Tissues as a synthetic target - a framework for the multiscale molecular design of thermogelling polymers

Tissues are living, water-swollen composite polymer networks whose dynamic biochemical composition, hierarchical architecture, and mechanics collectively regulate cell behavior and physiological function. Recreating these properties across biological and biomedical contexts (e.g., 2D and 3D cell culture, tissue engineering, organoid culture, and regenerative medicine) remains a critical challenge as existing synthetic matrices cannot fully recapitulate the multiscale organization and dynamic properties of native extracellular matrices. Most hydrogel platforms rely on "drag-n-drop" combinations of polymers, crosslinkers, fabrication methods, and bioactive motifs to approximate the biophysical and biochemical properties of an individual tissue or biomedical context. In this Review, we seek to motivate the pursuit of thermogel-based "plug-n-play" approaches by framing tissues as synthetic targets and examining the potential of polymers that undergo thermally-triggered assembly to serve as modular building blocks for next-generation synthetic ECMs. The ultimate goal is a universal framework for programming composition, structure, mechanics, and biofunction from a common multiscale molecular design language. We first closely examine the composition, assembly, and properties of ECMs to clearly establish targets of interest and processes that may serve as inspiration. Finally, we connect the thermodynamic principles of lower critical solution temperature behavior with macromolecular topology, phase separation, and hierarchical assembly to establish design opportunities for creating thermogelling polymers that more closely mimic the fibrous, hydrated, mechanically adaptive, and cell-instructive nature of native ECMs. We propose that future progress will require the integration of precise polymer synthesis, topology-dictated assembly, macromolecular crowding, high-throughput formulation, and multiscale characterization to establish predictive structure-assembly-property relationships. This framework is intended to facilitate the transition of thermogelling polymers from injectable or temperature-responsive materials to a latent scalable synthetic platform for writing bespoke tissue-like microenvironments from molecularly programmed building blocks.