Crosslinker structure modulates bulk mechanical properties and dictates hMSC behavior on hyaluronic acid hydrogels.
Crosslinker structure modulates bulk mechanical properties and dictates hMSC behavior on hyaluronic acid hydrogels.
复制标题
交联剂结构调节整体机械性能并决定 hMSC 在透明质酸水凝胶上的行为。
DOI：
10.1016/j.actbio.2022.11.027
复制
发表时间：
2023
影响因子：
9.7
通讯作者：
Rosales,AdrianneM
中科院分区：
文献类型：
--
作者：
Morton,LoganD;Castilla-Casadiego,DavidA;Palmer,AjayC;Rosales,AdrianneM
合成水凝胶是有吸引力的平台，部分原因是其高度可调的力学，影响细胞行为和分泌概况。这些力学通常通过改变凝胶中交联的数量或总聚合物浓度来控制，从而导致固有地将网络连接性与总模量耦合的结构-性质关系。相比之下，天然细胞外基质（ECM）含有结构化的生物聚合物，即使在低聚合物含量下也能形成刚性凝胶，促进3D细胞培养和可溶性因子的渗透性。为了模拟天然ECM的层次顺序，这项工作描述了一种合成水凝胶系统，其中使用序列定义的类肽交联剂的结构来调整力学，同时固定网络连接。研究了具有不同二级结构的类肽交联剂：1）螺旋的、分子刚性的类肽，2）非螺旋的、刚性较小的类肽，和3）非结构化的、相对柔性的类肽。当使用较高链刚度的交联剂时，本体水凝胶储能模量增加。体外研究评估了人间充质干细胞（hMSC）在每种水凝胶基质上的活力、增殖、细胞形态和免疫调节活性。基质力学调节hMSC在所开发的基质上的形态，并且所研究的所有水凝胶在TCP上的培养物上上调IDO产生。较软的底物进一步将此上调至平台。总的来说，该系统提供了一个仿生策略解耦水凝胶储能模量从网络连接，使系统的研究hMSC的行为和增强细胞的功能性的生物材料特性的治疗application.Statement的重要性调整水凝胶力学的各种策略已经开发出来，以控制人类间充质干细胞（hMSC）的行为和调节其免疫调节潜力。然而，这些策略通常将力学与网络连接性结合起来，这反过来又改变了其他水凝胶性质，例如渗透性，这可能对hMSC行为产生意想不到的影响。这项工作提出了一种策略，使用不同的二级结构和分子刚性的交联剂来调整水凝胶力学。该策略成功地将水凝胶模量与交联剂化学计量学结合，并模仿天然细胞外基质的分级性质。所开发的水凝胶的模量导致对hMSC形态和增殖的显著影响，并增加免疫调节潜力，表明分子刚性是控制工程化ECM力学用于治疗应用的有希望的途径。
Synthetic hydrogels are attractive platforms due in part to their highly tunable mechanics, which impact cell behavior and secretory profile. These mechanics are often controlled by altering the number of crosslinks or the total polymer concentration in the gel, leading to structure-property relationships that inherently couple network connectivity to the overall modulus. In contrast, the native extracellular matrix (ECM) contains structured biopolymers that enable stiff gels even at low polymer content, facilitating 3D cell culture and permeability of soluble factors. To mimic the hierarchical order of natural ECM, this work describes a synthetic hydrogel system in which mechanics are tuned using the structure of sequence-defined peptoid crosslinkers, while fixing network connectivity. Peptoid crosslinkers with different secondary structures are investigated: 1) a helical, molecularly stiff peptoid, 2) a non-helical, less stiff peptoid, and 3) an unstructured, relatively flexible peptoid. Bulk hydrogel storage modulus increases when crosslinkers of higher chain stiffness are used. In-vitro studies assess the viability, proliferation, cell morphology, and immunomodulatory activity of human mesenchymal stem cells (hMSCs) on each hydrogel substrate. Matrix mechanics regulate the morphology of hMSCs on the developed substrates, and all of the hydrogels studied upregulate IDO production over culture on TCP. Softer substrates further this upregulation to a plateau. Overall, this system offers a biomimetic strategy for decoupling hydrogel storage modulus from network connectivity, enabling systematic study of biomaterial properties on hMSC behavior and enhancement of cellular functionality for therapeutic applications.Statement of significanceVarious strategies to tune hydrogel mechanics have been developed to control human mesenchymal stem cell (hMSC) behavior and regulate their immunomodulatory potential. However, these strategies typically couple mechanics to network connectivity, which in turn changes other hydrogel properties such as permeability that may have unintended effects on hMSC behavior. This work presents a strategy to tune hydrogel mechanics using crosslinkers with different secondary structure and molecular rigidity. This strategy successfully decouples hydrogel moduli from crosslinker stoichiometry and mimics the hierarchical nature of the native extracellular matrix. The moduli of the developed hydrogels led to significant impacts on hMSC morphology and proliferation, and increased immunomodulatory potential, indicating that molecular rigidity is a promising avenue to control engineered ECM mechanics for therapeutic applications.