Bio-artificial liver

Abstract

A bioartificial liver support system for continuous and discontinuous procedures to provide liver support to a patient, comprising: a chamber containing biomass; a tubular system having multiple circuits adapted to provide independent circuit operation to an apheresis machine or patient; and a monitoring device having one or more sensors adapted to collect, record, analyze, download, and / or store data from the system.

Description

Technical Field

[0001] The present invention relates to the field of extracorporeal liver perfusion, and more particularly to bioartificial livers.

Background Art

[0002] Currently, the main treatment for acute and chronic liver diseases and liver failure is transplantation. However, such transplantation has the problem of being limited by the availability of donor organs. Therefore, in the case of patients with liver diseases or liver failure, a device that can temporarily perform the functions of the patient's liver and keep the patient alive until a suitable donor organ is found, or a device that can provide an environment that can surely support the patient while the patient's own liver recovers sufficient functions for survival is urgently needed.

[0003] To meet the above needs, two types of devices, namely, purely artificial liver machines and bioartificial liver machines, have been manufactured. Both types of machines rely on perfusion of the patient's plasma or blood into an extracorporeal circuit over a period of 6 hours or more.

[0004] Purely artificial liver machines are essentially physical or chemical and typically provide detoxification functions by adsorption or exchange using, for example, resins, charcoal, ion exchange columns, and / or albumin.

[0005] Bioartificial livers contain biological components such as hepatocytes, either alone or as a hybrid system in combination with an artificial device. Such systems typically use either human or animal (e.g., pig) hepatocytes.

[0006] Bioartificial livers using hollow fiber cartridges in which cells are separated from plasma or whole blood by a membrane have been developed.

[0007] European Patent No. 2170429 relates to a system capable of housing a biological chamber to form a bio-artificial liver. [Overview of the Initiative]

[0008] One of the problems associated with previous devices is the requirement that the bio-artificial liver device must be constantly connected to the patient and / or apheresis machine, otherwise requiring a restart. This invention seeks to address this problem.

[0009] According to a first aspect, a bioartificial liver support system is provided for continuous and discontinuous procedures to provide liver support to a patient, comprising: a chamber containing biomass; a tubing system having a plurality of circuits adapted to provide independent circuit operation to an apheresis machine or patient; and a monitoring device having one or more sensors adapted to collect, record, analyze, download, and / or store data from the system.

[0010] Preferably, the monitoring device further comprises a graphical user interface adapted for displaying data.

[0011] Preferably, the monitoring device comprises one or more sensors and a graphical user interface.

[0012] Preferably, the system allows a fluid containing, but not limited to, total plasma to perfuse biomass confined within a chamber in a fluidized bed configuration.

[0013] Preferably, the system can operate over a long period of time, such as several days.

[0014] Preferably, the chamber is sterile and / or disposable.

[0015] Preferably, the chamber comprises a base plate and a cylindrical wall.

[0016] In one embodiment, the chamber is given by the following formula: y = -0.00005ln(x) + 0.00036(correlation(R) 2 The value is 0.97085. Accordingly, at a flow rate of 320 ml / min, 3.67 × 10 at 1 mm above the base plate. -4 From m / s, it decreases with increasing cross-sectional area height, resulting in 2.58 × 10 at 10 mm. -4 It has an average flow velocity of up to m / s (1-10 mm above the base plate).

[0017] Preferably, if the chamber has an average flow rate according to the above parameters, this allows for satisfactory fluidization of the biomass within the chamber. Furthermore, the advantage of the above average flow rate (i.e., obtained with a fluid flow rate of 320 ml / min) is that it ensures a uniform distribution of flow through the chamber and the fluidized biomass, which affects cell proliferation both during biomass preparation and when the system is used for patient treatment. Without the above parameters, mass transfer is impaired, and channels may appear within the biomass that allow plasma flow to bypass the biomass, preventing the patient from benefiting from a fully functional biomass treatment. Moreover, without the above parameters, optimal fluidization of the biomass is not achieved within the system.

[0018] The fluid flow rate within the chamber is preferably in the range of 250 to 450 ml / min.

[0019] Preferably, the system is adapted to be able to operate independently of the apheresis machine and / or the patient. Preferably, the system is operable independently of the patient and / or the apheresis machine. Preferably, the system can be operated for several days when not connected to the patient or the apheresis machine. Preferably, the system is adapted to provide oxygen addition and / or filter replacement whether connected or not to the patient and / or the apheresis machine. Preferably, the system is adapted to provide temperature management.

[0020] Preferably, the system comprises a plurality of pumps. Preferably, the pumps operate during the operation of the system. Preferably, providing pumps adapted to operate during the operation of the system means that the biomass within the system remains viable.

[0021] Preferably, the system comprises a bypass circuit design.

[0022] Preferably, providing a pump and one or more bypass circuits within the system means that the system can operate independently of the apheresis machine (e.g., the system does not rely on one or more pumps provided within the apheresis machine).

[0023] Preferably, the system of the present invention enables continuous and discontinuous treatments that provide liver support and operate over a long period of several days, regardless of whether it is connected to the apheresis machine or the patient.

[0024] Preferably, the system has three circuits, and each circuit operates at a different speed. Preferably, the system comprises a high-speed circuit, a low-speed circuit, and a saline circuit.

[0025] Preferably, the system has three color-coded circuits and three bypass lines.

[0026] Preferably, the system comprises a patient bypass circuit design that enables the system to operate independently of the apheresis machine and / or the patient. Preferably, the combination of the pump and the patient bypass circuit design enables the system to operate independently of the patient and / or the apheresis machine.

[0027] In one embodiment, the bypass design may be adapted to stop the low-speed circuit while keeping the high-speed circuit in an operating state. In one embodiment, the saline bypass design may be adapted to stop the low-speed circuit while keeping the high-speed circuit and the saline circuit in an operating state. Preferably, providing the pump and the plurality of bypass circuits means that the flow through the system does not stop and thus prevents clotting from occurring.

[0028] Preferably, two circuits are connected via a splitter circuit to provide a flow split that depends on the set pump flow rate.

[0029] Preferably, the chamber is disposable. Preferably, the chamber is sterile. Preferably, the system delivers biological functions by excellent mass transfer of chemicals in the contained biomass between the chamber and the temperature-controllable circulating fluid in the tube system.

[0030] Preferably, the system comprises tubes. Preferably, the tubes in the system are sterile. Preferably, the tubes may be transparent.

