Bioartificial liver device

Abstract

A bioartificial liver device including a bioreaction chamber having a plurality of semi-permeable membranes and a plurality of filter spaces each confined by two adjacent semi-permeable membranes; a plurality of liver cell perfusion ports each communicating with one of the filter spaces for introducing the liver cells into the filter spaces, and a positive peristaltic pump. In the device, the semi-permeable membranes are disposed substantially horizontal with respect to the ground, and the positive peristaltic pump is adapted to drive the plasma flow from the bottom wall of the device to the top wall. The device of the invention improves the cell loading and the area for substance exchange between the blood and the liver cells.

Claims

1. A bioartificial liver device comprising: a housing comprising a top wall, a bottom wall, and a side wall; a chamber confined by the housing; a first semi-permeable membrane that is disposed within the chamber and subdivides the chamber into a plasma-separation chamber and a bioreaction chamber; a plurality of hollow fiber filaments disposed in the plasma-separation chamber; a blood inlet; a blood cell outlet; a first plasma opening; a second plasma opening; a separation pump; a plurality of second semi-permeable membranes disposed in the bioreaction chamber; a plurality of filter spaces; a plurality of liver cell perfusion port; a plasma outlet; and a positive peristaltic pump; wherein: the top wall and the bottom wall are adapted to be disposed substantially horizontal with respect to the ground; the top wall is adapted to be disposed above the bottom wall with respect to the ground; the side wall connects the top wall with the bottom wall; the blood inlet is disposed on the top wall and communicates with the plasma-separation chamber, for the purpose of introducing blood of a patient into the plasma-separation chamber; the blood cell outlet is disposed on the bottom wall and communicates with the plasma-separation chamber; one end of each hollow fiber filament communicates with the blood inlet, and the other end of the each hollow fiber filament communicates with the blood cell outlet; the first plasma opening is disposed at the bottom of the side wall that is adjacent to the bottom wall and communicates with the plasma-separation chamber, for the purpose of outputting the plasma generated by the plasma-separation chamber from the plasma-separation chamber; the second plasma opening is disposed on the bottom wall and communicates with the bioreaction chamber, for the purpose of introducing the plasma generated by the plasma-separation chamber into the bioreaction chamber; the first and second plasma openings are connected with each other via the separation pump; the second semi-permeable membranes are disposed substantially parallel to each other and to the top wall or the bottom wall; each of the filter spaces is confined by two adjacent second semi-permeable membranes; each of the liver cell perfusion ports is disposed on the side wall and communicates with one of the filter spaces, for the purpose of introducing liver cells into the filter spaces; the plasma outlet is disposed on the top wall and communicates with the bioreaction chamber, for the purpose of outputting the plasma generated by the bioreaction chamber; the blood cell outlet and the plasma outlet are connected to the positive peristaltic pump; and the positive peristaltic pump is adapted to provide plasma generated by the bioartificial liver device into the body of the patient.

2. The device of claim 1, wherein the second semi-permeable membranes and the first semi-permeable membrane are flat membrane, and fixedly connected to the housing.

3. The device of claim 1, wherein pore diameters among the second semi-permeable membranes gradually decrease from the one of the second semi-permeable membranes that is adjacent to the bottom wall to the one of the second semi-permeable membranes that is adjacent to the top wall.

4. The device of claim 1, wherein a third semi-permeable membrane is provided in the plasma outlet to prevent cells, cell products, or macromolecular substances in the bioreaction chamber that trigger allergy from entering into the body of a patient.

5. The device of claim 1, wherein a gas space is confined by the bottom wall and the one of the second semi-permeable membranes that is disposed adjacent to the bottom wall; a gas inlet that introduces air having oxygen is disposed on the side wall and communicates with the gas space; and a plurality of fiber filaments each of the which breathes is disposed in the gas space and communicates with the gas inlet.

6. The device of claim 5, wherein a sealed stent plate is disposed in the gas space and between the gas inlet and the fiber filaments; the sealed stent plate is spaced from the gas inlet; the sealed stent plate comprises a plurality of orifices; one end of each fiber filament is clamped in one of the orifices.

7. The device of claim 1, wherein a plurality of pairs of a backup outlet and a pressure sensor is disposed on the side wall, each pair communicates with one filter space.

8. The device of claim 1, wherein a water inlet is provided in and communicates with the blood inlet.

9. The device of claim 1, wherein the side wall of the housing is provided with a gas outlet/reserved opening, and the gas outlet/reserved opening communicates with the gas space.

10. The device of claim 1, further comprising heat preservation jacket that functions to control the device at the temperature of 37 C., and a shaker that functions to shake the device; the heat preservation jacket covers the housing, and the shaker is arranged outside the housing and connected to the housing.

11. The device of claim 1, wherein a pore diameter on the first semi-permeable membrane is 0.3 to 5 micrometers, and a pore diameter on the one of the second semi-permeable membranes that is adjacent to the bottom wall is 5 micrometers.

