The ability to specify
an adsorbed protein layer through the polymer
chemistry design of immunomodulatory biomaterials is important when
considering a desired immune response, such as reducing pro-inflammatory
activity. Limited work has been undertaken to elucidate the role of
monomer sequence in this process, when copolymeric systems are involved.
In this study, we demonstrate the advantage of an alternating radical
copolymerization strategy as opposed to a random statistical copolymerization
to order monomers in the synthesis of degradable polar-hydrophobic-ionic
polyurethanes (D-PHI), biomaterials originally designed to reduce
inflammatory monocyte activation. A monomer system consisting of a
vinyl-terminated polyurethane cross-linker, maleic acid (MA), and
ethyl vinyl ether (EVE), not only generated a diverse chemical environment
of polar, hydrophobic, and ionic functional groups, but also formed
a charge transfer complex (CTC) reactive to alternating polymerizations.
Conversion of MA and EVE occurred in a constant proportion regardless
of monomer availability, a phenomenon not observed in conventional
D-PHI formulations. For feeds with unequal molar quantities of MA
and EVE, the final conversion was limited and proportional to the
limiting reagent, leading to an overall higher polyurethane cross-linker
content. The presence of a reactive CTC was also found to limit the
monomer conversion. Compared to a D-PHI with random monomer arrangement
using methacrylic acid (MAA) and methyl methacrylate (MMA), a reduction
in Fab region exposure from adsorbed immunoglobulin G and a reduction
in average adherent monocyte activity were found in the sequence-controlled
version. These results represent the first example of using an alternating
copolymerization approach to generate regularly defined polymer chemistries
in radical chain-growth biomaterials for achieving immunomodulation,
and highlight the importance of considering sequence control as a
design strategy for future immunomodulatory biomaterial development.