A Multifunctional Bilayer Hydrogel for Effective Pancreatic Fistula Prevention and Post‐Surgical Adhesion Control

ABSTRACT Despite remarkable advancements in hydrogel‐based medical applications in recent years, their clinical translation for pancreatic fistula management remains challenging owing to the moist surgical environment and complex post‐pancreatectomy pathophysiology. To address the clinical need for reliable wet‐adhesion materials to prevent postoperative pancreatic fistula after distal pancreatectomy (DP‐POPF) and postoperative adhesive intestinal obstruction, we developed an asymmetric bilayer hydrogel (BH) patch that integrates an adhesive pancreatic layer (APL) and an anti‐adhesion layer (AAL). The APL combines N‐ hydroxysuccinimide‐mediated covalent bonding with xanthan gum‐driven interfacial dehydration for robust wet‐tissue adhesion, the AAL, composed of poly(sulfobetaine methacrylate)‐carboxymethyl chitosan, prevents fibrosis via surface hydration; the BH hydrogel incorporates Ceffe, a cell‐free fat extract possessing anti‐inflammatory and proangiogenic properties. The BH patch exhibits exceptional mechanical strength, prolonged post‐swelling adhesion retention, and enzymatic resistance. In vitro and in vivo studies confirm its outstanding biocompatibility, antibacterial efficacy, and adhesion prevention in rat models. In a DP rat model, the Ceffe@BH group displayed significantly reduced POPF incidence versus the normal saline and hand‐sewn anastomosis groups, as demonstrated by reduced drain fluid amylase, attenuated inflammation (↓TNF‐α/IL‐6), enhanced angiogenesis, and effective adhesion prevention. This suture‐free, multifunctional hydrogel presents a standardized solution for POPF with broad potential for wet‐tissue surgical applications.