[0031] Preferably, the system is adapted to monitor the in-line pressure, temperature, oxygen and fluid levels within the system. Preferably, the system is also adapted to measure one or more parameters such as pump speed, dissolved oxygen and / or bubble trap status.

[0032] Preferably, the system includes a safety mechanism to prevent untreated fluid from re-entering the patient's circulation. Preferably, the safety mechanism includes a one-way valve. Preferably, the system includes a one-way valve to ensure there is no backflow in the fluid pathway and no mixing of treated and untreated fluids. Preferably, the one-way valve prevents untreated plasma from returning to the patient.

[0033] Preferably, the chambers within the system can be rapidly replaced while connected to or disconnected from a patient or apheresis machine. Typically, the chambers are adapted to allow aseptic biomass inflow and outflow.

[0034] Preferably, the system functions as a perfusion system that mimics the relationship between portal vein and peripheral venous flow.

[0035] Preferably, the system includes multiple ports to allow inflow and outflow from the system in a sterile manner.

[0036] Typically, the chamber comprises (a) multiple biomass sampling ports, (b) an inlet, (c) an outlet, (d) a drain port, (e) oxygen inlet / outlet ports, (f) biomass inlet / outlet ports, (g) one or more filters, (h) a flow distributor, (i) air inlet / outlet vents to allow pressure release from the chamber, and / or (j) a thermal pocket for housing a temperature probe. Preferably, the sampling ports are located at different heights relative to the biomass in the chamber.

[0037] In one embodiment, the chamber may be injection molded.

[0038] Preferably, the chamber is cryogenically preserved.

[0039] Preferably, the system uses fresh, cryopreserved, and / or cryopreserved biomass and allows for the rapid delivery of temporary liver support to the patient using approximately 30–70% hepatocyte aggregates.

[0040] The chamber is preferably sized to hold hydrogel-encapsulated biomass equivalent to 30-70% of the number of human liver cells, which typically corresponds to 70 billion cells as organoids.

[0041] Preferably, the chamber includes a double-coiled gas-permeable oxygen supply path that can be connected to an oxygen supply source via an external port on the chamber.

[0042] Preferably, the chamber is provided with vents to allow for easy priming and discharge of the fluid and equalization of the pressure.

[0043] Typically, the chamber is adapted to cultivate biomass and then recover the biomass after cryopreservation before use in the system.

[0044] The chamber is preferably used to provide a fluidized bed having a height-to-diameter ratio of up to 2:1.

[0045] Preferably, the system housing is coated with an antimicrobial material.

[0046] Preferably, the system is adapted to allow for pressure equalization within the system. Preferably, this feature allows for pressure equalization in situations where there is a mismatch in pump speeds (for example, which may occur when the system is connected to an apheresis machine).

[0047] Preferably, the system includes vents to allow for the release of oxygen and other gases.

[0048] Preferably, the system is adapted to allow the replacement of modular filters using a bypass circuit design without impeding performance. Preferably, the system is adapted to operate simultaneously when recirculating, priming, or flushing separate filters.

[0049] Preferably, the system comprises one or more functional filters and / or one or more safety filters.

[0050] Preferably, the system includes a functional filter bypass that allows for the bypass of a functional filter, rather than a safety filter, as needed.

[0051] Preferably, the system allows for sample collection and sample / fluid addition via an injectable needle-free fluid port.

[0052] Preferably, the system comprises a Y-shaped component and a splitter reservoir having an internal filter for capturing leaked particles with a diameter greater than approximately 270 μm and for equalizing the pressure rise during the priming and / or treatment phases.

[0053] Preferably, the system is adapted to provide removal of DNA and endotoxins from the circulating fluid.

[0054] Preferably, a graphical user interface allows medical professional operators to save, permanently store, and / or download data.

[0055] Preferably, the graphical user interface includes a display that provides the following information: time, pump flow rate, temperature in the chamber, fluid or air present in the level detector, individual pressures and pressure trends across pressure transducers throughout the tube circuit, pressure differences between articles positioned in the circuit, and / or the level of dissolved oxygen in the high-speed flow circuit.

[0056] Preferably, the graphical user interface is adapted to show the temperature inside the chamber as a function of time.

[0057] Preferably, the graphical user interface is adapted to show the actual pressure difference across the chamber and / or filter set as a trend over time.

[0058] Preferably, the graphical user interface includes an alarm system to notify the user if a fault occurs in the system. Preferably, the alarm may be an audible, visual, or voice alarm. Preferably, the alarm can be activated if the temperature inside the chamber is outside the required range during system operation, or if the dissolved oxygen level in the high-speed flow circuit is outside the required range. In one embodiment, the graphical user interface warns the user according to the alarm status.

[0059] Preferably, a graphical user interface records system performance using inline / online monitoring. Preferably, a monitoring device comprising sensors and a graphical user interface is adapted to monitor parameters including, for example, temperature, pH, dissolved oxygen, glucose levels, and / or other metabolic levels.

[0060] Preferably, the system includes an air / liquid component that can be discharged or filled during system operation. In one embodiment, the air / liquid component may be monitored by an ultrasonic detection system.

[0061] Preferably, the system includes a light for illuminating the chamber. Preferably, the light allows the user to observe and determine the floor level of the biomass, for example, to optimize mass transfer.

[0062] Preferably, the system includes means for reducing or increasing the level of ambient light within the system. In one embodiment, the means for reducing or increasing the level of ambient light is a switch or a button. Preferably, by providing means for reducing or increasing the level of ambient light within the system, the system can respond to the difference in ambient background light between day and night, for example, to meet the patient's comfort expectations.

[0063] Preferably, the alarm sound can be reduced to accommodate the difference in ambient noise between day and night. Preferably, the alarm sound can be reduced or muted. Preferably, the system includes a button or switch for muting or reducing the alarm sound. In one embodiment, the alarm may be muted for about one minute before being restarted. Preferably, the alarm signal is reset when the alarm condition is resolved.

[0064] Preferably, the system is housed in a unit with four lockable wheels. Preferably, the system is mobile and can be moved so that it can be positioned in a desired location. Preferably, the system can operate at the patient's bedside.

[0065] Preferably, the system includes a handle or push rail. Preferably, the handle or push rail is positioned at a height substantially adjacent to an individual's waist. Preferably, the handle or push rail is positioned at an intermediate height to allow for easy movement of the system (for example, by pushing or pulling the system). Preferably, the system is housed within a unit to protect the electronic equipment and mechanisms contained within the unit.

