Department of Chemical and Biomolecular Engineering, The Institute for NanoBioTechnology, Physical-Sciences Oncology Center, Johns Hopkins University, Baltimore, MD, 21218, USA.
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
Adv Healthc Mater. 2017 Aug;6(16). doi: 10.1002/adhm.201700523. Epub 2017 May 23.
Gradient hydrogels have been developed to mimic the spatiotemporal differences of multiple gradient cues in tissues. Current approaches used to generate such hydrogels are restricted to a single gradient shape and distribution. Here, a hydrogel is designed that includes two chemical cross-linking networks, biofunctional, and self-healing networks, enabling the customizable formation of modular gradient hydrogel construct with various gradient distributions and flexible shapes. The biofunctional networks are formed via Michael addition between the acrylates of oxidized acrylated hyaluronic acid (OAHA) and the dithiol of matrix metalloproteinase (MMP)-sensitive cross-linker and RGD peptides. The self-healing networks are formed via dynamic Schiff base reaction between N-carboxyethyl chitosan (CEC) and OAHA, which drives the modular gradient units to self-heal into an integral modular gradient hydrogel. The CEC-OAHA-MMP hydrogel exhibits excellent flowability at 37 °C under shear stress, enabling its injection to generate gradient distributions and shapes. Furthermore, encapsulated sarcoma cells respond to the gradient cues of RGD peptides and MMP-sensitive cross-linkers in the hydrogel. With these superior properties, the dual cross-linked CEC-OAHA-MMP hydrogel holds significant potential for generating customizable gradient hydrogel constructs, to study and guide cellular responses to their microenvironment such as in tumor mimicking, tissue engineering, and stem cell differentiation and morphogenesis.
梯度水凝胶的设计是为了模拟组织中多种时空梯度信号的差异。目前用于生成此类水凝胶的方法仅限于单一的梯度形状和分布。在这里，设计了一种水凝胶，其中包含两个化学交联网络、生物功能和自修复网络，能够灵活地形成具有各种梯度分布和形状的模块化梯度水凝胶结构。生物功能网络是通过氧化透明质酸的丙烯酰基（OAHA）与基质金属蛋白酶（MMP）敏感交联剂和 RGD 肽的二硫键之间的迈克尔加成形成的。自修复网络是通过 N-羧乙基壳聚糖（CEC）和 OAHA 之间的动态席夫碱反应形成的，该反应促使模块化梯度单元自行修复成一个整体的模块化梯度水凝胶。在 37°C 下，CEC-OAHA-MMP 水凝胶在剪切应力下具有优异的流动性，使其能够注入以产生梯度分布和形状。此外，包封的肉瘤细胞对水凝胶中 RGD 肽和 MMP 敏感交联剂的梯度信号做出响应。具有这些优异性能的双重交联 CEC-OAHA-MMP 水凝胶在生成可定制的梯度水凝胶结构方面具有重要潜力，可用于研究和指导细胞对其微环境的反应，例如在肿瘤模拟、组织工程以及干细胞分化和形态发生中。
