Pareja Tello Rubén, Cerveró-Varona Adrián, Prencipe Giuseppe, Molinaro Giuseppina, Pinnarò Veronica, Haidar-Montes Arlette Alina, Correia Alexandra, Hietala Sami, Stöckl Johannes, Hirvonen Jouni, Barreto Goncalo, Russo Valentina, Barboni Barbara, Santos Hélder A
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, 00014 Helsinki, Finland.
Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy.
ACS Appl Mater Interfaces. 2025 Jan 15;17(2):2977-2990. doi: 10.1021/acsami.4c16659. Epub 2025 Jan 1.
Amniotic epithelial stem cells (AEC) hold potential for tissue regeneration, especially through their conditioned medium (AEC-CM) due to their immunomodulatory and regenerative effects. Nevertheless, advanced drug delivery systems such as hydrogels are needed to enable clinical applications. Herein, an gellable hyaluronic acid and polyethylene glycol-based iEDDA-cross-linked hydrogel was developed for the encapsulation and controlled release of AEC-CM. The developed system was formed by norbornene-modified hyaluronic acid and tetrazine-modified polyethylene glycol functionalized with heparin. The hydrogel was formed by mixing both precursor polymers, displaying fast cross-linking kinetics and showcasing a highly porous inner structure and low swelling properties. Moreover, the heparin-functionalized system allowed the sustained release of predominant growth factors from AEC-CM over 14 days. studies in peripheral blood mononuclear cells (PBMCs) showed an enhanced suppression efficacy and a significant shift toward the M2 macrophage phenotype in comparison with nonencapsulated AEC-CM. Therefore, this work provides a suitable alternative for the encapsulation of AEC-CM in a hydrogel formulation, highlighting its potential as an alternative immunomodulatory therapeutic tool for tissue regeneration.
羊膜上皮干细胞（AEC）具有组织再生的潜力，特别是通过其条件培养基（AEC-CM），因为它们具有免疫调节和再生作用。然而，需要先进的药物递送系统，如水凝胶，以实现临床应用。在此，开发了一种可凝胶化的透明质酸和基于聚乙二醇的应变促进点击化学（iEDDA）交联水凝胶，用于封装和控制释放AEC-CM。所开发的系统由降冰片烯修饰的透明质酸和用肝素功能化的四嗪修饰的聚乙二醇形成。通过混合两种前体聚合物形成水凝胶，其显示出快速的交联动力学，并展现出高度多孔的内部结构和低溶胀特性。此外，肝素功能化系统允许AEC-CM中的主要生长因子在14天内持续释放。对外周血单核细胞（PBMC）的研究表明，与未封装的AEC-CM相比，其抑制效果增强，并且向M2巨噬细胞表型发生了显著转变。因此，这项工作为将AEC-CM封装在水凝胶制剂中提供了一种合适的替代方案，突出了其作为组织再生的替代免疫调节治疗工具的潜力。