[0066] Preferably, the unit comprises two doors that open to about 180 degrees. Preferably, the doors may be made of a transparent material. Preferably, the doors may be made of glass or plastic material. Preferably, transparent glass or plastic doors allow the user to monitor the components within the system.

[0067] Preferably, the unit includes a drawer for storing consumable parts and an instruction manual.

[0068] Preferably, the unit includes one or more (typically three) access hatches to allow access to the system's electrical and electronic components. Typically, the access hatches are located at the rear of the unit.

[0069] Preferably, the system includes a surge protector and a dipole switch. Preferably, a dipole switch can be provided to ensure that the electrical connection to the trunk line leads only to the correct connection. Preferably, the surge protector and dipole switch are located at the rear of the system. Preferably, the surge protector and dipole switch are located between the commercial power supply and the system. Preferably, the dipole switch and surge protector are first items located between the commercial power supply and the system. Preferably, the surge protector and dipole switch are first items in the trunk cable from the electric trunk power supply. Preferably, the surge protector and dipole switch are medical grade approved.

[0070] Preferably, the system includes an eight-outlet commercial power strip.

[0071] Typically, the system includes a 24-volt power supply for the graphical user interface.

[0072] Preferably, the system includes a 5-volt power supply to the ultrasonic detector.

[0073] Preferably, the system includes one or more holders for power cables and oxygen supply tubes when not in use.

[0074] Preferably, the system includes a chamber holder. Preferably, the chamber holder allows for easy chamber swapping and prevents the chamber from tipping over and / or moving during use. Preferably, the chamber holder allows the chamber to be held in an orientation that allows for better fluidization, and therefore better mass transfer.

[0075] Preferably, the system includes at least one tube holder to prevent / reduce the risk of damage to the tubes within the system during system operation. Preferably, at least one tube holder is configured to hold the tubes in different orientations as required.

[0076] Preferably, the system includes holders for a plasma bag, a saline bag, and / or a waste fluid bag.

[0077] Preferably, the system includes an electronic preparation section for connecting six pressure transducers.

[0078] Preferably, the system includes one or more holders for filter mounting.

[0079] Typically, the system includes a tube diagram on the internal rear panel of the system. Preferably, the tube diagram allows the user to ensure that the tubes are correctly positioned within the system.

[0080] Preferably, the system includes a blood warmer for maintaining the circuit temperature within the system.

[0081] Preferably, the system includes colored and white clamps on the tube to distinguish their functions.

[0082] Preferably, the system is a mobile workstation that enables long-term continuous operation whether connected to or disconnected from a patient, and comprises a disposable, cryopreservable oxygenated fluid bed bioreactor chamber containing cells and / or organoids, a temperature probe, a reservoir for total plasma or circulating fluid, a set of tubes containing multiple filters and pressure transducers, an integrated filter, a dissolved oxygen probe, a tube holder, a pump, a graphical user interface for performance monitoring, and an ultrasonic air / level detector.

[0083] Preferably, the system includes a sensor cover. Preferably, the sensor cover prevents interference from ambient light.

[0084] Preferably, the normal operating range, warning range, and action request range of the system are visually observed in green, amber, and red.

[0085] Preferably, a thermal cover is provided around the outside of the chamber, which functions to maintain a uniform temperature inside the chamber.

[0086] According to a second aspect, a method is also provided for providing continuous and discontinuous treatments to a patient that provide liver support using the system according to the first aspect.

[0087] The present invention will be further described with reference to the following drawings, as an example. [Brief explanation of the drawing]

[0088] [Figure 1] This is a front view of the system according to one embodiment of the present invention. [Figure 2] This is a front view of the internal components of the system according to one embodiment of the present invention. [Figure 3] This is a rear view of the system according to one embodiment of the present invention. [Figure 4]This is a schematic diagram of a system according to one embodiment of the present invention. [Figure 5] This is a schematic diagram of a system according to one embodiment of the present invention. [Figure 6a] This is a side view of the chamber according to one embodiment of the present invention. [Figure 6b] This is a front perspective view of a chamber according to one embodiment of the present invention. [Figure 6c] This is a front view of the chamber according to one embodiment of the present invention. [Figure 7] This is a schematic diagram of a high-speed circuit according to one embodiment of the present invention. [Figure 8] This is a schematic diagram of a low-speed circuit according to one embodiment of the present invention. [Figure 9] This is a schematic diagram of a saline solution circuit according to one embodiment of the present invention. [Figure 10] This is a schematic diagram of a high-speed circuit according to one embodiment of the present invention, showing sections 1 to 7. [Figure 11] This is a schematic diagram of section 1 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 12] This is a schematic diagram of section 2 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 13] This is a schematic diagram of section 3 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 14] This is a schematic diagram of section 4 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 15] This is a schematic diagram of section 5 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 16] This is a schematic diagram of section 6 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 17] This is a schematic diagram of section 7 of the high-speed circuit shown in Figure 10, according to one embodiment of the present invention. [Figure 18] This is a schematic diagram of a low-speed circuit according to one embodiment of the present invention, showing sections 1 to 5. [Figure 19] This is a schematic diagram of section 1 of the low-speed circuit shown in Figure 18, according to one embodiment of the present invention. [Figure 20] This is a schematic diagram of section 2 of the low-speed circuit shown in Figure 18, according to one embodiment of the present invention. [Figure 21] This is a schematic diagram of section 3 of the low-speed circuit shown in Figure 18, according to one embodiment of the present invention. [Figure 22] This is a schematic diagram of section 4 of the low-speed circuit shown in Figure 18, according to one embodiment of the present invention. [Figure 23] This is a schematic diagram of section 5 of the low-speed circuit shown in Figure 18, according to one embodiment of the present invention. [Figure 24] This figure shows a one-way check valve that can be used according to one embodiment of the present invention. [Figure 25a] This figure shows a tube holder that can be used according to one embodiment of the present invention. [Figure 25b] This figure shows a tube holder that can be used according to one embodiment of the present invention. [Figure 26a] This figure shows a peristaltic pump that can be used with a high-speed circuit according to one embodiment of the present invention. [Figure 26b] This figure shows a peristaltic pump that can be used with a low-speed circuit according to one embodiment of the present invention. [Figure 26c] This figure shows a peristaltic pump that can be used with a saline circuit according to one embodiment of the present invention. [Figure 27] This is a graph showing the differential pressure measured within the system of the present invention. [Figure 28] This is a graph showing temperature and oxygen level measurements within the system of the present invention. [Figure 29] This graph shows the results from high-speed and low-speed pumps measured within the system of the present invention, as well as the bubble trap. [Figure 30] This graph shows the measured cell viability values ​​determined using the system of the present invention. [Figure 31] This is a graph showing the corrected glucose change measured within the system of the present invention. [Figure 32]This graph shows the changes in lactate dehydrogenase measured within the system of the present invention. [Figure 33] This graph shows the change in alkaline phosphatase measured within the system of the present invention. [Figure 34] This is a schematic diagram of a layout provided on a graphical user interface according to one embodiment of the present invention. [Figure 35] This is a schematic diagram of an electronic device system according to one embodiment of the present invention. [Figure 36] This is a schematic diagram illustrating the functionality of a system according to one embodiment of the present invention. [Figure 37] This graph shows the average flow velocity inside the chamber according to one embodiment of the present invention. [Modes for carrying out the invention]