12. The device of claim 1, wherein the first and second plasma openings are respectively connected to the separation pump via a connection pipe.

13. The device of claim 12, wherein a pressure detector is provided in the connection pipe.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is described hereinbelow with reference to accompanying drawings, in which the sole FIGURE is a schematic diagram of a bioartificial liver device comprising semi-permeable membranes according to the present invention.

(2) In the drawing, the following reference numbers are used: 1: plasma-separation chamber, 2: bioreaction chamber, 3: first semi-permeable membrane, 4: blood inlet, 5: blood cell outlet, 6: hollow fiber filament, 7: plasma outlet, 8: second semi-permeable membrane, 9: liver cell perfusion port, 10: filter space, 11: backup outlet, 12: pressure sensor, 13: fiber filament, 14: high-oxygen Water inlet, 15: positive peristaltic pump, 16: third semi-permeable membrane, 17: tubing, 18: gas outlet/reserved opening, 19: backup sample inlet of plasma separator, 20: pressure detector, 21: housing, 22: separation pump, 23: connection pipe, 24: gas inlet, 25: gas space, 26: sealed stent plate.

DETAILED DESCRIPTION OF THE EMBODIMENTS

(3) To further illustrate the invention, experiments detailing a bioartificial liver device comprising semi-permeable membranes are described below. It should be noted that the following examples are intended to describe and not to limit the invention.

(4) As shown in FIG. 1, a bioartificial liver device comprises: a housing comprising a top wall, a bottom wall, and a side wall; a chamber is confined by the housing 21. The chamber is subdivided into a plasma-separation chamber 1 and a bioreaction chamber 2 by a first semi-permeable membrane 3. The top wall and the bottom wall are adapted to be disposed substantially horizontal with respect to the ground; the top wall is adapted to be disposed above the bottom wall with respect to the ground; and the side wall connects the top wall with the bottom wall.

(5) A blood inlet 4 is disposed on the top wall and communicates with the plasma-separation chamber 1, for the purpose of introducing blood of the patient into the plasma-separation chamber 1; a blood cell outlet 5 is disposed on the bottom wall and communicates with the plasma-separation chamber 1; and a plurality of hollow fiber filaments 6 is disposed in the plasma-separation chamber 1, one end of each hollow fiber filament 6 communicates with the blood inlet, and the other end of the each hollow fiber filament 6 communicates with the blood cell outlet; one end of the hollow fiber filaments 6 communicates with the blood inlet 4, and the other end of the hollow fiber filaments 6 communicates with the blood cell outlet 5.

(6) A plasma outlet 7 is provided on the top wall of the housing 21. A plurality of second semi-permeable membranes 8 are substantially horizontally arranged with respect to the ground in the bioreaction chamber 2 for preventing free cells from passing through. Every two adjacent second semi-permeable membranes 8 and the side wall of the housing 21 confine an independent filter space 10. The side walls of the housing 21 corresponding to each independent filter space 10 is provided with a liver cell perfusion port 9. The bottom second semi-permeable membrane 8 that is adjacent to the bottom wall and the bottom wall of the housing 21 form a gas space 25. The gas space 25 is filled with fiber filaments 13 which are permeable to gas, and the side wall of the housing 21 corresponding to the gas space 25 is provided with a gas inlet 24 communicating with the fiber filaments 13. The plasma-separation chamber 1 and the bioreaction chamber 2 are connected via a separation pump 22. In particular, a first plasma opening that is disposed on the side wall of the housing 21 and communicates with the plasma-separation chamber 1 for outputting the plasma generated by the plasma-separation chamber 1, is connected to the separation pump 22 via a connection pipe 23, and a second plasma opening that is disposed on the bottom wall of the housing 21 and communicates with the bioreaction chamber 2 for introducing the plasma generated by the plasma-separation chamber 1 into the bioreaction chamber 2, is also connected to the separation pump 22 via a connection pipe 23. Both the second semi-permeable membrane 8 and the first semi-permeable membrane 3 are flat membrane, and are fixedly connected to the housing 21.

(7) The diameters of the pores among the second semi-permeable membranes 8 gradually decrease membrane by membrane in the direction away from bottom wall to the top wall. By setting the surface pore diameters on the second semi-permeable membranes 8 to be decreased membrane by membrane, the second semi-permeable membranes 8 are prevented from clogging, and a uniform plasma flow having a stable rate is ensured as well.

(8) A third semi-permeable membrane 16 is provided in the plasma outlet 7 for preventing cells from passing through the plasma outlet 7 into the body of the patient. The third semi-permeable membrane 16 serves to prevent cells, cell products, or macromolecular substance from entering the blood so as to prevent allergy.

(9) The gas space 25 is further provided with a sealed stent plate 26 for preventing plasma/pre-filled liquid flowing in or out from the gas inlet 24. The sealed stent plate 26 is disposed at a distance away from the gas inlet 24, and comprises a plurality of orifices. One end of each gas permeable fiber filament 13 is clamped in one orifice, and the fiber filaments communicate with the gas inlet 24 through the space between the sealed stent plate 26 and the gas inlet 24.

