Kirkpatrick Bruce E, Rubio Miranda T, Yendamuri Tvishi, Elmer Naomi V, Benoit Danielle S W, Guymon C Allan, Anseth Kristi S, Hebner Tayler S
Department of Chemical and Biological Engineering, University of Colorado Boulder, 596 UCB, Boulder, CO, 80309, USA.
BioFrontiers Institute, University of Colorado Boulder, 596 UCB, Boulder, CO, 80309, USA.
J Mater Chem B. 2025 Aug 5. doi: 10.1039/d5tb01237f.
Thiol-Michael addition reactions are widely used for forming cytocompatible and well-defined hydrogels. Numerous types of Michael acceptors have been implemented in these reactions; while maleimides enable rapid crosslinking under physiological conditions and are commonly used for their simplicity, slower-reacting electrophiles such as vinyl sulfones and acrylates offer distinct advantages including improved network homogeneity and ease of handling because of the slower reaction rates. Additionally, thiol-acrylate adducts are hydrolytically labile, whereas thiol-vinyl sulfone adducts are comparably more stable in aqueous environments. Building on our previous work demonstrating radical-mediated degradation of thiol-maleimide hydrogels, we sought to determine whether other thiol-Michael adducts are similarly susceptible to cleavage by radical species. Using both linear and network-forming polymer systems, we found that both Michael-adduct types undergo radical-mediated degradation to varying extents. Furthermore, acrylates are far more prone to radical homopolymerization, enabling semi-orthogonal degradation modes in hydrogels, wherein hydrolytic and radical responses are independently programmed according to the chemical structure and stoichiometric excess of the Michael acceptor. Extending the results of these findings in networks synthesized thiol-Michael addition, we also observed similar radical-mediated degradation behavior in thiol-norbornene networks formed thiol-ene photopolymerization, suggesting that even electron-rich thioethers are degradable under sufficiently aggressive initiation conditions where the concentration of radicals exceeds that of the crosslinks. Together, these results extend the chemical space for engineering hydrogels with variable degradation profiles and illustrate design principles for tuning material responses to multiple chemical stimuli.
硫醇-迈克尔加成反应被广泛用于制备具有细胞相容性且结构明确的水凝胶。在这些反应中已采用了多种类型的迈克尔受体；马来酰亚胺能在生理条件下实现快速交联，且因其操作简便而被普遍使用，而反应较慢的亲电试剂如乙烯基砜和丙烯酸酯则具有明显优势，包括由于反应速率较慢而使网络均匀性提高且易于处理。此外，硫醇-丙烯酸酯加合物在水解时不稳定，而硫醇-乙烯基砜加合物在水性环境中相对更稳定。基于我们之前关于自由基介导硫醇-马来酰亚胺水凝胶降解的研究工作，我们试图确定其他硫醇-迈克尔加合物是否同样容易受到自由基的裂解。使用线性和形成网络的聚合物体系，我们发现两种迈克尔加合物类型都不同程度地经历自由基介导的降解。此外，丙烯酸酯更容易发生自由基均聚反应，从而在水凝胶中实现半正交降解模式，其中水解和自由基响应可根据迈克尔受体的化学结构和化学计量过量独立编程。将这些研究结果扩展到通过硫醇-迈克尔加成合成的网络中，我们还在通过硫醇-烯光聚合形成的硫醇-降冰片烯网络中观察到类似的自由基介导的降解行为，这表明即使是富电子的硫醚在自由基浓度超过交联键浓度的足够剧烈的引发条件下也是可降解的。总之，这些结果扩展了用于设计具有可变降解特性的水凝胶的化学空间，并阐明了调节材料对多种化学刺激响应的设计原则。