[0089] The reference numbers used in the following description relate to the following components. 2. Bio-artificial liver (BAL) support system 4. Chamber 6. Tube System 8. Graphical User Interface (GUI) 20. Wheels 24. Handle 26. One-way valve 28. Peristaltic pump 40. Tube holder 50.High speed circuit 52.Low speed circuit 54. Physiological saline circuit 56. Bypass Circuit 60. Safety filter 62. Pressure transducer 100. Filter 101. Hydrophobic filter 102. Clamp 104. Cap 106. Female Lure Lock (FLL) 107. Male Lure Lock (MLL) 108. Rotating Male Lure Lock (RMLL) 110. Air trap chamber 114. Pump tubing 116. Blood warming tube

[0090] Referring to the drawings, a bioartificial liver support system 2 is provided for continuous and discontinuous procedures to provide liver support to a patient, comprising a chamber 4 containing biomass, a tube system 6 having multiple circuits adapted to provide (multiple) independent circuit operations, and a monitoring device having one or more sensors adapted to collect, record, analyze, and store data from the system.

[0091] Referring to the drawings, the monitoring device preferably further comprises a graphical user interface (GUI) 8 adapted for displaying data.

[0092] The monitoring device preferably comprises one or more sensors and a graphical user interface, and is adapted to collect, record, analyze, store, and display data from the system.

[0093] In one embodiment, the present invention relates to a liver support system that can be used to treat patients suffering from liver failure.

[0094] Chamber 4 is a disposable biocartridge, as shown in Figure 6, adapted to hold alginate-encapsulated liver-derived cells, which are spheroids, and to create a microgravity environment through its function as a fluid-bed bioreactor. It is used during three different stages, the first two of which are during the production of ATMP (Advanced Therapeutic Drug) biomass. The first stage is the proliferation of biomass cells into microspheroids as microbeads are fluidized in the chamber, which is connected to a reservoir (bioreactor reservoir) for recirculation. The second stage is the retrieval of cells after cryopreservation in a cryobag or the chamber itself. In the third stage, the chamber is used in a workstation to provide the patient with some of the functions of a bioartificial liver, via its connection to a giving set and via an apheresis machine.

[0095] Chambers are typically manufactured from medical-grade materials, namely injection-molded cyclic olefin copolymers, 316 stainless steel, and medical-grade silicone used for gas tubing (platinum-hardened USP Class VI) and silicone gaskets.

[0096] The chamber design allows for sterile bead sampling, addition and removal of hydrogel beads while maintaining sterility, oxygenation, temperature monitoring, and fluidization of the bead biomass.

[0097] The chamber is given by the following formula: y = -0.00005ln(x) + 0.00036(correlation(R) 2 The value is 0.97085. Accordingly, at a flow rate of 320 ml / min, 3.67 × 10 at 1 mm above the base plate. -4 From m / s, it decreases with increasing cross-sectional area height, resulting in 2.58 × 10 at 10 mm. -4 It is preferable to have an average flow velocity of up to m / s (1-10 mm above the base plate).

[0098] Figure 37 shows a graph illustrating the average velocity inside the chamber according to one embodiment of the present invention.

[0099] Preferably, if the chamber has an average flow rate according to the above parameters, this allows for satisfactory fluidization of the biomass within the chamber. The advantage of the above average flow rate (obtained with a fluid flow of 320 ml / min) is that it ensures a uniform distribution of an optimal level of flow through the chamber and the fluidized biomass, which affects cell proliferation both during biomass preparation and when the system is used for patient treatment.

[0100] Preferably, the fluid flow rate range is 250 to 450 ml / min.

[0101] The disadvantage of not operating within the above parameters is that if the best fluidization of the biomass is not achieved, mass transfer will be impaired, and channels may emerge that allow plasma flow to bypass the biomass, preventing the patient from benefiting from a fully functional biomass treatment.

[0102] It will be understood that the average velocity will vary with different flow rates of liquid passing through the chamber. Although the average velocity value will change, the relationship between the values ​​1 mm above the base plate and 10 mm above the base plate remains the same as defined above.

[0103] In one embodiment, temperature stability within the chamber can be enhanced by the use of a thermal cover for the chamber provided within the system.

[0104] Furthermore, the system may be equipped with one or more sensor covers to prevent interference from ambient light.

[0105] All components of the bioartificial liver are connected via a "fluid supply set" of tubing, which is also connected to the apheresis machine, and the apheresis machine is then connected to the patient. Three flow circuits exist: a treatment (high-speed) circuit consisting of a high-speed circuit that operates at a flow rate approximating the flow rate of blood flow through the liver; a low-speed circuit that operates at a flow rate matching the plasma flow rate from the apheresis machine, where the plasma flow rate depends on the total blood flow from the patient, along with the patient's hematocrit (e.g., the ratio of the patient's plasma to blood cells); and a saline circuit used for bypass and priming purposes. Each type of circuit has an element of peristaltic pump tubing that connects to a peristaltic pump 28 specific to the particular circuit to which it belongs. There are fluid inlet route connections and outlet line route connections (i.e., the line returning to the patient via the apheresis machine) to allow attachment from the patient to the apheresis machine. A diagram of the fluid transfer through the system is shown in Figure 4.

