Chemistry: molecular biology and microbiology – Maintaining blood or sperm in a physiologically active state...
Reexamination Certificate
2000-10-24
2001-10-09
Redding, David A. (Department: 1744)
Chemistry: molecular biology and microbiology
Maintaining blood or sperm in a physiologically active state...
C210S645000, C210S646000, C210S651000, C604S005010, C604S005040
Reexamination Certificate
active
06300054
ABSTRACT:
BACKGROUND OF THE INVENTION
Liver failure leads to the accumulation of toxins such as ammonia in the blood of patients. Apparatuses for removing these blood toxins (also called liver assist systems) have been developed and are grouped into passive or bioactive devices. Passive devices generally remove the toxins by hemodialysis, hemoperfusion, or plasma exchange, while bioactive devices can include living cells which remove or convert the blood toxins. An example of a bioactive liver assist system containing hepatocytes is described in U.S. Pat. No. 5,643,794.
SUMMARY OF THE INVENTION
The invention is based on the discovery that astrocytes can remove toxins from a biological fluid. Accordingly, the invention features a system for removing toxins from a biological fluid by treating the fluid with astrocytes. The system includes a first container having a first port for receiving the biological fluid, a second port through which the biological fluid exits the first container, and astrocytes residing in the first container. The system provides a means to contact a volume of fluid, significantly larger than the volume held by the container, with astrocytes by continuously passing portions of the fluid through the container via the first and second ports. Thus, a continuous flow system including the above container can be small relative to the volume of the fluid to be treated.
The system described above includes one or more of the following features. For example, the system can further include a conduit for circulating the biological fluid, the conduit being connected to the first port and second port. The conduit allows additional elements of the system to be connected to the system. These elements include (1) a pump connected within the conduit and adapted to circulate the biological fluid through the conduit; (2) a heater connected within the conduit and adapted to maintain the biological fluid within a temperature range; (3) an oxygenator connected within the conduit and adapted to supply oxygen to the biological fluid; (4) an inlet configured to receive the biological fluid from an external system (e.g., a plasma separation machine), and an outlet configured to return a portion of the biological fluid to the external system; and (5) a bypass structure which, upon actuation, prevents flow of the biological fluid between the conduit and the external system. Thus, the system for removing the toxins can be connected to an external system that, for example, separates debris and solid material from a biological fluid before it enters the toxin-removing system. The bypass structure is useful for diverting the biological fluid from the system when there is a catastrophic failure in the container. Such a failure may allow astrocytes to be intermixed with and to contaminate the fluid in the absence of the bypass structure.
In one particular embodiment, the system includes a second container connected within the conduit and having a third port for receiving the biological fluid, a fourth port through which the biological fluid exits the second container, and non-astrocyte cells (e.g., hepatocytes) residing in the second container. Alternatively, the non-astrocyte cells can reside in the first container along with the astrocytes. The non-astrocyte cells can assist the astrocytes in clearing toxins from the biological fluid. The first or second container can be a hollow fiber bioreactor such as that described in U.S. Pat. No. 5,643,794, in which case the biological fluid passes through a lumenal space of the hollow fibers and the cells reside outside of the lumenal space. The hollow fibers can be made of a semi-permeable membrane having pores with a diameter of less than about 2 &mgr;m (e.g., about 0.1 &mgr;m to 1 &mgr;m). In general, suitable membranes allow transport of solutes, including proteins such as albumin, and other molecules to reach cells so that cells can clear complexed toxins (albumin-bound toxins).
The above arrangement of hollow fibers prevents the loss of cells from the container and contamination of the biological fluid with the cells. However, a barrier such as hollow fibers is not necessary to prevent such loss or contamination. For example, the cells can adhere to an interior surface of the container, thereby preventing the loss of cells and contamination of the fluid. The cells also can be encapsulated.
Another aspect of the invention features a container which includes a first compartment for receiving the biological fluid, a second compartment adjacent to the first compartment, and a first porous barrier which separates the first compartment from the second compartment. The first porous barrier is impermeable to astrocytes residing in the second compartment.
The container can include a third compartment adjacent to the first compartment or second compartment, a second porous barrier which separates the third compartment from the first compartment or second compartment, the second porous barrier being impermeable to non-astrocyte cells, and non-astrocyte cells (e.g., hepatocytes) residing in the third compartment. Alternatively, the non-astrocyte cells can reside in the second compartment, in which case the first porous barrier is impermeable to the non-astrocyte cells as well as astrocytes. Non-astrocyte cells (e.g., hepatocytes) can facilitate the removal of similar or different toxins from the biological fluid, or aid in the viability or function of astrocytes. A porous barrier suitable for use with this container includes a metal mesh with pores small enough to block passage of astrocytes or other cells through the barrier. Other examples of porous barriers include membranes made of polyethylene, polypropylene, polycarbonate, teflon, cellulosics (such as cellulose acetate), polysulfone, polyether sulfone, polyvinyl alcohol, or polyacrylonitrile.
The invention also includes a method of treating a biological fluid suitable for administering to an animal by contacting the biological with astrocytes, separating the biological fluid from the astrocytes, and administering (e.g., intravenously) the biological fluid to an animal. Optional features of the method include contacting the biological fluid with non-astrocyte cells (e.g., hepatocytes) and separating the biological fluid from the non-astrocytes cells. This method can be used to treat, for example, blood directly flowing from a patient blood vessel into the system described above and back to the patient, thereby treating (e.g., removing toxins from) the whole blood or a component thereof (e.g., plasma).
The biological fluid treatable in the above-described system, container, and method is any fluid that is derived from or suitable for delivery into an animal, especially a human. Such fluids include whole blood, plasma, serum, lymph, cerebralspinal fluid, and artificial or synthetic blood products. Astrocytes which are used to practice the invention include mammalian astrocytes, such as bovine, porcine, murine, rat, primate, and human astrocytes.
One of the most serious side-effects of liver failure (especially in acute liver failure) is bran swelling, which can lead to a coma or even death within a few days. Unfortunately, the compounds causing this swelling is largely unknown. A key feature of the invention is the use of astrocytes, a cell type not previously recognized for its utility in devices and methods for removing a toxin (e.g., ammonia) from a biological fluid such as plasma. Thus, astrocytes are particularly useful for removing toxins from plasma in patients experiencing liver failure, thereby alleviating brain swelling.
Other features and advantages of the invention will become apparent from the following drawings and detailed description, and also from the claims.
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Butterworth Roger
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Redding David A.
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