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Biomaterials Formed by Nucleophilic Addition

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Biomaterials Formed by Nucleophilic Addition (19) & (11) EP 1 181 323 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C08G 63/48 (2006.01) C08G 63/91 (2006.01) 29.06.2011 Bulletin 2011/26 C12N 11/02 (2006.01) C12N 11/04 (2006.01) C12N 11/06 (2006.01) C12N 11/08 (2006.01) (2006.01) (2006.01) (21) Application number: 00910049.6 G01N 33/544 G01N 33/545 G01N 33/546 (2006.01) G01N 33/549 (2006.01) A61K 9/00 (2006.01) A61K 9/06 (2006.01) (22) Date of filing: 01.02.2000 A61K 47/48 (2006.01) A61L 24/00 (2006.01) A61L 24/04 (2006.01) A61L 26/00 (2006.01) A61L 27/26 (2006.01) A61L 27/52 (2006.01) A61L 31/04 (2006.01) A61L 31/14 (2006.01) C08G 81/00 (2006.01) (86) International application number: PCT/US2000/002608 (87) International publication number: WO 2000/044808 (03.08.2000 Gazette 2000/31) (54) BIOMATERIALS FORMED BY NUCLEOPHILIC ADDITION REACTION TO CONJUGATED UNSATURATED GROUPS BIOMATERIALIEN DIE DURCH NUKLEOPHILE REAKTION AUF KONJUGIERTEN UNGESÄTTIGTEN GRUPPEN ADDIERT SIND BIOMATERIAUX FORMES PAR REACTION D’ADDITION NUCLEOPHILE A DES GROUPES NON SATURES CONJUGUES (84) Designated Contracting States: • LUTOLF, Matthias AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU CH-8005 Zurich (CH) MC NL PT SE • PRATT, Alison CH-8044 Zurich (CH) (30) Priority: 01.02.1999 US 118093 P • SCHOENMAKERS, Ronald CH-8044 Zurich (CH) (43) Date of publication of application: • TIRELLI, Nicola 27.02.2002 Bulletin 2002/09 CH-8006 Zurich (CH) • VERNON, Brent (60) Divisional application: CH-8157 Dielsdorf (CH) 10181654.4 / 2 311 895 (74) Representative: Klunker . Schmitt-Nilson . Hirsch (73) Proprietors: Patentanwälte • Eidgenössische Technische Hochschule Zürich Destouchesstrasse 68 8092 Zürich (CH) 80796 München (DE) • Universität Zürich 8006 Zürich (CH) (56) References cited: US-A- 5 268 305 US-A- 5 427 915 (72) Inventors: US-A- 5 567 422 US-A- 5 635 207 • HUBBELL, Jeffrey, A. CH-8126 Zumikon (CH) • ELBERT, Donald CH-8044 Zurich (CH) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 181 323 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 181 323 B1 • ZHAO X ET AL: "NOVEL DEGRADABLE POLY • HERN D L ET AL: "INCORPORATION OF (ETHYLENE GLYCOL) HYDROGELS FOR ADHESION PEPTIDES INTO NONADHESIVE CONTROLLED RELEASE OF PROTEIN" HYDROGELS USEFUL FOR TISSUE JOURNAL OF PHARMACEUTICAL SCIENCES, RESURFACING" JOURNAL OF BIOMEDICAL AMERICAN PHARMACEUTICAL ASSOCIATION. MATERIALS RESEARCH, WILEY, NEW YORK, WASHINGTON, US, vol. 87, no. 11, November NY, US, vol. 39, 1998, pages 266-276, 1998 (1998-11), pages 1450-1458, XP000783392 XP002949005 ISSN: 0021-9304 ISSN: 0022-3549 2 EP 1 181 323 B1 Description Background of the Invention 5 [0001] The present invention relates to biomaterials formed by nucleophilic addition reactions to conjugated unsatu- rated groups, and the uses of such biomaterials. [0002] Synthetic biomaterials, including polymeric hydrogels can be used in a variety of applications, including phar- maceutical and surgical applications. They can be used, for example, to deliver therapeutic molecules to a subject, as adhesives or sealants, as tissue engineering and wound healing scaffolds, and as cell transplant devices. 10 [0003] Zhao X et al: "Novel Degradable Poly(ethylene glycol) hydrogels for Controlled Release of Protein" Journal of Pharmaceutical Sciences, American Pharmaceutical Association. Washington, US, vol. 87, no. 11, November 1998 (1998-11), pages 1450-1458, discloses biomaterials in the form of hydrogels made from polyethylene glycol formed in the presence of proteins via nucleophilic substitution reactions between activated PEG-carboxylic acids and PEG- nucleophiles. The hydrogels can be used as delivery carriers for bioactive drugs. 15 [0004] While much progress has been made in the field of polymeric biomaterials, further developments must be made in order for such biomaterials to be used optimally in the body. For, example the formation of biomaterials in the presence of sensitive biological materials is difficult to achieve because the components of the biomaterials do not exhibit a high degree of self selectivity. 20 Summary of the Invention [0005] New polymeric biomaterials, including polymeric hydrogels, have been developed for medical treatments. They are unique in their use of addition reactions between a strong nucleophile and a conjugated unsaturation, for polymerizing or cross-linking two or more components in a manner that can be accomplished in the presence of sensitive biological 25 materials. This would include formation of biomaterials in the presence of [0006] Subject-matter of the present invention is a method for making a biomaterial as claimed in claim 1, and a biomaterial obtainable by such method as claimed in claim 19. Subject-matter of the present invention is also a scaffold suitable for regenerating a tissue as claimed in claim 24. Further subject- matter of the present invention