[0106] Chamber 4 is located within the high-speed circuit. The high-speed circuit is where the patient's plasma is processed and operates approximately 10 times faster than the low-speed circuit. The safety filter (60) and functional filter (100) are located within the low-speed circuit, which returns the plasma to the patient. From the low-speed circuit, the processed plasma is typically delivered to an apheresis machine, where the cellular components of the blood are restored, and then returned to the patient. The saline circuit allows for the recirculation of the functional filter via a peristaltic pump if the low-speed circuit must be temporarily stopped. The saline circuit also allows for heparinization of the filter as needed, particularly during filter change intervals. The system typically comprises two sets of two filters (60 and 100) that can be used in parallel, thus allowing for filter replacement or switching during processing. To replace the filter, the primary filter may be clamped so that the flow can be transferred to the secondary filter.

[0107] Figure 5 shows schematic diagrams of the high-speed circuit 50, the low-speed circuit 52, the saline solution circuit 54, and the bypass circuit 56.

[0108] The fluid supply set typically includes six pressure transducers for pressure monitoring to alert the user if filter replacement may be necessary. Dissolved oxygen consumption of the biomass is monitored using an in-line oxygen sensor. The bio-artificial liver biomass requires oxygen to maintain viability, and when oxygen drops to a critical point, oxygen is replenished directly into the biomass chamber using gas diffusion through thin-walled silicone tubing.

[0109] The one-way valve 26 is positioned in the patient bypass line, which allows only treated plasma that has passed through the safety filter and functional filter to return to the high-speed circuit as needed, while blocking the flow of the opposite fluid. Thus, the one-way valve prevents untreated plasma from returning to the patient.

[0110] Therefore, a "fluid supply set" is a disposable, sterile tubing set manufactured for connection to a workstation's biomass cartridge and a plasma exchange device for clinical practice.

[0111] Most of the tubing in a fluid supply set is made from medical-grade polyvinyl chloride (PVC) material. PVC tubing is a transparent, flexible tubing widely used as a component of medical products due to its chemical compatibility and manufacture from non-toxic resins, as well as its smooth inner and outer surfaces that prevent deposit buildup and reduce the possibility of bacterial infection. PVC tubing also does not contain plasticizers.

[0112] When a peristaltic pump is used, specific peristaltic pump tubing is used instead of PVC tubing. The peristaltic pump tubing allows the pump to create flow around the fluid supply set circuit. The peristaltic pump tubing preferably contains pharmed BPT material or an equivalent material.

[0113] Preferably, the system includes a bypass circuit design that allows the system to operate independently of the apheresis machine and / or the patient. Preferably, the combination of the pump and the bypass circuit design allows the system to operate independently of the patient and / or the apheresis machine.

[0114] The system also includes male and female Luer connectors. These connectors are required to make connections at discontinuous tubing sections in all fluid supply sets. Preferably, connections can only be made from male to female orientation to prevent mispositioning of the tubing. Furthermore, other components within the system are connected via these connectors (e.g., connections to pressure transducers, bags, and plasmapheresis devices). The system also includes "rotating Luer" connectors that allow for more stable or permanent connections between different components, thereby reducing the possibility of accidental disconnection of tubing.

[0115] The system also features multiple T-shaped connectors and / or adapters, and T-shaped tube fittings for connecting different tube loops. The joints are created by inserting the tubes into the connectors and bonding the solvent. If the tubes being connected are of different sizes, they are called adapters.

[0116] The system also features multiple Y-shaped connectors / adapters, with two types of Y-shaped tube fittings for connecting different tube loops to each other. The first type is a lure-free connector, with two symmetrical upper branches at the top, spaced approximately 60 degrees apart. All joints are formed by inserting and bonding the tube into the connector. The second type is similar, however, the main part of the Y-shaped connector in this case is linear, with a single branch at an angle of approximately 30 degrees on one side, which can form a joint by rotating a male lure in place. These connectors are known as adapters when the tubes to be connected are of different sizes.

[0117] The system also includes a saline bag, which is a standard saline bag for intravenous injection of the patient. This is used for saline recirculation of the functional filter and safety filter, as well as for re-heparinization of the functional filter. The waste bags are two 3-liter bags located in the slow circuit for collecting waste during the priming and treatment phases. The waste arises from the initial priming, functional recirculation, and re-heparinization of the circuit.

[0118] Drip chambers are provided within the system to serve different functions for fluid supply sets in different parts of the circuit. A fluid supply set typically includes an inverted drip chamber with two drip chambers positioned between two Y-shaped connectors. The inverted drip chamber includes a filter with a cover cap located on top, the filter having a length of approximately 60 mm and a diameter of approximately 10-15 mm. In one embodiment, the inverted drip chamber is bonded to a tube (high-speed circuit tube) with an outer diameter of 6.8 mm.

[0119] The system also features a high-speed-low-speed circuit splitter chamber located within the high-speed circuit. It has a single downward flow inlet coming from an inverting drip chamber and a dual upper outlet that allows the flow to be split between the high-speed and low-speed circuits. The outlet ports connect to sensors in the high-speed circuit and the low-speed circuit.

[0120] The system also includes an air trap / level sensor, i.e., a drip chamber placed in a low-speed circuit to prevent air bubbles from reaching the patient. There is no internal filter inside this drip chamber. The air trap / level sensor has a 0.2 μm sterile hydrophobic filter (101) at the top to allow air to be exhausted.

[0121] The system also includes a drip chamber for the saline bag, i.e., a simple spiked through-flow chamber placed in the saline circuit for observing the droplets.

[0122] A pressure transducer 62 located within the system converts the pressure waveform into an electrical signal. The six pressure transducers allow the operator to monitor the technical function of the bio-artificial liver circuit while the patient is connected. In one embodiment, the six pressure transducers are positioned in the fluid delivery set and used to monitor pressure rises that potentially indicate an obstruction in the circuit. If a filter is blocked or a clamp remains unintentionally closed, high-pressure readings are recorded. In one embodiment, the circuit uses a TruWave PX600 Edwards Sciences pressure transducer.

[0123] The one-way valve 26 allows fluid flow in only one direction but blocks fluid flow in the opposite direction. In one embodiment, the one-way valve (Figure 24) comprises polycarbonate and silicone. Typically, the one-way valve is lipid-resistant and exhibits resistance to stress cracking when in contact with lipid emulsions. The one-way valve has a female Luer lock inlet and a male Luer lock outlet. This is placed in the infusion set in the patient bypass line to prevent any plasma in the high-speed circuit from flowing back into the patient without passing through safety and functional filters.

