ABSTRACT A critical frontier in modern medicine involves developing advanced biomaterials capable of dynamically interacting with biological systems to orchestrate healing. Tissue adhesives exemplify this shift, representing a paradigm change from passive fixation to active repair. However, their clinical application is limited by the substantial heterogeneity of tissue characteristics. Herein, we developed a versatile polythioketal (PTK)‐based polyurethane tissue adhesives (PUTAs) platform with tunable mechanical properties and degradation rates. Systematic modulation of ethylene glycol (EG) unit length and thioketal (TK) linkage density within the polythioketal (PTK) diol backbone enabled precise control over material hydrophilicity and degradation site availability, yielding degradation rates spanning from 10% per week to 10% per month in physiological environments. By selecting different PTK diols and diisocyanates, we engineered materials with tissue‐matching mechanics (from 10 2 –10 5 kPa). The resulting PUTAs demonstrated superior adhesion to both soft (>135 kPa) and hard tissues (>6 MPa), substantially outperforming commercial cyanoacrylate glue. All formulations exhibited excellent biocompatibility and effectively promoted healing in both full‐thickness skin wounds and skull open fractures in rodent models. This tunable tissue‐adhesive platform presents a highly adaptable blueprint for clinical translation, paving the way for a broadly applicable design framework for next‐generation biomaterials.
Li et al. (Wed,) studied this question.