(10) The side wall of the housing 21 corresponding to the filter space 10 is further provided with a backup outlet 11 and a pressure sensor 12. The pressure sensor 12 detects whether there is a clogged second semi-permeable membrane 8 between two adjacent filter spaces 10. In the event of clogging, two backup outlets 11 communicating the two adjacent filter spaces 10 are connected by adjusting a valve (not shown) in order to prevent circulation interruption caused by the clogged filter semi-permeable membrane 8 by allowing the plasma to pass through the backup outlets 11, so that the treatment can be continued.

(11) Further, a high-oxygen water inlet 14 is provided in and communicates with the blood inlet 4. And one of the connection pipes 23 is further provided with a pressure detector 20. Water having high oxygen content is introduced into the device through the high-oxygen water inlet 14 to oxygenate the plasma while ensuring the oxygen supply to the cells, thereby achieving a better cell culture effect.

(12) The side wall of the housing 21 corresponding to the gas space 25 is provided with a gas outlet/reserved opening 18.

(13) The device further comprises a heat preservation jacket (not shown) and a shaker (not shown) arranged outside the housing 21. The temperature of the heat preservation jacket maintains at 37 C. The bioartificial liver device of the invention has a temperature that is controlled to 37 C. by means of the heat preservation jacket and is continually shaken by means of the shaker to avoid cell accumulation thus achieving an optimum treatment effect.

(14) The pore diameters of the first semi-permeable membrane 3 is 0.3 to 5 micrometers, and the pore diameter of the bottom second semi-permeable membrane 8 that is adjacent to the bottom wall is 5 micrometers.

(15) The blood cell outlet 5 and the plasma outlet 7 are connected to a positive peristaltic pump 15 via by a tubing 17. Circulation in the system is driven by the positive peristaltic pump 15. The plasma-separation chamber 1 is also provided with a backup sample inlet 19.

(16) The principle of the present invention is as follows:

(17) Liver cell perfusion of the present invention is performed with a microcarrier perfusion method. That is, the cells adhered to the microcarriers are perfused through each liver cell perfusion port 9 along with the microcarriers, and the perfused volume is about two-thirds of the volume of the filter layer 10.

(18) When blood enters the plasma separator 1 via the blood inlet 4, the blood is separated by means of the hollow fiber filaments 6. Blood cells and part of the plasma flow out of the blood cell outlet 5, and the remaining plasma enters the bioreactor 2 through the connection pipe 23. The plasma is first in the interlayer 25 with the fiber filaments 13. Oxygen is introduced into the interlayer 25 through the gas inlet 24. Then the plasma passes through the bottom second semi-permeable membrane 8 into the filter space 10, makes adequate reaction with the cells in the layer space 10, and enters the next filter space 10 after the reaction. In this manner, the plasma passes sequentially through the second semi-permeable membranes 8 layer by layer until it passes through the bottom second semi-permeable membrane 8. Finally, the plasma is discharged through the plasma outlet 7 and is mixed with the blood cells and the part of plasma discharged through the blood cell outlet 5 to be infused into the body.

(19) The inventor has found that the horizontal arrangement of the second semi-permeable membranes 8 has the following advantages:

(20) 1. Plasma flows from the bottom to the top to resist some gravity effect to make the cell distribution more uniform. However, if the second semi-permeable membranes in the bioreactor are vertically arranged, the cells tend to be deposited at the bottom.

(21) 2. When the cells are deposited, the horizontally distributed cells are deposited on the second semi-permeable membranes 8. As such, when the plasma passes through the second semi-permeable membranes 8, the plasma can be in more adequate contact with the cells for substance metabolism. Compared with bioreactors in which the second semi-permeable membranes are vertically arranged, the cells are deposited in a larger area, which is advantageous for substance exchange.

(22) Since the second semi-permeable membrane 8 near the outlet end of the connection pipe 23 is more prone to clogging, the design in which the pore diameters of the second semi-permeable membranes 8 are decreased one by one in the direction away from the outlet end of the connection pipe 23 enables the second semi-permeable membranes 8 not only to stabilize the plasma flow rate, but also to avoid clogging. Meanwhile, the pressure sensor 12 can detect whether there is a clogged second semi-permeable membrane 8. In the event of clogging, two backup outlets 11 are connected to prevent circulation interruption caused by the clogged second semi-permeable membrane 8 by allowing the plasma to pass through the backup connection pipe into the next second semi-permeable membrane 8 that is not clogged, so that the treatment can be continued.

(23) Unless otherwise indicated, the numerical ranges involved in the invention include the end values. While particular embodiments of the invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the invention in its broader aspects, and therefore, the aim in the appended claims is to cover all such changes and modifications as fall within the true spirit and scope of the invention.