[0124] Table 1 below shows the length tolerances for tubes that can be used in the fluid supply set, depending on the length of the tube used. [Table 1]

[0125] The high-speed circuit was divided into seven sections. Figure 10 shows the high-speed circuit, and the individual sections are shown in Figures 11 to 17.

[0126] The low-speed circuit was divided into five sections. Figure 18 shows the low-speed circuit, and Figures 19 to 23 show the individual sections of the low-speed circuit.

[0127] The various sections of the high-speed and low-speed circuits are prepared in individual bags for sterilization. Each section has a line drawing of that section on a label printed on the bag so that it can be matched with the instructions for use.

[0128] The system also includes vents to ensure that excess oxygen is removed from the workstation and does not accumulate. The location of these vents was chosen to be as close to the oxygen source as possible. The vents consist of four sections: a 3D-printed grommet inserted into a gap in the workstation frame, a micro-sponge-like membrane seated inside the grommet, and two micro-mesh sections that close the opening.

[0129] The system also features drawers that can be easily opened regardless of the main workstation door. The sides of the drawers serve as supports for the upper shelf on which the pump sits and are reinforced with extra material to prevent warping.

[0130] Workstations must have dipole switches and surge protectors in accordance with safety requirements for use in hospitals and clinical settings.

[0131] Data was collected and monitored during system operation. Such data included pressure, differential, oxygen, temperature, bubble trap status, and pump speed.

[0132] The system pressure thresholds are shown in Table 2 below. [Table 2]

[0133] The system comprises a functional filter and a safety filter 60. In one embodiment, the functional filter was a 3M Zeta Plus encapsulated filter 60ZB05A with a 340 cm² surface. The Zeta Plus filter is composed of cellulose and a positively charged resin that draws negatively charged contaminants from the fluid. The positive charge can reduce negatively charged DNA, endotoxins, and some proteins. However, the filter does not bind to patient-beneficial proteins such as albumin. The filter shape is lenticular, and various surface sizes are available. The 340 cm² surface filter size was selected for its high capacity with a relatively low dead volume (approximately 1 L). It complies with USP88 Class VI biological reactivity testing and has an FDA drug master file. The filter is 1020 cm² 2 A filter would also work.

[0134] In one embodiment, the safety filter was a Betafine 3M PPG series 0.6 μm 5-inch filter capsule. The safety filter performs size exclusion (0.6 μm) fluid particle filtration. The multilayer filter design with stepped porosity allows for the capture of larger particulate contaminants in the outer media layer. Thus, stepped particle filtration is present throughout the filter media. This extends the filter life (30-50%, depending on the application) compared to a uniform porous media filter.

[0135] Betafine filters are manufactured using an alternating pleat configuration that provides a larger open space (up to 50%) between the pleats. Advanced Pleating Technology (APT) allows for greater contaminant filling between the pleats in the inner diameter. The filter layer is based on polypropylene material, which is manufactured without adhesives and surfactants and provides a low extractable level when used with a suitable solvent.

[0136] With a flow rate of 9.1 liters / minute for water (2 gallons / minute), the differential pressure of a 5-inch Betafine filter is 0.1 bar (1.5 psi, 77.5 mmHg). Regarding pressure capacity, the maximum forward differential pressure the filter can withstand is 4 bar (3000 mmHg at 25°C), and the maximum operating pressure at 40°C is 4 bar. The recommended differential pressure for filter replacement is 2.4 bar (1800 mmHg).

[0137] The workstation contains three peristaltic pumps 28, and includes a graphical interface with a digital LCD to display pump performance. The pump located on the left is used for the high-speed circuit (pump 1), the pump located in the center is used for the low-speed circuit (pump 2), and the pump located on the right is used for the saline circuit (pump 3). The actual pumps and their positions within the workstation can be seen in Figure 1. Pumps 1 and 2 are connected to the GUI controller to monitor the flow rate applied during treatment. They are fitted with open-head sensors to stop the drive motor when the pump head is opened. Table 3 shows the maximum speeds of the three pumps. [Table 3]

[0138] The system typically comprises multiple optical sensors. The measurement principle of the optical sensors is as follows: LED light transmitted through an optical fiber excites an optical oxygen sensor, causing it to fluoresce. Oxygen partial pressure is independent of the oxygen level. The optical sensor measures oxygen partial pressure in either a dissolved or gaseous state. The optical sensor is integrated into the inner surface of a flow-through cell (T-shaped connector) that enables in-line measurement of oxygen partial pressure. The optical sensors are typically sterilized and pre-calibrated beforehand to be ready for use and to provide a non-invasive, non-contact technique. The system may further comprise at least one sensor cover.

[0139] The system typically features an access hatch located on the rear of the workstation.

[0140] The graphical user interface 8 includes a display that provides the following information: time, pump flow rate, temperature in the chamber, fluid or air present in the level detector, individual pressures and pressure trends across pressure transducers throughout the tubing circuit, pressure differences between items positioned in the circuit, and / or the level of dissolved oxygen in the high-speed flow circuit. During the procedure, the graphical user interface is used to monitor the procedure status. This is typically done in conjunction with controlling the pump flow rate, pressure, temperature, and patient status during the procedure. The graphical user interface may include a digital touchscreen that passively reads input from sensors to alert the user of any problems (e.g., pressure increase, abnormal oxygen levels, etc.) and is used to log data for post-procedure analysis, for example. An example of a display provided in the graphical user interface is shown in Figure 34.

[0141] Referring to Figure 34, the following information can be provided on the graphical user interface. 1. Individual pressure values 2. % Dissolved Oxygen (DO) Value 3. Temperature value 4. Information on bubble traps 5. High-speed pump speed value 6. Low-speed pump speed value 7. Differential pressure value The GUI can also provide the following information and / or control: 1. Alarm mute control 2. Main light brightness control 3. System (BAL) Light Control 4. Day / Night Mode 5. Data logging and download 6. Display of trends (e.g., oxygen / temperature trend, difference trend, pressure transducer trend) 7. Alarm demonstration (for example, allowing users to test alarms) 8. Patient / Hospital ID Data 9. Selecting a setup or treatment mode 10. User access level "Login" control

[0142] The graphical user interface includes an alarm system to notify the user if a fault occurs in the system. Preferably, the alarm may be an audible alarm, a visual alarm, or a voice alarm. Preferably, the alarm can be activated when the temperature inside the chamber is outside the required range during system operation, or when the dissolved oxygen level in the high-speed flow circuit is outside the required range, or when the pressure or pressure difference is outside the required operating range. In one embodiment, the graphical user interface warns the user according to the alarm status.

