Fabrication of hydrogel microspheres via microfluidics using inverse electron demand Diels-Alder click chemistry-based tetrazine-norbornene for drug delivery and cell encapsulation applications

Rubén Pareja Tello, Shiqi Wang, Flavia Fontana, Alexandra Correia, Giuseppina Molinaro, Sandra López Cerdà, Sami Hietala, Jouni Hirvonen, Goncalo Barreto, Hélder A. Santos*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

5 Citations (Scopus)
33 Downloads (Pure)

Abstract

Microfluidic on-chip production of polymeric hydrogel microspheres (MPs) can be designed for the loading of different biologically active cargos and living cells. Among different gelation strategies, ionically crosslinked microspheres generally show limited mechanical properties, meanwhile covalently crosslinked microspheres often require the use of crosslinking agents or initiators with limited biocompatibility. Inverse electron demand Diels Alder (iEDDA) click chemistry is a promising covalent crosslinking method with fast kinetics, high chemoselectivity, high efficiency and no cross-reactivity. Herein, in situ gellable iEDDA-crosslinked polymeric hydrogel microspheres are developed via water-in-oil emulsification (W/O) glass microfluidics. The microspheres are composed of two polyethylene glycol precursors modified with either tetrazine or norbornene as functional moieties. Using a single co-flow glass microfluidic platform, homogenous MPs of sizes 200-600 μm are developed and crosslinked within 2 minutes. The rheological properties of iEDDA crosslinked bulk hydrogels are maintained with a low swelling degree and a slow degradation behaviour under physiological conditions. Moreover, a high-protein loading capacity can be achieved, and the encapsulation of mammalian cells is possible. Overall, this work provides the possibility of developing microfluidics-produced iEDDA-crosslinked MPs as a potential drug vehicle and cell encapsulation system in the biomedical field.

Original languageEnglish
Pages (from-to)4972-4984
Number of pages13
JournalBiomaterials Science
Volume11
Issue number14
DOIs
Publication statusPublished - 13 Jun 2023
MoE publication typeA1 Journal article-refereed

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