Bio-polymer and scaffold-sheet method for tissue engineering

• US 20090093565A1
• Filed: 10/04/2007
• Published: 04/09/2009
• 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
• Granted Patent: US 7,923,486 B2
• Time in Patent Office: Days
• 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 scaffold polymer for tissue engineering comprising:

a crosslinked urethane-containing polyester.

2. The scaffold polymer according to claim 1, wherein:

the crosslinked urethane-containing polyester comprises;

a sub-micron surface roughness and tortuous tunnels, wherein

the tortuous tunnels are at a same order of fenestration size of elastic lamina.

3. A method of synthesizing a biomaterial, the method comprising:

adding citric acid and 1,8 octane diol in a molar ratio of 1;

1.1 to a flask, forming a mixture;

melting the mixture at a melting temperature;

allowing the mixture to react, creating a pre-polymer;

dissolving the pre-polymer in dioxane;

precipitating a polymer in water, removing any unreacted monomers and oligomers;

freeze drying the polymer;

dissolving the freeze dried polymer in N,N′

-dimethylformamide;

adding 1,6-hexane diisocyanate (HDI) in about a 1;

0.9, prepolymer to HDI ratio, under continuous stirring to form pre-crosslinked urethane-containing polyester (CUPE) solution, by introducing urethane linkage in the polymer;

assessing reaction completeness using Fourier Transform Infra Red Spectroscopy (FT-IR);

determining reaction completion by an absence of isocyanate group in the FT-IR;

purifying pre-CUPE solution by dropping the pre-CUPE solution into water while stirring;

drying the purified pre-CUPE under vacuum; and

heating pre-CUPE at a temperature in a range of 60-120°

C. for a time in a range of one day to 2 weeks with or without vacuum in an oven to obtain CUPE polymers, the biomaterial.

4. A small diameter blood vessel graft comprising:

a CUPE tubular scaffold;

at least one HASMC seeded CUPE scaffold sheet, which is wrapped around the CUPE tubular scaffold;

at least one HAFB seeded CUPE scaffold sheet, which is wrapped around the at least one wrapped HASMC seeded scaffold sheet; and

HAECs seeded in the lumen of the CUPE tubular scaffold.

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

forming linear pre-polymers, which are polyester;

using a diisocyanate as a linker;

introducing urethane bonds into the formed polyester, yielding urethane-containing linear polymers;

crosslinking the resulting urethane containing linear polymers to form CUPEs via post-polymerization.

6. The method of claim 5, wherein:

the crosslinking forms crosslinks between CUPE chains, owing to an ester bond formation between a free hydroxyl group and a free carboxyl group on a backbone of resulting urethane containing linear polymers.

7. The method of claim 5, further comprising:

mixing a porogen in with pre-CUPE or Pre-POC solution to create nano-featured scaffolds.

8. The method of claim 7, wherein:

the porogen is poly(ethylene glycol)dimethyl ether (PEGDM).

9. The method of claim 7, further comprising:

leaching out the porogen after solvent evaporation and post-polymerization.

10. The method of claim 7, wherein:

citric acid is one of monomers used in forming the linear pre-polymers.

23. The method of claim 5, wherein:

L-cysteine is incorporated into the pre-polymer.

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

forming pre-polymers via polycondensation, using multifunctional monomers;

using a diisocyanate as a linker;

introducing urethane bonds into the formed pre-polymers, yielding urethane-containing linear polymers, pre-CUPEs;

crosslinking the resulting the urethane-containing linear pre polymers to form CUPEs via post-polymerization.

12. The method of claim 11, 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).

13. The method of claim 11, wherein:

at least one of citric acid and malic acid is a multifunctional monomer used in the forming of the crosslinked polymer via polycondensation.

14. The method of claim 11, wherein:

multifunctional include diols, to create the pre-polymers.

15. The method of claim 14, wherein:

the diols are aliphatic diols, which comprise between 2 and 20 carbons, inclusively.

16. The method of claim 14, 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.

17. The method of claim 14, wherein:

the diols are unsaturated, in which an aliphatic chain contains one or more double bonds.

18. The method of claim 14, wherein:

The diols are macrodiols and may have various molecular weights.

19. The method of claim 18, wherein:

the macrodiols are poly(ethylene glycol) (PEG).

20. The method of claim 14, wherein a combination diols react with multifunctional monomers to synthesize the pre-polymers.

21. The method of claim 11, further comprising:

incorporating amino acids into the pre-polymers through condensation reactions.

22. The method of claim 21, wherein:

L-cysteine is the amino acid incorporated into the pre-polymer.