Two-dimensional and three-dimensional cell culture systems are widely used for biological studies, and are the basis of the organoid, tissue engineering and organ-on-chip research fields in applications such as disease modelling and drug screening. The natural extracellular matrix of tissues, a complex scaffold with varying chemical and mechanical properties, has a critical role in regulating important cellular functions such as spreading, migration, proliferation and differentiation, as well as tissue morphogenesis. Hydrogels are biomaterials that are used in cell culture systems to imitate critical features of a natural extracellular matrix. Chemical strategies to synthesize and tailor the properties of these hydrogels in a controlled manner, and manipulate their biological functions in situ, have been developed. In this Review, we provide the rational design criteria for predictably engineering hydrogels to mimic the properties of the natural extracellular matrix. We highlight the advances in using biocompatible strategies to engineer hydrogels for cell culture along with recent developments to dynamically control the cellular environment by exploiting stimuli-responsive chemistries. Finally, future opportunities to engineer hydrogels are discussed, in which the development of novel chemical methods will probably have an important role.
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