Click hydrogels, microgels and nanogels: Emerging platforms for drug delivery and tissue engineering

Hydrogels, microgels and nanogels have emerged as versatile and viable platforms for sustained protein release, targeted drug delivery, and tissue engineering due to excellent biocompatibility, a microporous structure with tunable porosity and pore size, and dimensions spanning from human organs, cells to viruses. In the past decade, remarkable advances in hydrogels, microgels and nanogels have been achieved with click chemistry. It is a most promising strategy to prepare gels with varying dimensions owing to its high reactivity, superb selectivity, and mild reaction conditions. In particular, the recent development of copper-free click chemistry such as strain-promoted azide-alkyne cycloaddition, radical mediated thiol-ene chemistry, Diels-Alder reaction, tetrazole-alkene photo-click chemistry, and oxime reaction renders it possible to form hydrogels, microgels and nanogels without the use of potentially toxic catalysts or immunogenic enzymes that are commonly required. Notably, unlike other chemical approaches, click chemistry owing to its unique bioorthogonal feature does not interfere with encapsulated bioactives such as living cells, proteins and drugs and furthermore allows versatile preparation of micropatterned biomimetic hydrogels, functional microgels and nanogels. In this review, recent exciting developments in click hydrogels, microgels and nanogels, as well as their biomedical applications such as controlled protein and drug release, tissue engineering, and regenerative medicine are presented and discussed.