Post-Electrospinning “Triclick” Functionalization of Degradable Polymer Nanofibers

Abstract

4-Dibenzocyclooctynol (DIBO) was used as an initiator for the ring-opening copolymerization of ε-caprolactone and 1,4,8-trioxaspiro[4.6]-9-undecanone (TOSUO) resulting in a series of DIBO end-functionalized copolymers. Following deprotection of the ketone group, the polymers were derivatized with aminooxyl-containing compounds by oxime ligation. Mixtures of keto-and alkyne-derivatized polymers were co-electrospun into well-defined nanofibers containing three separate chemical handles. Strain-promoted azide alkyne cycloaddition (SPAAC), oxime ligation, and copper-catalyzed azide alkyne cycloaddition (CuAAC) were used to sequentially functionalize the nanofibers first with fluorescent reporters and then separately with bioactive Gly-Arg-Gly-Asp-Ser (GRGDS), BMP-2 peptide, and dopamine. This translationally relevant approach facilitates the straightforward derivatization of diverse bioactive molecules that can be controllably tethered to the surface of nanofibers. P olymeric nanofibers have been studied extensively for applications in wound healing and regenerative medicine. 1 Most polymers can be fabricated into nanofibers via melt or electrospinning with highly tunable size and morphology by manipulating various experimental parameters. 2 Nanofibers have been found to influence cell function in a number of ways including morphology, confinement via contact guidance, and mechanical properties. 3,4 While there have been several reports of methods for placing bioactive groups on nanofibers, 5−8 degradable polymers present some significant limitations with regard to conjugation chemistry. To preserve the structural and morphological integrity of the nanofibers, any conjugation method must be compatible with a solvent system orthogonal to the solubility parameters of the polymer. One strategy to overcome this limitation has been to introduce the bioactive species prior to electrospinning. 9,10 While some have successfully utilized this approach, it is inefficient in that a significant fraction of the bioactive species are buried in the nanofiber and, as such, are not bioavailable to the target cell population. The lack of control over surface functionality severely complicates any manufacturing process and regulatory strategy when trying to advance these materials to clinical applications.There have been several demonstrations of peptide-modified nanofibers in biomedicine including bone, 11 neural, 12−14 and vascular applications. 15,16 However, other than integrinmediated adhesion via Gly-Arg-Gly-Asp-Ser (GRGDS) peptides, there are no reports describing the use and utility of multiple (≥3) bioactive groups attached to nanofibers. However, in higher organisms, it is well established that multiple bioactive molecules work synergistically in time-and concentration-dependent manners to regulate any number of cellular functions. 17−19 In order to mimic these complex interactions, strategies for controllably derivatizing electrospun nanofibers are needed to advance our understanding of cellular behavior in vitro and in vivo...

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Ring‐Opening Copolymerization of Maleic Anhydride with Functional Epoxides: Poly(propylene fumarate) Analogues Capable of Post‐Polymerization Modification

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Molecular Architecture and Enhanced Thermal Stability of Electrospun Poly(ε‐caprolactone)/Aminopropyl Isobutyl Polyhedral Oligomeric Silsesquioxane Hybrid Fibers

“…The unique example reported here brings significant insight into the design of hierarchically structured materials with embedded functional ingredients simply through manipulating the phase separation behaviors of complex systems. Furthermore, the AMPOSS existing on the fibers surface also provides chemically active sites for building additional functionality through postelectrospinning functionalization techniques …”