Title:

Synthesis of Bio-Orthogonal Hydrogels via Penicillamine Beta-Thiolactone-Mediated Native Chemical Ligation

Traditional monolayer cell cultures, while widely used, fail to fully replicate the complex in vivo cellular environment. Covalently cross-linked 3D scaffolds offer a more physiologically relevant alternative due to their structural stability and ability to mimic soft tissue architecture. Effective hydrogel cross-linking strategies must demonstrate biocompatibility, rapid kinetics, and minimal cytotoxic byproducts. Native chemical ligation (NCL) is a promising method for hydrogel formation, but prior approaches using alkyl thioesters suffer from slow reaction rates and release of cytotoxic thiol byproducts. In this work, we present a modified NCL strategy using a β-thiolactone to accelerate gelation and eliminate free thiol byproduct release. By functionalizing a 4-arm polyethylene glycol (PEG) with penicillamine-β-thiolactone (PBET), we achieved enhanced reaction kinetics and thiol retention within the hydrogel matrix. This approach represents a significant advancement in the design of cytocompatible, efficient cross-linking strategies for 3D cell culture applications.

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