Bio-polymer and scaffold-sheet method for tissue engineering

• US 7,923,486 B2
• Filed: 10/04/2007
• Issued: 04/12/2011
• Est. Priority Date: 10/04/2007
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Yang, Jian, Dey, Jagannath
• Primary Examiner(s): Eashoo; Mark
• Assistant Examiner(s): Scott; Angela C
• Application Number:
  US11/906,962
• Publication Number:
  US 20090093565A1
• Time in Patent Office: 1,286 Days
• Field of Search: 523/113, 532/113
• US Class Current: 523/113
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: C08L 67/00 Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers

Abstract

A method of making a new type of biomaterials, biodegrable crosslinked urethane-containing polyester (CUPE) elastomers and a scaffold-sheet engineering method for tissue engineering applications is provided. CUPEs can be synthesized by forming a linear pre-polymer, which is a polyester, introducing the urethane bonds into polyester using a diisocyanate as a linker, and crosslinking the resulting urethane containing linear polymers to form CUPEs via post-polymerization. This family of polymers, CUPEs, exhibit excellent biocompatibility with desired degradation. Tissue engineering scaffolds made of CUPEs are soft and elastic, and have good mechanical strength. Complex tissue grafts can be constructed by a novel layer-by-layer (LBL) scaffold-sheet engineering design using CUPE sheets. CUPE scaffolds can provide openings for cell to cell communication across scaffold layers and angiogenesis into the depth of the construct. Biomolecules, such as anticoagulants, can be incorporated into the CUPE polymers, increasing their viability as vascular graft scaffolds.

Claims

1. A method of synthesizing a biomaterial cross-linked urethane-doped polyester polymer comprising the steps of:

combining at least one multi-functional monomer comprising at least 2 carboxyl and at least one diol to form a polyester polymer;

adding one or more di-isocyanate monomers to the polyester polymer to form a urethane doped polyester; and

forming ester-bond crosslinks between the urethane doped polyester through the condensation of the side carboxyl groups and hydroxyl groups on the polyester polymer chains to form a crosslinked urethane doped polyester polymer network with one or more urethane/urea bonds doped in the polyester chains between the ester-bond crosslinks.

2. The method of claim 1, further comprising the step of adding di-isocyanate monomer to the polyester polymer and extending the polyester polymer by adding diamine or diol monomers or their combinations to the polyester polymer to form an extended urethane doped polyester which can be further crosslinked by ester bond formation to form crosslinked urethane doped polyester network.

3. The method of claim 1, further comprising:

mixing a porogen in with the urethane doped polyester to create nano-featured scaffolds.

4. The method of claim 3, wherein the porogen is poly(ethylene glycol)dimethyl ether.

5. The method of claim 3, wherein the at least one multi-functional monomer comprises citric acid.

6. The method of claim 1, wherein L-cysteine is incorporated into the pre-polymer.

7. A method of synthesizing a biomaterial polymer, the method comprising:

forming pre-polymers via polycondensation of multifunctional monomers and diols;

adding a diisocyanate as a linker of the pre-polymers to introduce urethane bonds into the formed pre-polymers to form urethane-containing linear polymers;

crosslinking the urethane-containing linear polymers through forming ester-bond crosslinks via condensation reactions between the side carboxyl groups and the hydroxyl groups in the linear polymers to form crosslinked urethane-containing (doped) polyester network.

8. The method of claim 7, wherein the diisocyanate used as linker to bridge pre-polymer chains is selected from a group consisting of diphenylsulfone di-isocyanate (SDI), hexamethylene di-isocyanate (HDI) and lysine di-isocyanate (LDI).

9. The method of claim 7, wherein at least one of citric acid and malic acid is a multifunctional monomer used in the forming of the crosslinked polymer via polycondensation.

10. The method of claim 7, wherein multifunctional include diols, to create the pre-polymers.

11. The method of claim 10, wherein the diols are aliphatic diols, which comprise between 2 and 20 carbons, inclusively.

12. The method of claim 10, wherein the diols are aliphatic, linear, unsaturated diols, with a hydroxyl moiety being present at the C1 and Cx position, wherein x is the terminal carbon of the diols.

13. The method of claim 10, wherein the diols are unsaturated, in which an aliphatic chain contains one or more double bonds.

14. The method of claim 10, wherein the diols are macrodiols and may have various molecular weights.

15. The method of claim 14, wherein the macrodiols are poly(ethylene glycol) (PEG).

16. The method of claim 10, wherein a combination diols react with multifunctional monomers to synthesize the pre-polymers.

17. The method of claim 7, further comprising incorporating amino acids into the pre-polymers through condensation reactions.

18. The method of claim 17, wherein L-cysteine is the amino acid incorporated into the pre-polymer.

19. A method of synthesizing a biomaterial cross-linked urethane-containing polyester polymer-comprising the steps of:

combining at least one multi-functional acid containing monomer and at least one diol to form a polyester polymer;

adding one or more di-isocyanate monomers to the polyester polymer to form a urethane doped polyester;

forming ester-bond crosslinks between the urethane doped polyesters by the condensation of side carboxyl groups and hydroxyl groups on the urethane doped polyester to form a crosslinked urethane doped polyester polymer network; and

adding one or more porogens to the crosslinked urethane doped polyester polymer network;

leaching out at least a portion of the one or more porogens;

or

adding di-isocyanate monomer to the polyester polymer to form isocyanate terminated polyesters;

adding diamine or diols monomers to extend the urethane doped polyester to form an extended urethane doped polyester polymer; and

crosslinking the extended urethane doped polyester via ester-bond crosslinks formed by the condensations of the side carboxyl groups and hydroxyl groups on the extended urethane doped polyester polymers to form crosslinked urethane doped polyester network;

or

adding more di-isocyanates as crosslinkers to crosslink urethane-doped polyester polymers.