Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G 1M1, Canada.
Ted Rogers Centre for Heart Research, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1M1, Canada.
ACS Biomater Sci Eng. 2020 Aug 10;6(8):4433-4445. doi: 10.1021/acsbiomaterials.0c00496. Epub 2020 Jul 8.
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.
通过对免疫调节生物材料的聚合物化学设计来指定吸附蛋白质层的能力对于考虑所需的免疫反应（例如减少促炎活性）非常重要。当涉及共聚体系时，已经进行了有限的工作来阐明单体序列在该过程中的作用。在这项研究中，我们展示了与随机统计共聚相比，交替自由基共聚策略在可降解极性-疏水性-离子型聚氨酯（D-PHI）合成中的优势，生物材料最初旨在减少炎症单核细胞的激活。由乙烯基封端的聚氨酯交联剂、马来酸（MA）和乙基乙烯基醚（EVE）组成的单体系统不仅产生了多种多样的极性、疏水性和离子官能团的化学环境，而且还形成了对交替聚合有反应性的电荷转移复合物（CTC）。MA 和 EVE 的转化率无论单体的可用性如何都以恒定比例发生，这是在常规 D-PHI 配方中未观察到的现象。对于 MA 和 EVE 摩尔量不等的进料，最终转化率受到限制且与限制试剂成比例，导致整体聚氨酯交联剂含量更高。还发现存在反应性 CTC 会限制单体转化率。与使用甲基丙烯酸（MAA）和甲基丙烯酸甲酯（MMA）的具有随机单体排列的 D-PHI 相比，在序列控制版本中，发现吸附免疫球蛋白 G 的 Fab 区域暴露减少，平均粘附单核细胞活性降低。这些结果代表了首次使用交替共聚方法在自由基链增长生物材料中生成规则定义的聚合物化学以实现免疫调节的实例，并强调了考虑序列控制作为未来免疫调节生物材料开发的设计策略的重要性。
