United States Patent:  6,042,909

Assignee:  Circe Biomedical, Inc. (Lexington, MA)

Filed:  September 3, 1997

The invention features an empty device for receiving a bioactive agent. The device includes a biocompatible and semi-permeable membrane that defines an enclosed space; the membrane also has at least one end that defines an opening for introducing the bioactive agent into the enclosed space. The device is configured to be placed in an animal. In one embodiment of the invention, the membrane has an inner surface and an outer surface, where the inner surface defines the inner surface, and includes a biocompatible adhesive in the general region of the opening to allow sealing of the opening after the introduction of the bioactive agent into the enclosed space. Another embodiment of the invention includes a biocompatible frame mounted in supporting relationship to the membrane and defining an opening for introducing the bioactive agent into the enclosed space. The frame has greater porosity than the membrane.

SUMMARY OF THE INVENTION

In general, the invention features a device for receiving one or more bioactive agents, such as healthy, infected, or malignant cells, enzymes, or infectious agents. The device includes one or more biocompatible and semi-permeable membranes and a frame or adhesive to enable the sealing of the device.

An embodiment of the invention features an empty device for receiving a bioactive agent. The device includes a biocompatible and semi-permeable membrane having an inner surface and an outer surface, where the inner surface defines an enclosed space; the membrane also has at least one end that defines an opening for introducing the bioactive agent into the enclosed space; a biocompatible adhesive in the general region of the opening to allow sealing of the opening after the introduction of the bioactive agent into the enclosed space. The device is configured to be placed in an animal.

The biocompatible adhesive can be, for example, a heat sealable polymer conduit extending beyond the end of the membrane for a length sufficient for heat sealing the conduit without causing the membrane to be contacted in the heat sealing process. The conduit in this example overlaps with and is secured to a terminal portion of the outer surface of the membrane.

The membrane can have a second end that defines an opening, in which case the device also includes a second heat sealable polymer conduit extending beyond the second end.

The heat sealable polymer conduit or conduits can be made of polyurethane, for instance.

The membrane can be in the form of a preformed bag. Examples of bags include bullet-shaped devices, balloons, and cylindrical tubes having one end closed and one end remaining open.

In regard to any of the devices, the membrane can be made of a copolymer of acetonitrile and vinyl chloride. The membrane can have, for example, a hydraulic permeability of 8-70 ml/min/m² /mmHg and a molecular weight cut-off value of 20-150 Kdal.

Another embodiment of the invention features a second device for receiving a bioactive agent. The device features a biocompatible and semi-permeable membrane defining an enclosed space; and a biocompatible frame mounted in supporting relationship to the membrane and defining an opening for introducing the bioactive agent into the enclosed space. The frame has greater porosity than the membrane; and the device is configured to be placed in an animal.

The device can also include a biocompatible member that seals the opening. The member can be formed of a resilient material, for example.

In some cases, the member also includes an outer component of a first material and an inner component of a second material having a different hardness from the first material. The outer component is inserted into the opening and has an orifice for snugly receiving the inner component.

The frame can be in the form of a porous cylinder.

In regard to any of the devices, the membrane can be made of a copolymer of acetonitrile and vinyl chloride. The membrane can have a hydraulic permeability of 8-70 ml/min/m² /mmHg (or even 25-50 ml/min/m² /mmHg) and a molecular weight cut-off value of 20-150 Kdal.

The term "biocompatible" refers to the property of not inducing fibrosis, inflammatory response, host rejection response, or cell adhesion, following in vivo implantation. What is meant by "fibrosis" is tissue growth encapsulating the device.

An animal can be a human or a non-human animal such as a mouse, monkey, dog, rat, monkey, goat, reptile, bird, or guinea pig.

A biocompatible member can be, for example, a plug that is inserted into the opening of the device or a cap that fits over the end of the device to block the opening.

Semi-permeable membranes allow molecules smaller than a predetermined size (i.e., the molecular weight cut-off, or "MWCO") to pass freely from one side of the membrane to the other. In the present invention, the MWCO of all membranes were determined by single protein rejections. The rejection percentages indicated are the percentage of protein that is retained by the membrane (i.e., does not pass through the pores).

