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Research Topics > Mussel Adhesive Protein Mimetics
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.
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.
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