[0143] The system includes lights for illuminating the chamber. Preferably, the lights allow the user to observe and determine the floor level of the biomass, for example, to optimize mass transfer.

[0144] The system includes means for reducing or increasing the level of ambient light within the system. In one embodiment, the means for reducing or increasing the level of ambient light is a switch or a button. Preferably, by providing means for reducing or increasing the level of ambient light within the system, the system can respond to the difference in ambient background light between day and night, for example, to meet the patient's comfort expectations.

[0145] The alarm sound can be muted or reduced to accommodate the difference in ambient noise between day and night. Preferably, the system includes a button or switch for muting or reducing the alarm sound.

[0146] Figure 35 shows an overview of a system electronics according to one embodiment of the present invention. This overview shows a configuration in which data from pressure sensors 1-6, a temperature sensor, and an oxygen probe are collected and supplied to a graphical user interface. In this embodiment, inputs from various sensors are displayed on the graphical user interface. The data is processed by software within the system and then displayed on the graphical user interface. The data is used to determine whether a particular sensor is within a specified range, and if it is not, an alarm is triggered. The converted sensor data is also sent to a data logger, which is updated during system use and can be used to show data trends. The information displayed on the graphical user interface allows the operator to monitor and log several elements of the device's functionality, including pressure, pump speed, temperature, dissolved oxygen concentration, and bubble trap status. These readings provide an indication of the device's functionality. In the embodiment shown in Figure 35, several sensors are provided but are not implemented. These sensors may be implemented in other embodiments of the present invention.

[0147] Figure 36 shows an overview of the system's functionality. This figure illustrates how sensor inputs are converted into values ​​(for example, when measuring temperature, the unit is converted to a value in degrees Celsius). The system evaluates whether this value falls within a specified range. The value is displayed in the graphical user interface. If the value is outside the range, an alarm is triggered. Figure 36 also shows whether the data is logged by the system and used, for example, for analysis at a later stage.

[0148] Typically, a graphical user interface displays color-coded values: green indicates an acceptable operating range, amber indicates high, i.e., out of range—warning, and red indicates high, i.e., out of range—action required (see Table 2). Thus, amber presents a warning to the user, and red indicates that action is required.

[0149] The system is housed in a unit equipped with four lockable wheels 20. Preferably, the system is mobile and can be moved so that it can be positioned in a desired location. Preferably, the system can operate at the patient's bedside.

[0150] The system includes a handle or push rail 24. Preferably, the handle or push rail is positioned at a height substantially adjacent to an individual's waist. Preferably, the handle or push rail is positioned at an intermediate height to allow for easy movement of the system (for example, by pushing or pulling the system). Preferably, the system is housed within a unit to protect the electronic equipment and mechanisms contained within the unit.

[0151] The unit features two doors that open to approximately 180 degrees. Preferably, the doors are made of glass or transparent plastic. Preferably, glass doors are provided, allowing the user to monitor the components within the system.

[0152] The unit includes a drawer for storing consumable parts and instruction manuals.

[0153] The unit features three access hatches to allow access to the system's electrical and electronic components. Typically, the access hatches are located at the rear of the unit.

[0154] This system includes surge protectors and dipole switches to ensure that electrical connections to the trunk line lead only to correct connections. Preferably, the surge protectors and dipole switches are located at the rear of the system. Preferably, the surge protectors and dipole switches are first elements in the trunk cable from the power trunk.

[0155] The system includes an eight-outlet commercial power strip and a 24-volt power supply for the graphical user interface.

[0156] The system includes a 5-volt power supply for the ultrasonic detector.

[0157] The system includes holders for power cables and / or oxygen supply tubes when not in use.

[0158] The system includes a chamber holder. Preferably, the chamber holder facilitates chamber swapping and prevents the chamber from tipping over during use.

[0159] The system includes a tube holder 40 to prevent / reduce the risk of damage to the tubes within the system during system operation (see, for example, Figure 25).

[0160] The system further includes holders for plasma bags, saline bags, and / or waste fluid bags.

[0161] The system includes a holder for the filter attachment.

[0162] The system includes a tube diagram on the internal rear surface of the system. Preferably, the tube diagram allows the user to ensure that the tubes are correctly positioned within the system.

[0163] The system includes a blood warmer to maintain the circuit temperature within the system.

[0164] The system includes colored and white clamps on the tubes to distinguish functions. The clamps are shown in Figure 102. The clamps used in the system come in various sizes and have colors according to their specific function in this system. In addition, the system typically includes colored tubes (e.g., red, blue, and green striped tubes) which may also be used to distinguish functions.

[0165] During operation, the system monitors, collects, and records data including pressure, differential, oxygen, temperature, bubble trap status, and pump speed. Some of the results for the measured parameters are shown in the figure below.

[0166] Figure 27 is a graph showing the differential pressure measured within the system of the present invention.

[0167] Figure 28 is a graph showing temperature and oxygen level measurements within the system of the present invention.

[0168] Figure 29 is a graph showing the results from high-speed and low-speed pumps measured within the system of the present invention, as well as the bubble trap.

[0169] Figure 30 is a graph showing the measured cell viability values ​​determined using the system of the present invention.

[0170] In addition to cell count and viability data, samples were collected and cellular functionality was evaluated at several point in time.

[0171] Figure 31 is a graph showing the corrected glucose change measured within the system of the present invention.

[0172] Figure 32 is a graph showing the change in lactate dehydrogenase measured within the system of the present invention.

[0173] Figure 33 is a graph showing the change in alkaline phosphatase measured within the system of the present invention.

[0174] Therefore, the system includes a "feed set" of tubing connected to a biomass chamber, functional filter, and safety filter, all within the workstation. The feed set is connected to and from the apheresis machine.

Claims

1. A bioartificial liver support system for continuous and discontinuous procedures to provide liver support to a patient, comprising: a chamber containing biomass; a tubular system having multiple circuits adapted to provide (multiple) independent circuit operations to the patient and / or an apheresis machine; and a monitoring device having one or more sensors for measurement, adapted to collect, record, analyze, download, and store data from the system.

