Transglutaminase mediated high molecular weight hyaluronan hydrogels
AssigneeETH Zurich
InventorsNicolas BROGUIERE, Emma CAVALLI, Marcy ZENOBI-WONG
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Abstract
The invention relates to a process for forming a hyaluronan hydrogel, comprising the steps of providing a hyaluronan donor peptide conjugate and a hyaluronan acceptor peptide conjugate each represented by a general formula I, wherein 10% of R1 moieties are represented by a general formula II, wherein L is a 2 to 6 atom linker moiety and Pep is a transglutaminase donor or acceptor peptide, and the rest of R1 moieties are represented by —COOH, and (b) adding a factor XIII polypeptide and a thrombin polypeptide, or a factor XIIIa polypeptide. The invention further relates to compositions and hydrogels characterized by the depicted chemistry.
Claims17
A process for forming a hyaluronan hydrogel, comprising the steps of:
- providing an aqueous solution, said aqueous solution comprising
- a first hyaluronan peptide conjugate comprising a transglutaminase donor peptide and
- a second hyaluronan peptide conjugate comprising a transglutaminase acceptor peptide,
- wherein said first hyaluronan peptide conjugate and said second hyaluronan peptide conjugate are each represented by a general formula I,
- wherein 5% to 20%, of R1 moieties are represented by a general formula II,
- wherein
- L is a linker moiety, wherein L is NH-Alk or O-Alk or NH—NH—CO-Alk, where Alk is a C1-C5 alkyl, and
- Pep is a transglutaminase donor peptide or a transglutaminase acceptor peptide, respectively, and the rest of R1 moieties are represented by —COOH;
- and
- adding to said aqueous solution a transglutaminase capable of covalently linking said transglutaminase donor peptide to said transglutaminase acceptor peptide, wherein the transglutaminase donor peptide or the transglutaminase acceptor peptide is
- a factor XIII polypeptide and a thrombin polypeptide, or
- a factor XIIIa polypeptide.
A composition comprising a hyaluronan polymer of general formula I,
- wherein 5% to 20%, 8-12%, or approximately 10% of R1 moieties are represented by a general formula II,
- wherein
- L is a linker moiety, wherein the linker moiety is NH-Alk or O-Alk or NH—NH—CO-Alk, where Alk is a C1-C5 alkyl, and
- Pep is a transglutaminase donor peptide or a transglutaminase acceptor peptide, respectively, and the rest of the R1 moieties are represented by COOH.
A hydrogel for tissue engineering obtained by the process of forming a hyaluronan hydrogel, comprising the steps of:
- providing an aqueous solution comprising
- a first hyaluronan peptide conjugate comprising a transglutaminase donor peptide and
- a second hyaluronan peptide conjugate comprising a transglutaminase acceptor peptide,
- wherein* said first hyaluronan peptide conjugate and said second hyaluronan peptide conjugate are each represented by a general formula I,
- wherein 5% to 20% of R1 moieties are represented by a general formula II,
- wherein
- L is NH-Alk, O-Alk or NH—NH—CO-Alk, wherein Alk is a C1-C5 alkyl, and
- Pep is a transglutaminase donor peptide or a transglutaminase acceptor peptide, respectively, and the rest of the R1 moieties are represented by —COOH;
- and
- adding to said aqueous solution, a transglutaminase that is capable of covalently linking the transglutaminase donor peptide to the transglutaminase acceptor peptide,
- wherein the transglutaminase is
- a factor XIII polypeptide and a thrombin polypeptide, or
- a factor XIIIa polypeptide,
- wherein the hydrogel comprises 0.5% to 4% of cross-linked hyaluronan in water (w/v),
- wherein the hyaluronan has a mean molecular weight by mass (Mw) between 250 kg/mol and 2,000 kg/mol, and
- wherein, after gelation, a disk of the hydrogel exhibits less than 20% swelling or shrinking in disk diameter upon immersion in an isotonic aqueous buffer for three days.
Dependencies are inferred from the claim text.