Artificial pancreatic perfusion device with temperature sensitive matrix

• US 5,116,494 A
• Filed: 03/25/1991
• Issued: 05/26/1992
• Est. Priority Date: 08/25/1989
• Status: Expired due to Fees

• Current Assignee: CB Biomedical, Inc. (Arbios Systems, Inc.)
• Original Assignee: W R Grace & Company - CONN (Standard Industries Holdings, Inc.)
• Inventors: Sullivan, Susan J., Chick, William L.
• Primary Examiner(s): Jones, W. Gary
• Application Number:
  US07/674,787
• Time in Patent Office: 428 Days
• Field of Search: 210/192, 210/321.78, 210/321.79, 210/321.8, 210/371.87, 210/321.88, 210/321.89, 210/209, 210/198.1, 210/645, 210/742, 210/781, 210/774, 210/806, 604/4, 604/175, 435/283, 435/284, 435/285, 435/286, 424/424, 424/556
• US Class Current: 210/192
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61L 27/04 Metals or alloys
• CPC Class Codes: A61L 27/14 Macromolecular materials
• CPC Class Codes: A61M 1/1678 intracorporal peritoneal dialysis A61M1/28
• CPC Class Codes: A61M 1/3472 with treatment of the filtrate
• CPC Class Codes: A61M 1/3475 with filtrate treatment agent in the same enclosure as the membrane
• CPC Class Codes: A61M 1/3489 by biological cells, e.g. bioreactor
• CPC Class Codes: A61M 1/3493 using treatment agents in suspension
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48

Abstract

A device which serves as an artificial pancreas comprises a hollow fiber which is surrounded by islets of Langerhans enclosed in a housing. The islets are suspended in a temperature sensitive matrix which is sufficiently viscous to support islets at a temperature below about 45° C. and sufficiently fluid to enable removal of islet suspension at a temperature above about 45° C. A warm (e.g., 48° to 50° C.) solution may be flushed through the device to change the physical state of the temperature sensitive matrix from a semi-solid state to a liquified semi-gel state. The temperature sensitive supporting material also enables long term maintenance of islet cells in in vitro culture.

Claims

1. An artificial pancreatic perfusion device for providing insulin to an individual, the device comprising:

a) a hollow fiber having one end connected to a blood vessel through a connecting means to receive blood from the individual and an opposite end connected to a blood vessel through a second connecting means to return blood to the individual, the hollow fiber having a porosity which selectively allows substances to pass transversely therethrough, such that blood flows within the hollow fiber, along the length of the fiber; and

b) a housing containing a suspension of pancreatic islets of Langerhans, the suspension including pancreatic islets distributed in a temperature sensitive supporting material about the hollow fiber such that the hollow fiber is surrounded by pancreatic islets along its length, the supporting material characterized by (i) being sufficiently viscous at temperatures below about 45°

C. to maintain distribution of the islets with respect to the hollow fiber, and (ii) being sufficiently fluid at temperatures above about 45°

C. to enable removal of the islet suspension for subsequent replacement thereof.

2. An artificial pancreatic perfusion device as in claim 1 wherein the islet suspension is removable from the housing by suction means.

3. An artificial pancreatic perfusion device as in claim 1 wherein the supporting material comprises agar.

4. An artificial pancreatic perfusion device as in claim 1 wherein the islet suspension further includes at least one of collagen, laminin and growth factors.

5. In an artificial pancreatic perfusion device for providing insulin to an individual, the device comprising (i) a hollow fiber with a porosity that selectively allows substances to pass transversely therethrough and (ii) a housing containing a suspension of pancreatic islets of Langerhans about the hollow fiber, the improvement comprising:

a temperature sensitive matrix in which the islets are distributed and suspended to form a pipettable islet suspension, the matrix being sufficiently viscous at temperatures below about 45°

C. to physically suspend and maintain the islets positioned about the hollow fiber and sufficiently fluid at temperatures above about 45°

C. to enable removal of the islet suspension for subsequent replacement thereof.

6. An artificial pancreatic perfusion device as in claim 5 wherein the matrix is a semi-gel at temperatures above about 45°

C.

7. An artificial pancreatic perfusion device as in claim 5 wherein the matrix includes agar.

8. A method for seeding a device with islets of Langerhans on multiple occasions before and after use of the device for the production of insulin, comprising the steps of:

(a) forming an islet suspension by distributing the islets in a temperature sensitive supporting material sufficiently viscous at temperatures below about 45°

C. to physically suspend the islets and sufficiently fluid at temperatures above about 45°

C. to enable removal of the islet suspension from the device as desired;

(b) introducing a first portion of islet suspension into the device, such first portion sufficient for the production of a desired amount of insulin by the device, wherein such first portion is in a semi-gel state;

(c) cooling to form a semi-solid matrix;

(d) subsequently warming to convert the semi-solid matrix to a semi-gel;

(e) withdrawing some or all of said first portion of islet suspension from the device; and

(f) introducing a second portion of islet suspension into the device, such second portion sufficient for the production of a desired amount of insulin by the device, wherein such second portion is in a semi-gel state.

9. A method for seeding as in claim 8 wherein the step of forming the islet suspension includes:

(i) preparing an islet mixture comprising islets, supporting material and cell culture medium;

(ii) maintaining said islet mixture in in vitro culture; and

(iii) processing the islet mixture to obtain islet suspension for use in the steps of introducing the islet suspension into the device in steps (b) or (f).

10. A method for seeding as claimed in claim 9 wherein the islet mixture is maintained in culture at about 37°

C.

11. A method for seeding as claimed in claim 9 wherein the islet mixture is warmed to at least 45°

C., and is processed to obtain islet suspension for introduction into the device by centrifuging such that a culture medium phase and an islet suspension phase are formed, and removing the culture medium phase to isolate the islet suspension phase.

12. A method for seeding as claimed in claim 8 wherein the device is an artificial pancreas device.

13. A method of preparing islets of Langerhans for use in a device, comprising the steps of:

(a) providing islets;

(b) combining the islets with cell culture medium and a sufficient amount of a supporting material to form an islet mixture, the supporting material being sufficiently viscous at temperatures below about 45°

C. to maintain suspension of the islets and sufficiently fluid at temperatures above about 45°

C. to enable removal of the inlet suspension from the device; and

(c) storing the islet mixture under in vitro culture conditions suitable for maintaining islets; and

(d) forming a pipettable islet suspension phase from an amount of the islet mixture, by removing the cell culture medium from the islet mixture.

14. A method of preparing islets as claimed in claim 13 wherein the supporting material comprises agar.

15. A method of preparing islets as claimed in claim 13 wherein the step of forming a pipettable islet suspension includes the steps of:

warming the islet mixture to at least about 45°

C.;

removing the islet mixture from in vitro culture;

centrifuging the islet mixture to form a culture medium phase and an islet suspension phase; and

isolating the islet suspension phase for use in the device.

16. A method of preparing islets of Langerhans for use in a device, comprising the steps of:

(a) providing islets;

(b) combining the islets with cell culture medium and a sufficient amount of a supporting material to form an islet mixture, the supporting material being sufficiently viscous at temperatures below about 45°

C. to maintain suspension of the islets and sufficiently fluid at temperatures above about 45°

C. to enable removal of the islet suspension from the device;

(c) storing the islet mixture under in vitro culture conditions suitable for maintaining islets;

(d) warming the islet mixture to at least about 45°

C.;

(e) removing the islet mixture from in vitro culture;

(f) centrifuging the islet mixture to form a culture medium phase and an islet suspension phase; and

(g) isolating the islet suspension phase for use in the device.