway and opening the non-whole liver purification pathway at maximum flow rate using the second valve.

14. The method as described in claim 11, characterized in that, The step of activating the whole liver purification pathway in debug mode until the perfusion pressure of the whole liver reaches a preset value includes: activating the first valve, closing the second valve and the third valve, wherein the flow rate of the first valve is adjusted according to the feedback data of the first pressure sensor and the second pressure sensor.

15. The method as described in claim 11, characterized in that, In the full purification mode, the third valve remains closed or is intermittently opened.

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

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