Multifunctionalizable hydrogel coatings on titanium interfaces are useful in a wide range of biomedical applications utilizing titanium-based materials. In this study, furan-protected maleimide groups containing multi-clickable biocompatible hydrogel layers are fabricated on a titanium surface. Upon thermal treatment, the masked maleimide groups within the hydrogel are converted to thiol-reactive maleimide groups. The thiol-reactive maleimide group allows facile functionalization of these hydrogels through the thiol-maleimide nucleophilic addition and Diels-Alder cycloaddition reactions, under mild conditions. Additionally, the strained alkene unit in the furan-protected maleimide moiety undergoes radical thiol-ene reaction, as well as the inverse-electron-demand Diels-Alder reaction with tetrazine containing molecules. Taking advantage of photo-initiated thiol-ene 'click' reactions, we demonstrate spatially controlled immobilization of the fluorescent dye thiol-containing boron dipyrromethene (BODIPY-SH). Lastly, we establish that the extent of functionalization on hydrogels can be controlled by attachment of biotin-benzyl-tetrazine, followed by immobilization of TRITC-labelled ExtrAvidin. Being versatile and practical, we believe that the described multifunctional and transformable 'clickable' hydrogels on titanium-based substrates described here can find applications in areas involving modification of the interface with bioactive entities.
Keywords: Diels–Alder; click reactions; coatings; hydrogels; inverse-electron Diels–Alder; multi-functional; polymers; thiol-ene; thiol-maleimide; titanium interfaces.