Injectable Shear-Thinning Polyampholyte Hydrogel Derived From Functionalized Hyaluronan for pH-Responsive Prevention...

Postoperative peritoneal adhesion (PPA) is a pathological fibrous connection that forms between peritoneal surfaces after abdominal surgery, often resulting in infertility, intestinal obstruction, and increased difficulty during secondary operations. Despite numerous biomaterial-based strategies for adhesion prevention, their efficacy remains limited. To address this challenge, we synthesized N,N-dimethylaminopropylamine-conjugated hyaluronic acid (HA-DMAPA), reporting the first preparation of this conjugate. This polyampholyte rapidly forms a hydrogel under physiological conditions via reversible electrostatic intra- and intermolecular interactions between the tertiary amines of DMAPA and the unreacted carboxyl groups of HA, exhibiting pH-dependent gelation and degradation. The HA-DMAPA hydrogel demonstrated mechanical stability near its isoelectric point (pH 5-5.5) and accelerated degradation at physiological pH 7.4, indicating its potential as an inflammation-responsive polyampholyte. The material showed excellent injectability and instant self-healing due to strong shear-thinning properties, along with minimal cytotoxicity, reduced cell adhesion, enzymatic degradability, and remarkable hemocompatibility despite amine modification. In vivo, HA-DMAPA effectively reduced severe postoperative peritoneal adhesions in both rat cecum abrasion and partial hepatectomy models. Overall, this newly developed polyampholyte hydrogel derived from functionalized hyaluronan is simple, safe, and highly practical for surgical use, offering a promising strategy for preventing severe adhesions that remain challenging to manage in clinical practice.