Chemical and biological engineering strategies to make and modify next-generation hydrogel biomaterials

Progress and potentialAdvanced hydrogel biomaterials have enabled near-limitless opportunities in tissue engineering, synthetic biology, therapeutic design and delivery, and advanced information storage. Innovation underlying these novel constructs stems from creative integration of cutting-edge efforts from traditionally disparate disciplines including click chemistry, enzymatic semisynthesis, and DNA nanotechnology. As these material tools mature beyond permissive and statically uniform 3D scaffolds to user-customized and exogenously controlled 4D environments, a systematic attempt to define past achievements and chart future frontiers is essential.SummaryThere is a growing interest in the development of technologies to probe and direct in vitro cellular function for fundamental organoid and stem cell biology, functional tissue and metabolic engineering, and biotherapeutic formulation. Recapitulating many critical aspects of the native cellular niche, hydrogel biomaterials have proved to be a defining platform technology in this space, catapulting biological investigation from traditional two-dimensional (2D) culture into the 3D world. Seeking to better emulate the dynamic heterogeneity characteristic of all living tissues, global efforts over the last several years have centered on upgrading hydrogel design from relatively simple and static architectures into stimuli-responsive and spatiotemporally evolvable niches. Toward this end, advances from traditionally disparate fields, including bioorthogonal click chemistry, chemoenzymatic synthesis, and DNA nanotechnology, have been co-opted and integrated to construct 4D-tunable systems that undergo preprogrammed functional changes in response to user-defined inputs. In this review, we highlight how advances in synthetic, semisynthetic, and bio-based chemistries have played a critical role in the triggered creation and customization of next-generation hydrogel biomaterials. We also chart how these advances stand to energize the translational pipeline of hydrogels from bench to market and close with an outlook on outstanding opportunities and challenges that lay ahead.Graphical abstract