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Author: de Miguel-Jiménez, Adrián × Type: Text ×

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    Gelation kinetics of thiol-methylsulfone (MS) hydrogel formulations for 3D cell culture
    (Washington, D.C. : American Chemical Society, 2022) de Miguel-Jiménez, Adrián; Ebeling, Bastian; Paez, Julieta I.; Fink-Straube, Claudia; Pearson, Samuel; del Campo, Aranzazu
    Crosslinking chemistries that allow hydrogel formation within minutes are essential to achieve homogeneous networks and cell distributions in 3D cell culture. Thiol-methylsulfone (MS) crosslinking chemistry offers minutes-scale gelation under near-physiological conditions showing many desirable attributes for 3D cell encapsulation. Here we investigate the gelation kinetics and mechanical properties of PEG-based hydrogels formed by thiol-tetrazole methylsulfone (TzMS) crosslinking as a function of buffer, crosslinker structure, and degree of TzMS functionalization. Appropriate buffer selection ensured constant pH throughout crosslinking. The formulation containing cell adhesive ligand RGD and enzymatically-degradable peptide VPM gelled in ca. 4 min at pH 7.5, and stiffness could be increased from hundreds of Pascals to > 1 kPa by using excess VPM. The gelation times and stiffnesses for these hydrogels are highly suitable for 3D cell encapsulations, and pave the way for reliable 3D cell culture workflows in pipetting robots.
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    Cytocompatibility Evaluation of PEG-Methylsulfone Hydrogels
    (Berkeley, CA : University of California, 2023) Trujillo, Sara; Kasper, Jennifer; de Miguel-Jiménez, Adrián; Abt, Britta; Bauer, Alina; Mekontso, Joëlle; Pearson, Samuel; del Campo, Aránzazu
    Methylsulfone derivatized poly(ethylene) glycol (PEG) macromers can be biofunctionalized with thiolated ligands and cross-linked with thiol-based cross-linkers to obtain bioactive PEG hydrogels for in situ cell encapsulation. Methylsulfonyl-thiol (MS-SH) reactions present several advantages for this purpose when compared to other thiol-based cross-linking systems. They proceed with adequate and tunable kinetics for encapsulation, they reach a high conversion degree with good selectivity, and they generate stable reaction products. Our previous work demonstrated the cytocompatibility of cross-linked PEG-MS/thiol hydrogels in contact with fibroblasts. However, the cytocompatibility of the in situ MS-SH cross-linking reaction itself, which generates methylsulfinic acid as byproduct at the cross-linked site, remains to be evaluated. These studies are necessary to evaluate the potential of these systems for in vivo applications. Here we perform an extensive cytocompatibility study of PEG hydrogels during in situ cross-linking by the methylsulfonyl-thiol reaction. We compare these results with maleimide-thiol cross-linked PEGs which are well established for cell culture and in vivo experiments and do not involve the release of a byproduct. We show that fibroblasts and endothelial cells remain viable after in situ polymerization of methylsulfonyl-thiol gels on the top of the cell layers. Cell viability seems better than after in situ cross-linking hydrogels with maleimide-thiol chemistry. The endothelial cell proinflammatory phenotype is low and similar to the one obtained by the maleimide-thiol reaction. Finally, no activation of monocytes is observed. All in all, these results demonstrate that the methylsulfonyl-thiol chemistry is cytocompatible and does not trigger high pro-inflammatory responses in endothelial cells and monocytes. These results make methylsulfonyl-thiol chemistries eligible for in vivo testing and eventually clinical application in the future.