Materials Science and Engineering Program, University of California, Riverside, 900 University Avenue, Riverside, California 92521, United States.
Department of Bioengineering, University of California, Riverside, 900 University Avenue, Riverside, California 92521, United States.
ACS Appl Bio Mater. 2021 Mar 15;4(3):2408-2428. doi: 10.1021/acsabm.0c01300. Epub 2021 Feb 15.
This article reports tunable crosslinking, reversible phase transition, and three-dimensional printing (3DP) of hyaluronic acid (HyA) hydrogels via dynamic coordination of Fe ions with their innate carboxyl groups for the first time. The concentrations of Fe and H ions and the reaction time determine the tunable ratios of mono-, bi-, and tridentate coordination, leading to the low-to-high crosslinking densities and reversible solid-liquid phase transition of HyA hydrogels. At the monodentate-dominant coordination, the liquid hydrogels have low crosslinking densities (HyA_L). At the mixed coordination of mono-, bi-, and tridentate bonding, the solid hydrogels have medium crosslinking densities (HyA_M). At the tridentate-dominant coordination, the solid hydrogels have high crosslinking densities (HyA_H). The reversible solid-liquid phase transitions among HyA_L, HyA_M, and HyA_H were achieved via controlling the concentrations of Fe and H ions and reaction time. When the crosslinking densities are between HyA_L and HyA_M, the hydrogels become 3D printable (HyA_P). HyA_P hydrogels were 3D-printed successfully using cold-stage or direct writing methods, and the 3D constructs achieved better structural stability using the latter method. In the direct exposure culture with bone marrow-derived mesenchymal stem cells, the 3D-printed HyA_H (HyA_H_3D) and HyA_H hydrogels showed higher average cell adhesion densities than the HyA_M, HyA_P, and HyA_L hydrogel groups under both direct and indirect contact conditions. For all hydrogel groups, cell adhesion densities under direct contact conditions were statistically lower than the same groups under indirect contact conditions. In this article, we elucidated the mechanisms of dynamic coordination and the relationships among the key parameters in controlling the tunable crosslinking, reversible phase transition, and 3DP of HyA hydrogels without blending with other polymers or adding functional groups. This approach can be potentially adapted to crosslink and 3D print other polymeric hydrogels with carboxyl groups, which is promising for a wide range of applications.
本文首次报道了通过 Fe 离子与天然羧基的动态配位，实现透明质酸（HyA）水凝胶的可调交联、相转变和三维打印（3DP）。Fe 和 H 离子的浓度和反应时间决定了单、双和三配位的可调比例，从而导致 HyA 水凝胶的低至高交联密度和固液相转变的可逆性。在单齿配位占主导的情况下，液体水凝胶具有低交联密度（HyA_L）。在单、双和三配位的混合配位下，固体水凝胶具有中等交联密度（HyA_M）。在三齿配位占主导的情况下，固体水凝胶具有高交联密度（HyA_H）。通过控制 Fe 和 H 离子的浓度和反应时间，可以实现 HyA_L、HyA_M 和 HyA_H 之间的可逆固液相转变。当交联密度在 HyA_L 和 HyA_M 之间时，水凝胶可进行 3D 打印（HyA_P）。使用冷台或直接书写方法成功地对 HyA_P 水凝胶进行了 3D 打印，并且后一种方法使 3D 构建体具有更好的结构稳定性。在骨髓间充质干细胞的直接暴露培养中，与 HyA_M、HyA_P 和 HyA_L 水凝胶组相比，3D 打印的 HyA_H（HyA_H_3D）和 HyA_H 水凝胶在直接和间接接触条件下的平均细胞黏附密度更高。对于所有水凝胶组，在直接接触条件下的细胞黏附密度均明显低于间接接触条件下的同一组。在本文中，我们阐明了动态配位的机制以及控制 HyA 水凝胶可调交联、相转变和 3DP 的关键参数之间的关系，而无需与其他聚合物共混或添加官能团。该方法有望适应具有羧基的其他聚合物水凝胶的交联和 3D 打印，具有广泛的应用前景。
