Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands.
Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands.
J Am Chem Soc. 2024 Sep 4;146(35):24330-24347. doi: 10.1021/jacs.4c04988. Epub 2024 Aug 20.
Dynamic hydrogels are attractive platforms for tissue engineering and regenerative medicine due to their ability to mimic key extracellular matrix (ECM) mechanical properties like strain-stiffening and stress relaxation while enabling enhanced processing characteristics like injectability, 3D printing, and self-healing. Systems based on imine-type dynamic covalent chemistry (DCvC) have become increasingly popular. However, most reported polymers comprising aldehyde groups are based on either end-group-modified synthetic or side-chain-modified natural polymers; synthetic versions of side-chain-modified polymers are noticeably absent. To facilitate access to new classes of dynamic hydrogels, we report the straightforward synthesis of a water-soluble copolymer with a tunable fraction of pendant aldehyde groups (12-64%) using controlled radical polymerization and their formation into hydrogel biomaterials with dynamic cross-links. We found the polymer synthesis to be well-controlled with the determined reactivity ratios consistent with a blocky gradient microarchitecture. Subsequently, we observed fast gelation kinetics with imine-type cross-linking. We were able to vary hydrogel stiffness from ≈2 to 20 kPa, tune the onset of strain-stiffening toward a biologically relevant regime (σ ≈ 10 Pa), and demonstrate cytocompatibility using human dermal fibroblasts. Moreover, to begin to mimic the dynamic biochemical nature of the native ECM, we highlight the potential for temporal modulation of ligands in our system to demonstrate ligand displacement along the copolymer backbone via competitive binding. The combination of highly tunable composition, stiffness, and strain-stiffening, in conjunction with spatiotemporal control of functionality, positions these cytocompatible copolymers as a powerful platform for the rational design of next-generation synthetic biomaterials.
动态水凝胶因其能够模拟关键的细胞外基质（ECM）机械性能（如应变硬化和应力松弛），同时具有增强的加工特性（如可注射性、3D 打印和自修复），因此成为组织工程和再生医学的有吸引力的平台。基于亚胺型动态共价化学（DCvC）的系统变得越来越流行。然而，大多数报道的包含醛基的聚合物都是基于末端基团修饰的合成或侧链修饰的天然聚合物；侧链修饰的聚合物的合成版本明显不存在。为了方便获得新类别的动态水凝胶，我们报告了使用可控自由基聚合合成具有可调节比例的侧挂醛基（12-64%）的水溶性共聚物的简单方法，并将其形成具有动态交联的水凝胶生物材料。我们发现聚合物合成具有良好的控制，确定的反应性比率与块状梯度微结构一致。随后，我们观察到亚胺型交联的快速凝胶化动力学。我们能够将水凝胶的刚度从约 2 至 20kPa 变化，将应变硬化的起始点调整到与生物学相关的范围（σ≈10Pa），并使用人真皮成纤维细胞证明细胞相容性。此外，为了开始模拟天然 ECM 的动态生化性质，我们强调了在我们的系统中对配体进行时间调制的潜力，以通过竞争结合在共聚物主链上证明配体置换。高度可调的组成、刚度和应变硬化的组合，结合功能的时空控制，使这些细胞相容性共聚物成为下一代合成生物材料的合理设计的强大平台。