is a combination of two or more precursor components for forming the biomaterial of he present invention, and the use of the biomaterial 30 components for preparing a medicinal material. Such combination and use, respectively, are claimed in independent claims 34 and 27, 28, 30, 31, and 33. [0007] Specific embodiments of the present invention are claimed in the respective dependent claims. drugs, including proteinsand DNA, formation of biomaterialsin the presence of cells andcell aggregates, andalso formation ofbiomaterials in vivo either within the body or upon the surface of the body. It is possible to form these biomaterials in the presence 35 of sensitive biological materials because of the high self- selectivity of the addition reactions between strong nucleophiles and conjugated unsaturations, that are employed. The strong nucleophile of particular interest in the method described herein is the thiol. [0008] In the formation of the biomaterial in the presence of the sensitive biological materials, two or more liquid components can be mixed together and react to form either an elastic solid, a viscoelastic solid (like a typical solid gel, 40 for example, a gel like gelatin), a viscoelastic liquid (like a typical gel that can be induced to flow, for example, a gel like petroleum jelly), a viscoelastic liquid that is formed of gel microparticles (such as a Carbopol™ gel) or even a viscous liquid of a considerably higher viscosity than either of the two precursor components that are mixed together. The chemical conversion from the precursors to the final material is so selective that it can be carried out in the presence of the sensitive biological material, including the case when the biological material is the body itself. 45 [0009] A novel family of potentially highly biomimetic synthetic polymers has been developed. These polymers can: (i) be converted from liquid precursors to polymeric linear or cross-linked biomaterials either in the laboratory or in situ at a site of implantation; (ii) be hydrogels or more substantially non- swelling materials; (iii) present bioactive molecules that serve as adhesion sites, to provide traction for cell invasion; (iv) present bioactive molecules that serve as protease substrate sites, to make the material degrade in response to enzymes, such as collagenase or plasmin, which are 50 produced by cells during cell migration; (v) present growth factor binding sites, to make the material interact with growth factors in a biomimetic manner, by binding them and then releasing them on cellular demand; and (vi) provide for the delivery of protein drugs by hydrolysis or enzymatic degradation of groups contained within the backbone of the polymers that form the gel. [0010] Accordingly, in a first aspect the invention features a method for making a biomaterial, involving combining two 55 or more precursor components of the biomaterial under conditions that allow polymerization of the two components, where polymerization occurs through self selective reaction between a strong nucleophile and a conjugated unsaturated bond or a conjugated unsaturated group, by nucleophilic addition. The functionality of each component is at least two, and the biomaterial does not comprise unprocessed albumin. In addition, the conjugated unsaturated bond or group is 3 EP 1 181 323 B1 not a maleimide or a vinyl sulfone. [0011] In one embodiment of the first aspect of the invention, the components are selected from the group consisting of oligomers, polymers, biosynthetic proteins or peptides, naturally occurring peptides or proteins, processed naturally occurring peptides or proteins, and polysaccharides. The polymer may be poly(ethylene glycol), poly(ethylene oxide), 5 poly(vinylalcohol), poly(ethylene- co-vinyl alcohol), poly (acrylicacid), poly (ethylene-co-acrylic acid),poly (ethyloxazoline), poly(vinyl pyrrolidone), poly(ethylene-co-vinyl pyrrolidone), poly(maleic acid), poly(ethylene-co-maleic acid), poly(acry- lamide), or poly(ethylene oxide)-co-poly(propylene oxide) block copolymers. The peptide may comprise an adhesion site, growth factor binding site, or protease binding site. [0012] In another embodiment, the components are functionalized to comprise a strong nucleophile or a conjugated 10 unsaturated group or a conjugated unsaturated bond. Preferably the strong nucleophile is a thiol or a group containing a thiol. Preferably the conjugated unsaturated group is an acrylate, an acrylamide, a quinone, or a vinylpyridinium, for example, 2- or 4-vinylpyridinium. In another embodiment, one component has a functionality of at least three. [0013] In yet other embodiments of the first aspect of the invention, the method further comprises combining the precursor components with a molecule that comprises an adhesion site, a growth factor binding site, or a heparin binding 15 site and also comprises either a strong nucleophile or a conjugated unsaturated bond or a conjugated unsaturated group.
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