Department of Biomedical Engineering, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong 999077, China.
Mater Horiz. 2021 Jun 1;8(6):1722-1734. doi: 10.1039/d1mh00244a. Epub 2021 Apr 13.
Dynamic hydrogels cross-linked by weak and reversible physical interactions enhance the 3-dimensional (3D) spreading and mechanosensing abilities of encapsulated cells in a matrix. However, the highly dynamic nature of these physical cross-links also results in low mechanical stiffness in the hydrogel network and high tether compliance of the cell adhesion motifs attached to the network. The resulting low force feedback of the soft hydrogel network impedes the efficient activation of mechanotransduction signalling in the encapsulated cells. Herein, we demonstrate that the chemical incorporation of acryloyl nanoparticle-based cross-linkers creates regionally stiff network structures in the dynamic supramolecular hydrogels without compromising the dynamic properties of the cell-adaptable inter-nanoparticle hydrogel network. The obtained dynamic hydrogels with a heterogeneous hydrogel network topology expedite the development of adhesion structures, 3D spreading, and mechanosensing of the encapsulated stem cells, as evidenced by the upregulated expression of key biomarkers such as vinculin, FAK, and YAP. This enhanced spreading and mechanotransduction promotes the osteogenic differentiation of the encapsulated stem cells. In contrast, doping with physically entrapped nanoparticles or molecular cross-linkers (PEGDA) cannot locally reinforce the dynamic hydrogel network and therefore fails to facilitate cell mechanosensing or differentiation in the 3D hydrogels. We further show that the dynamic hydrogels with a locally stiffened network promote the in situ regeneration of bone defects in an animal model. Our findings provide valuable insights into the design of the supramolecular dynamic hydrogels with biomimetic hierarchical biomechanical structures as the optimized carrier material for stem cell-based therapies.
通过弱和可逆的物理相互作用交联的动态水凝胶增强了基质中被包裹细胞的 3 维（3D）扩散和机械感知能力。然而，这些物理交联的高度动态性质也导致水凝胶网络的机械刚度低和附着在网络上的细胞粘附基序的链柔韧性高。软水凝胶网络的低力反馈阻碍了被包裹细胞中机械转导信号的有效激活。在此，我们证明了丙烯酰基纳米粒子基交联剂的化学掺入在动态超分子水凝胶中创建了局部刚性网络结构，而不会影响可适应细胞的纳米粒子间水凝胶网络的动态特性。所获得的具有不均匀水凝胶网络拓扑结构的动态水凝胶加速了被包裹干细胞的粘附结构、3D 扩散和机械感知的发展，这表现在关键生物标志物如 vinculin、FAK 和 YAP 的表达上调。这种增强的扩散和机械转导促进了被包裹干细胞的成骨分化。相比之下，掺杂物理包埋的纳米粒子或分子交联剂（PEGDA）不能局部增强动态水凝胶网络，因此不能促进 3D 水凝胶中的细胞机械感知或分化。我们进一步表明，具有局部增强网络的动态水凝胶促进了动物模型中骨缺损的原位再生。我们的研究结果为设计具有仿生分级生物力学结构的超分子动态水凝胶提供了有价值的见解，这些水凝胶作为基于干细胞的治疗的优化载体材料。
