Tissue formation by injecting a cell-polymeric solution that gels in vivo

• US 5,709,854 A
• Filed: 04/30/1993
• Issued: 01/20/1998
• Est. Priority Date: 04/30/1993
• Status: Expired due to Term

• Current Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Atala, Anthony, Vacanti, Charles A., Paige, Keith T., Griffith-Cima, Linda
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/056,140
• Time in Patent Office: 1,726 Days
• Field of Search: 424/426, 424/93.7, 435/240.1, 435/178, 435/1, 435/182, 435/395, 435/396, 435/397, 435/1.1, 252/315.01
• US Class Current: 424/93.7
• CPC Class Codes: A61F 2/0036 implantable A61F2/0018 takes precedence
• CPC Class Codes: A61F 2/0059 Cosmetic or alloplastic implants A61F2/10 - A61F2/16, A61F2/28 take precedence
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2310/00365 Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61F 2310/00383 Gelatin
• CPC Class Codes: A61K 35/34 Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes vascular smooth muscle A61K35/44
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/222 Gelatin
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3826 Muscle cells, e.g. smooth muscle cells
• CPC Class Codes: A61L 27/383 Nerve cells, e.g. dendritic cells, Schwann cells
• CPC Class Codes: A61L 27/3839 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3847 Bones
• CPC Class Codes: A61L 27/3852 Cartilage, e.g. meniscus
• CPC Class Codes: A61L 27/3882 Hollow organs, e.g. bladder, esophagus, urether, uterus
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: C08L 5/04 Alginic acid; Derivatives thereof
• CPC Class Codes: C08L 5/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C12N 5/0068 : General culture methods using substrates for specific animal cell type C12N5/06

Abstract

A cell-polymeric solution is injected into an animal where the polymer crosslinks to form a polymeric hydrogel containing dispersed cells and the cells form new tissue in the animal. The polymer is biodegradable and is a natural polymer such as alginate or a synthetic polymer. The cells are chondrocytes, osteoblasts, muscle cells, fibroblasts or cells acting primarily to synthesize, secret or metabolize materials. Crosslinking of the polymer results from using cations or anions, altering the pH or changing the temperature. A polyion such as polyethyleneimine or polylysine can be added before injection to stabilize the polymeric hydrogel. A kit for tissue formation is provided by combining the cell-polymeric solution with a means for injecting the solution into an animal.

Claims

1. A method for injecting a cell suspension into an animal to form tissue within the animal comprising

forming a cell-polymeric solution by mixing a solution of a biodegradable, biocompatible natural or synthetic organic polymer, wherein the polymer is capable of being cross-linked via covalent, ionic, or hydrogen bonds to create a three-dimensional open-lattice structure which entraps water molecules to form a gel, with dissociated cells, wherein the cells are selected from the group consisting of chondrocytes, osteoblasts, muscle cells, fibroblasts, and cells acting primarily to synthesize, secret or metabolize materials, to form an injectable cell-polymeric solution having cells dispersed therein and

injecting the cell-polymeric solution into the animal which crosslinks to form a polymeric hydrogel having cells dispersed therein inside the animal, whereby the cells form tissue.

2. The method of claim 1 wherein crosslinking of the polymer solution is initiated prior to implantation in the animal.

3. The method of claim 1 wherein crosslinking of the polymer solution is initiated after the polymer solution is injected into the animal.

4. The method of claim 1 wherein the polymer is selected from the group consisting of alginate, polyphosphazines, polyethylene-oxide-polypropylene glycol block copolymers, poly(acrylic acids), poly(methacrylic acids, poly(vinyl acetate), and sulfonated polymers.

5. The method of claim 4 wherein the polymer solution is crosslinked by using ions, altering the pH or changing the temperature.

6. The method of claim 1 wherein the polymer solution is crosslinked by interaction with cations selected from the group consisting of copper, calcium, aluminum, magnesium, strontium, barium, tin, and di-, tri- and tetrafunctional organic cations;

or anions selected from the group consisting of low molecular weight dicarboxylic acids, sulfate ions and carbonate ions.

7. The method of claim 4 wherein the hydrogel is further stabilized by cross-linking with a polyion added to the cell-polymeric solution before injection.

8. The method of claim 1 wherein the cells are selected from the group consisting of chondrocytes, muscle cells, fibroblasts, and cells acting primarily to synthesize, secret or metabolize materials.

9. The method of claim 1 wherein the polymer is a synthetic polymer.

10. A kit for formation of tissue at a site in a patient comprising

An injectable cell-polymeric solution comprising a biodegradable, biocompatible natural or synthetic organic polymer, wherein the polymer crosslinks after injection via covalent, ionic, or hydrogen bonds to create a polymeric hydrogel having dispersed therein dissociated heterologous cells, wherein the cells are selected from the group consisting of chondrocytes, osteoblasts, muscle cells, fibroblasts, and cells acting primarily to synthesize, secret or metabolize materials, the hydrogel consisting of the injected cell-polymeric solution,

in combination with means for injecting the cell-polymeric solution into the site in the patient where tissue is to be formed.

11. The kit of claim 10 wherein the polymer is a synthetic polymer.