Microfabricated capsules for immunological isolation of cell transplants

• US 5,893,974 A
• Filed: 06/06/1994
• Issued: 04/13/1999
• Est. Priority Date: 03/07/1994
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Ferrari, Mauro, Keller, Christopher G.
• Primary Examiner(s): Drodge, Joseph W.
• Application Number:
  US08/254,330
• Time in Patent Office: 1,772 Days
• Field of Search: 210/321.87, 210/321.88, 210/500.22, 210/500.26, 210/500.27, 210/650, 210/651, 264/4, 264/42, 264/43, 264/45.1, 264/45.2, 264/45.5, 424/424, 424/451, 424/DIG. 7, 435/176, 435/240.22, 604/890.1, 604/891.1, 604/892.1, 428/312.6, 428/402, 423/338, 423/339, 423/348, 423/349, 423/350, 156/145
• US Class Current: 210/483
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0097 Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips intradermal microneedle arrays A61K9/0021; MEMS in general B81B7/02
• CPC Class Codes: B01D 2323/08 Specific temperatures applied
• CPC Class Codes: B01D 2323/081 Heating
• CPC Class Codes: B01D 2325/04 Characteristic thickness
• CPC Class Codes: B01D 39/1692 Other shaped material, e.g. perforated or porous sheets
• CPC Class Codes: B01D 39/20 of inorganic material, e.g. asbestos paper, metallic filtering material of non-woven wires porous ceramic material C04B38/00 ; sintering metals C22C1/04; making porous sintered metal bodies B22F3/10, honeycomb filters B01D46/2418, materials used for filtering exhaust gases of an internal combustion engine F01N3/022, ceramic honeycomb structures C04B38/0006
• CPC Class Codes: B01D 67/0058 by selective elimination of components, e.g. by leaching
• CPC Class Codes: B01D 67/0062 by micromachining techniques, e.g. using masking and etching steps, photolithography
• CPC Class Codes: B01D 67/0072 by deposition from the gaseous phase, e.g. sputtering, CVD, PVD
• CPC Class Codes: B01D 67/0083 Thermal after-treatment
• CPC Class Codes: B01D 69/02 characterised by their properties
• CPC Class Codes: B01D 69/12 Composite membranes; Ultra-thin membranes
• CPC Class Codes: B01D 69/1214 Chemically bonded layers, e.g. cross-linking
• CPC Class Codes: B01D 71/02 Inorganic material
• CPC Class Codes: B01D 71/0215 Silicon carbide; Silicon nitride; Silicon oxycarbide
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50
• CPC Class Codes: B81B 1/002 Holes characterised by their shape, in either longitudinal or sectional plane
• CPC Class Codes: B81B 1/004 Through-holes, i.e. extending from one face to the other face of the wafer
• CPC Class Codes: B81C 1/00246 Monolithic integration, i.e. micromechanical structure and electronic processing unit are integrated on the same substrate
• CPC Class Codes: B81C 2201/032 : LIGA process
• CPC Class Codes: B81C 2203/0728 : Pre-CMOS, i.e. forming the micromechanical structure before the CMOS circuit
• CPC Class Codes: B81C 99/0085 : using moulds and master templates, e.g. for hot-embossing
• CPC Class Codes: C04B 41/4582 : Porous coatings, e.g. coating containing porous fillers
• CPC Class Codes: C23C 16/01 : on temporary substrates, e.g. substrates subsequently removed by etching
• CPC Class Codes: G03F 7/00 : Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor using photoresist structures for special production processes, see the relevant places, e.g. B44C, H01L, e.g. H01L21/00, H05K
• CPC Class Codes: G03F 7/0015 : Production of aperture devices, microporous systems or stamps
• CPC Class Codes: Y10T 428/249969 : Of silicon-containing material [e.g., glass, etc.]

Abstract

The present invention provides a capsule made of a biologically compatible material with sufficient mechanical strength to form a very thin membrane shell having at least a region with approximately uniformly sized and spaced holes or pores that are large enough to let a desired biologically active molecular product through, while blocking the passage of all larger immunological molecules. The present invention thus provides an immunological isolation of cell transplants contained therein. The present invention also provides a free standing thin film structure that may be used as a component of such a capsule and method for the fabrication of such component and capsules.