Pore size is not easily defined, as there is always a broad range of pore sizes on a given membrane skin. Proteins often interact with the pores in the polymer skin, leaving a deposit that can act as a secondary boundary or rejecting layer. The thickness of the layer varies with, for example, the hydrophobicity of the polymer, the type of protein and the flow properties of the solution (pressure and shear rate) challenging the membrane. For MWCO measurement, a series of single solutes (i.e., typically spherical proteins of various sizes) are used in rejection testing. Smaller proteins pass through the pores (low rejection by the skin) while larger proteins are mostly retained (high rejection). By plotting the rejection curve against the molecular weight of the proteins used as solutes, the MWCO can be deduced.

Hydraulic permeability is defined as the volume of water that can flow through a porous substance per unit of time per unit of surface area per unit of water pressure; thus it can be measured in units of ml/min/m² /mmHg. It is measured by forcing clean water (e.g., water for injection, U.S.P., or "WFI") having a known pressure through a sample of the substance having known dimensions, then measuring the volume of water that emerges from the opposite face of the material after a prescribed length of time has elapsed.

Lengths of the membranes can be sealed into a cylindrical device in which the membranes' inner lumens are separated from the outer membrane surfaces and a chamber is formed between the outer surface of the membranes and the device. The outer chamber is referred to as the "shell side." Water or protein solutions, or both, are passed through the inner lumens of the membranes in the devices. The pressure applied by the solutions is controlled and is referred to as the "transmembrane pressure." While most of the solution is recirculated through the membrane lumens, a portion will cross the membrane wall to the shell side. A peristaltic pump can be used to drive the flow. The solution is drawn from a reservoir, through the pump to an inlet, through the lumens of the membranes, out of the device through an outlet, and back into the reservoir, thereby recirculating the solution. The rate of the fluid (sec^-1) over the inner membrane surface is usually regulated, as is the pressure applied to the surface. The pressure can be regulated (e.g., with a clamp on the outlet tubing) such that the pressure drop across the device is minimized.

For clean water, the rate (volume/time) of passage through the walls is referred to as the flux, or normalized permeability (volume/time/surface area/pressure). When proteins of known size are used as markers, dilute solutions are prepared and recirculated as described above in the context of MWCO determination. The percentage of protein that remains recirculating in solution and does not cross the membrane wall is referred to as the percent protein rejection. Generally, a series of proteins of known molecular weight and similar shape are used.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

An advantage of the devices is ease of use. The new devices facilitate the introduction of bioactive material into a host and, subsequently, the recovery of that material without sacrificing the host.

There are also advantages that pertain more particularly to devices that have at least one heat sealable polymeric conduit extending beyond the ends of the membrane: 1) there is little, if any, damage to the membrane structure when heat sealing the conduits; 2) there are no toxic adhesives necessary; such compounds could potentially contaminate the cells; 3) the conduits are generally homogenous films, which heat seal reproducibly and create an effective barrier against leakage; 4) the conduits can be made of materials (e.g., polyurethane) that are fairly free of tissue growth or fibrosis; and 5) because it is the conduit, not the membrane, that is heat sealed, the membrane characteristics (e.g., MWCO, hydraulic permeability, and porosity) are unaffected.

Claim 1 of 3 Claims

1. An empty device for receiving a bioactive agent, comprising:

a biocompatible and semi-permeable membrane having an inner surface and an outer surface, wherein said inner surface defines an enclosed space; said membrane also having one end that defines an opening for introducing the bioactive agent into said enclosed space; and

a biocompatible adhesive in the general region of said opening to allow sealing of said opening after the introduction of the bioactive agent into said enclosed space, wherein said biocompatible adhesive is a heat sealable polymer conduit extending beyond said end of said membrane for a length sufficient to allow heat sealing of said conduit without causing said membrane to be contacted with a heated element in the heat sealing process; said conduit overlapping and being secured to a terminal portion of the outer surface of said membrane,

wherein said device is configured to be placed in an animal and said membrane is in the form of a preformed bag.

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