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Mussel Adhesive Protein Mimetics

Mussels and other marine organisms secrete remarkable protein-based adhesive materials for adherence to the substrates upon which they reside. The protein adhesives are secreted as fluids that undergo an in-situ crosslinking or hardening reaction leading to the formation of a solid adhesive plaque, which mediates the attachment of the organism to a variety of substrates (e.g. minerals, metal surfaces, and wood). One of the unique structural features of mussel adhesive proteins (MAPs) is the presence of L-3,4-dihydroxyphenylalanine (DOPA), an amino acid that is believed to be responsible for both adhesive and crosslinking characteristics of MAPs. DOPA is formed in these proteins by post-translational hydroxylation of tyrosine residues. Although the exact role of DOPA in these proteins is not known, recent evidence suggests that bulk oxidation of DOPA residues leads to intermolecular crosslinking of the plaque proteins giving rise to solidification of the adhesive, whereas interfacial adhesion to substrates is generally believed to be due to chemical interactions between the unoxidized catechol form of DOPA and functional groups at the surface of the solid substrate. Despite extensive studies conducted by Herbert Waite and others that have led to an increased understanding of these remarkable natural adhesives, there remains an incomplete understanding of their adhesive and cohesive mechanisms. Furthermore, mussel adhesive mimetic polymers have not been extensively developed for medical applications.

Our group is actively developing synthetic polymers that mimic the composition and properties of adhesive proteins found in nature. We have several projects whose goals are 1) to employ molecular-level adhesion experiments to gain a detailed understanding of the role of DOPA in biological adhesion; and 2) to use this information to motivate the design of new DOPA-containing macromolecular biomaterials. For example, in one project DOPA containing peptides are being incorporated into biocompatible polymers for potential use as adhesive biomaterials. To facilitate the solid phase synthesis of DOPA-containing peptides for this project, we developed a new Fmoc-DOPA(Ceof) building block, which we used to synthesize a decapeptide motif derived from a mussel adhesive protein (Tetrahedron Letters, vol. 41, 2000, pp. 5795-5798).

Our initial approach was to design gel-forming polymers consisting of single DOPA residues coupled to the endgroups of linear and branched PEGs (Biomacromolecules, vol. 3, 2002, pp. 1038-1047), which rapidly polymerized into hydrogels upon addition of enzymatic and chemical oxidizers. There is some evidence in the literature that the unoxidized (catechol) form of DOPA is more adhesive to metal oxide surfaces than oxidized forms of DOPA. Although adhesion experiments designed to test this hypothesis are underway (collaboration with the Shull group), we have also been exploring the design of DOPA-containing polymers that have the ability to solidify without relying upon oxidation of DOPA. Our first effort in this area was to couple DOPA residues to the endgroups of ABA type block copolymers, and to take advantage of thermal gelation of aqueous solutions of these polymers. DOPA-containing PEO-PPO-PEO block copolymers were synthesized, and aqueous solutions of these polymers were found to undergo a sol-gel transition when warmed from ambient to body temperature(Biomacromolecules, vol. 3, 2002, pp. 397-406).

To the best of our knowledge, this was the first report of a DOPA-containing polymer that is capable of gelling in the absence of oxidizing agents. In the same paper, we demonstrated that the introduction of DOPA significantly increased the adhesive interactions of the block copolymers to mucin, a major macromolecular component of mucosal membranes.

We also exploring the use of transglutaminase enzymes to crosslink DOPA-c ontaining peptide modified polymers into hydrogels (Journal of the American Chemical Society, vol. 125, 2003, pp. 14298-14299). More information can be found in the section on Injectable Biomaterials and Tissue Engineering.

More recently, we have been designing DOPA mimetic monomers capable of polymerization by free radical or atom transfer radical polymerization (ATRP) methods. In a recent paper, N-methacrylated DOPA monomers were synthesized and copolymerized with PEG diacrylate by ultraviolet and visible light to form hydrogels( Lee J. Biomaterials Science Paper 2004). To our knowledge, this is the first report of a DOPA-containing hydrogel formed by photopolymerization. Despite a retarding inhibitory effect of DOPA on photopolymerization,
DOPA-containing monomers were successfully incorporated into PEG hydrogels. A contact mechanical test was performed on the photocured gels and the elastic moduli were obtained by fitting the load-displacement data using a Hertzian relationship, demonstrating that the gels possess moduli sufficient for use in many biomedical applications. Controlled polymerization techniques such as ATRP are also being explored for synthesis of DOPA containing polymer hydrogels. Experiments aimed at determining the adhesive properties of these hydrogels are underway. The resulting hydrogels do not require oxidizing reagents to gel; the incorporation of DOPA into hydrogels in the unoxidized state may prove to be an important tool in further understanding the role of DOPA in mussel adhesive proteins and may lead to new adhesive hydrogels for biomedical applications.

Finally, we are also utilizing mussel adhesive protein mimetic peptides to anchor nonfouling polymers onto surfaces for control of biointerfaces. More information on this project can be found in the section on Biointerfaces/Biofouling Research.