Polymeric Smart Materials with Incorporated Small Molecules for Tissue Engineering: A Comprehensive Review.

This review presents an interdisciplinary analysis of small-molecule-encapsulated smart polymer materials for tissue engineering. Key design principles, including biocompatibility, degradation, and mechanical properties, are discussed, as well as the fabrication methods (hydrogels, electrospinning, porous matrices, and 3D printing). The following strategies for the immobilization of therapeutic agents are compared: physical retention, affinity binding, secondary carriers, post-loading, and covalent conjugation. Four main release mechanisms are analyzed, as well as material characterization, and the release kinetics are discussed. Preclinical in vitro and in vivo studies, including the disease models and the mechanistic validation, are presented, as well as a critical review of the clinical trials, identifying the following main reasons for failure: the lack of the superiority over the standard therapy, the complexity of the manufacturing, and the scale-up. The role of artificial intelligence in the acceleration of property prediction and system optimization is highlighted. Limitations are outlined and it is shown that successful translation requires a minimum level of sufficient complexity and a reproducible relationship between the structure, release, and the therapeutic window.