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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 in situ 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. In vitro 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.

The electrospinning technique is a commonly employed approach to fabricate fibers intended for various tissue engineering applications. The aim of this study is to develop a novel strategy for tendon repair through the use of aligned poly(ε-caprolactone) (PCL) and poly(glycerol sebacate) (PGS) fibers fabricated in benign solvents, and further explore the potential application of PGS in tendon tissue engineering (TTE). The fibers were characterized for their morphological and physicochemical properties; amniotic epithelial stem cells (AECs) were used to assess the fibers teno-inductive and immunomodulatory potential due to their ability to teno-differentiate undergoing first a stepwise epithelial to mesenchymal transition, and due to their documented therapeutic role in tendon regeneration. The addition of PGS to PCL improved the spinnability of the polymer solution, as well as the uniformity and directionality of the so-obtained fibers. The mechanical properties were in the range of most TTE applications, specifically in the case of PCL/PGS 4:1 and 2:1 ratios. Compared to PCL alone, the same ratios also allowed a better AECs infiltration and growth over 7 days of culture, and triggered the activation of tendon-related genes (SCX, COL1, TNMD) and the expression of tenomodulin (TNMD) at the protein level. Concerning the immunomodulatory properties, both PCL and PCL/PGS fibers negatively affected the immunomodulatory profile of AECs, up-regulating both anti-inflammatory (IL-10) and pro-inflammatory (IL-12) cytokines over 7 days of culture. Overall, PCL/PGS 2:1 fibers fabricated with benign solvents proved to be the most suitable composition for TTE application based on their topographical cues, mechanical properties, biocompatibility, and teno-inductive properties., (© 2024 The Author(s). Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)