Claims

1. A microfabricated containment capsule, comprising:

a shell formed of a thin film inorganic material, said shell having the shape of a right cylinder and including annular walls and planar end faces;

at least one porous area in said shell, said porous area comprising pores of predetermined, approximately uniform size and distribution;

said shell providing a selective molecular barrier between the interior and the exterior of said capsule; and

wherein said annular walls comprise high vertical aspect ratio thin-films and at least one of said end faces comprises a thin-film membrane filter.

2. A containment capsule according to claim 1, wherein said filter is bonded to said annular walls by a sealant.

3. A containment capsule according to claim 2, wherein said sealant is a biocompatible, polymeric material.

4. A containment capsule according to claim 3, wherein said sealant is polyethylene.

5. A method of fabricating a containment capsule, comprising:

forming a mold in a substrate for a shell having at least one opening;

lining said mold with a sacrificial layer;

growing a thin film on said sacrificial layer until said mold is filled;

removing said sacrificial layer to remove said shell from said mold;

placing an item to be contained within a space defined by said shell; and

covering the at least one opening in said shell with a microfabricated thin-film membrane filter.

6. A method according to claim 5, wherein said item comprises a biologically-active-molecule-producing agent.

7. A method of fabricating a containment capsule, comprising:

patterning a masking layer on a substrate with a pattern of discrete perforations, representing a side wall structure of said capsule;

photoelectrochemically etching holes in the substrate according to said pattern;

oxidizing and etching said holes until they merge to form a mold;

lining said mold with a sacrificial layer;

growing a thin film on said sacrificial layer until said mold is filled;

forming a first microfabricated thin-film membrane filter on a first open end of said side wall structure;

etching said sacrificial layer to remove said side wall structure and filter from said mold;

placing a biologically-active-molecule-producing agent within a space defined by said side wall structure and filter; and

forming a second microfabricated thin-film membrane filter on a second open end of said side wall structure.

8. A microfabricated containment capsule, comprising:

a shell formed of a thin film inorganic material, said shell including high vertical aspect thin film side walls and rib members to provide additional structural support for said side walls;

a first porous area microfabricated at one end of the shell, and a second porous area microfabricated at another end of the shell, the first and second porous areas having opposing faces with an array of pores of predetermined, approximately uniform size and distribution for filtering particles across the opposing faces; and

said shell providing a selective molecular barrier between the interior and the exterior of said capsule.

9. A microfabricated containment capsule, comprising:

a shell formed of a thin film inorganic material, said shell having the shape of a right cylinder and including high vertical aspect thin film annular walls and planar end faces;

a first porous area microfabricated at one end of the shell and a second porous area being microfabricated at another end of the shell, the first and second porous areas having opposing faces with pores of predetermined, approximately uniform size and distribution for filtering particles across the opposing faces; and

said shell providing a selective molecular barrier between the interior and the exterior of said capsule.

10. A microfabricated containment capsule, comprising:

a shell formed of a high vertical aspect thin film wall;

a first porous area microfabricated at one end of the shell and a second porous area being microfabricated at another end of the shell, the first and second porous areas having opposing faces with pores of predetermined, approximately uniform size and distribution for filtering particles across the opposing faces; and

said shell providing a selective molecular barrier between the interior and the exterior of said capsule;

wherein said capsule is attached to other like capsules, to form a sheet comprising a plurality of said capsules.

11. A microfabricated containment capsule, comprising:

a shell formed of a thin film inorganic material, said shell having the shape of a right cylinder and including high vertical aspect thin film annular walls and planar end faces, said shell providing a selective molecular barrier between an interior and an exterior of said capsule; and

a porous semiconductor substrate portion covering a substantial portion of one of said annular walls or said planar end faces, said porous semiconductor substrate portion having opposing faces with pores of predetermined, approximately uniform size and distribution for filtering particles across the opposing faces.