From passive sealing to active microenvironment remodeling: design strategies, biological effects, and translational challenges of multifunctional hydrogels for postoperative pancreatic fistula prevention.

Postoperative pancreatic fistula (POPF) remains one of the most common and potentially lethal complications following pancreatic surgery, with reported incidence rates ranging from 20% to 64%. Conventional sealing materials-including fibrin glue and polyglycolic acid felt-face rapid degradation in the protease-rich pancreatic microenvironment and loss of adhesion in wet conditions, resulting in a marked contradiction between early positive randomized trials and subsequent negative meta-analyses. In recent years, multifunctional hydrogels have been driving a conceptual transition from "passive physical barriers" to "active microenvironment remodeling" for POPF prevention. This review examines hydrogel design strategies tailored to the extreme postoperative pancreatic microenvironment across multiple dimensions: in the domain of enzyme management, we compare the active enzyme-capturing strategy based on D-amino acid peptides, the enzyme-cleavage-site-elimination strategy using recombinant collagen, and the structural tolerance strategy of self-assembling peptides; in structural-functional integration, we analyze how asymmetric bilayer designs simultaneously achieve wet tissue sealing and anti-adhesion; in functional integration, we delineate the evolutionary trajectory of PVA-based platforms from pure physical barriers to antibacterial/anti-inflammatory/pro-healing multifunctional composites; and in the temporal dimension, we evaluate innovative therapeutic frameworks including "full-cycle management" and dual-functional integration of POPF prevention with tumor immunotherapy. We further provide a critical analysis of key translational gaps from five perspectives: species disparities in animal models, quantitative matching of degradation kinetics with anastomotic healing windows, surgical handlability, scalable manufacturing and sterilization, and the diagnostic-therapeutic closed loop. Among the studies reviewed, all therapeutic multifunctional hydrogels remain at the proof-of-concept stage, predominantly in rat models, with SmartPAN-a diagnostic leak indicator-being the only POPF-related hydrogel device to have entered human trials. Establishing standardized pancreatic juice tolerance assessment systems, validating long-term efficacy and safety in large animal models, and achieving precise quantitative matching between degradation kinetics and anastomotic healing timelines represent the most urgent tasks for advancing clinical translation in this field.