2. The bio-artificial liver support system according to claim 1, wherein the monitoring device further comprises a graphical user interface adapted for displaying the data.

3. A bioartificial liver support system according to claim 1 or 2, adapted to allow operation independently of the apheresis machine and / or the patient.

4. A bioartificial liver support system according to any one of claims 1 to 3, comprising a bypass circuit design that enables operation independently of the apheresis machine and / or the patient.

5. A bio-artificial liver support system according to any one of claims 1 to 4, comprising three circuits, each adapted to operate at a different speed.

6. The bio-artificial liver support system according to claim 5, comprising a high-speed circuit, a low-speed circuit, and a saline solution circuit.

7. The bio-artificial liver support system according to any one of claims 1 to 6, wherein each of the plurality of circuits and bypass lines is color-coded.

8. A bio-artificial liver support system according to any one of claims 1 to 7, wherein two circuits are connected via a splitter circuit to provide a flow division dependent on a set pump flow rate.

9. The bio-artificial liver support system according to any one of claims 1 to 8, wherein the monitoring device is adapted to monitor inline pressure, temperature, oxygen, and fluid levels within the system.

10. A bio-artificial liver support system according to any one of claims 1 to 9, comprising a safety mechanism for preventing untreated fluid from re-entering the patient's circulation.

11. The bio-artificial liver support system according to claim 10, wherein the safety mechanism comprises a one-way valve and / or a plurality of bypass circuits.

12. The bio-artificial liver support system according to any one of claims 1 to 11, wherein the chamber can be quickly replaced.

13. A bio-artificial liver support system according to any one of claims 1 to 12, having a port for enabling inflow and outflow from the system in a sterile manner.

14. The bio-artificial liver support system according to any one of claims 1 to 13, wherein the chamber comprises (a) a plurality of biomass sampling ports, (b) an inlet, (c) an outlet, (d) a drain port, (e) an oxygen inlet / outlet port, (f) a biomass inlet and outlet for filling or discharging biomass (preferably hydrogel-encapsulated spheroids), (g) one or more filters, (h) a flow distributor, and / or (i) an air inlet / outlet vent for releasing pressure from the chamber, and (j) a thermal pocket for housing a temperature probe.

15. The bio-artificial liver support system according to claim 14, wherein the sampling port is provided at a different height from the biomass in the chamber.

16. The bio-artificial liver support system according to any one of claims 1 to 15, wherein the chamber includes a double-coiled gas-permeable oxygenation pathway that can be connected to an oxygen supply source via an external port on the chamber.

17. A bio-artificial liver support system according to any one of claims 1 to 16, comprising a Y-shaped component and a splitter reservoir with an internal filter for capturing leaked particles larger than 270 μm in diameter and for equalizing pressure rise during the priming and / or treatment phase.

18. The bio-artificial liver support system according to any one of claims 1 to 17, wherein the graphical user interface enables the data to be saved, permanently stored, and / or downloaded by a medical professional or operator.

19. The bioartificial liver support system according to any one of claims 1 to 18, wherein the graphical user interface comprises a display that provides the following information: time, pump flow rate, temperature in the chamber, fluid or air present in the level detector, individual pressures and pressure trends across the pressure transducers throughout the tube circuit, pressure differences between articles positioned in the circuit, and / or the level of dissolved oxygen in the high-speed flow circuit.

20. The bio-artificial liver support system according to any one of claims 1 to 19, wherein the graphical user interface includes an alarm system for notifying the user when a failure occurs in the system, and preferably the alarm can be an audible alarm, a visual alarm, or a voice alarm.

21. The bio-artificial liver support system according to any one of claims 1 to 20, wherein the graphical user interface records the performance of the system using inline / online monitoring.

22. The bioartificial liver support system according to claim 21, wherein the graphical user interface can be adapted to monitor parameters including pH, glucose and / or other metabolic levels.

23. The bio-artificial liver support system according to any one of claims 1 to 22, comprising an air / liquid component that can be discharged or filled during the operation of the system.

24. The bio-artificial liver support system according to claim 23, wherein the air / liquid components can be monitored by an ultrasonic detection system.

25. The bio-artificial liver support system according to any one of claims 1 to 24, further comprising a light for illuminating the chamber.

26. The bio-artificial liver support system according to claim 25, further comprising means for reducing or increasing the level of ambient light within the system.

27. A bio-artificial liver support system according to any one of claims 20 to 26, wherein the alarm sound can be reduced to accommodate the difference in ambient noise between day and night.

28. A bio-artificial liver support system according to any one of claims 1 to 27, provided within a unit comprising four lockable wheels, a handle or push rail, and / or two doors that open up to 180 degrees.

29. The bio-artificial liver support system according to any one of claims 1 to 28, further comprising a tube circuit diagram on the internal rear surface of the system.

30. The bio-artificial liver support system according to any one of claims 1 to 29, further comprising means for heating the fluid in the system to a desired temperature.

31. A bio-artificial liver support system according to any one of claims 1 to 30, comprising two sets of filters adapted for use in parallel.

32. The bio-artificial liver support system according to claim 31, comprising a safety filter and a functional filter.

33. The aforementioned chamber is given by the following formula: y = -0.00005ln(x) + 0.00036(correlation(R) ２ The value is R ２ (= 0.97085) Accordingly, at a flow rate of 320 ml / min, 3.67 × 10 at 1 mm above the base plate. －４ From m / s, it decreases with the height of the cross-sectional area, to 2.58 × 10 at 10 mm. －４ A bio-artificial liver support system according to any one of claims 1 to 32, having an average flow velocity of up to m / s (1 to 10 mm above the base plate).

34. The bio-artificial liver support system according to any one of claims 2 to 33, wherein the normal operating range, warning range, and action request range of the system are visually observed in green, amber, and red.

35. The bio-artificial liver support system according to claim 34, wherein the aforementioned colors are provided on the graphical user interface within the system.

36. A bio-artificial liver support system according to any one of claims 1 to 35, wherein a thermal cover that functions to maintain a uniform temperature inside the chamber is provided around the outside of the chamber.

37. A bio-artificial liver support system according to any one of claims 1 to 36, comprising a sensor cover.

38. A method for providing continuous and discontinuous treatments to a patient that provide liver support using a bio-artificial liver support system according to any one of claims 1 to 38.

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