Smart hydrogels delivered by high pressure aerosolization can prevent peritoneal adhesions

Helena Braet; Peter-Paul Fransen; Yong Chen; Simon Van Herck; Remco Mariën; Valérie Vanhoorne; Wim Ceelen; Annemieke Madder; Steven Ballet; Richard Hoogenboom; Bruno De Geest; Anne Hoorens; Patricia Y W Dankers; Stefaan C De Smedt; Katrien Remaut

doi:10.1016/j.jconrel.2023.08.042

Smart hydrogels delivered by high pressure aerosolization can prevent peritoneal adhesions

J Control Release. 2023 Oct:362:138-150. doi: 10.1016/j.jconrel.2023.08.042. Epub 2023 Aug 31.

Authors

Affiliations

¹ Department of Pharmaceutics, Ghent University, Ghent, Belgium; CRIG - Cancer Research Institute Ghent, Ghent, Belgium.
² UPyTher BV, Eindhoven, the Netherlands.
³ Department of Pharmaceutics, Ghent University, Ghent, Belgium.
⁴ CRIG - Cancer Research Institute Ghent, Ghent, Belgium; Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
⁵ CRIG - Cancer Research Institute Ghent, Ghent, Belgium; Department of Organic and Macromolecular Chemistry, Ghent University, Ghent, Belgium.
⁶ Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
⁷ CRIG - Cancer Research Institute Ghent, Ghent, Belgium; Department of Pathology, Ghent University Hospital, Ghent, Belgium.
⁸ Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
⁹ Department of Pharmaceutics, Ghent University, Ghent, Belgium; CRIG - Cancer Research Institute Ghent, Ghent, Belgium. Electronic address: katrien.remaut@ugent.be.

PMID: 37619864
DOI: 10.1016/j.jconrel.2023.08.042

Abstract

Postoperative peritoneal adhesions occur in the majority of patients undergoing intra-abdominal surgery and are one of the leading causes of hospital re-admission. There is an unmet clinical need for effective anti-adhesive biomaterials, which can be applied evenly across the damaged tissues. We examined three different responsive hydrogel types, i.e. a thermosensitive PLGA-PEG-PLGA, a pH responsive UPy-PEG and a shear-thinning hexapeptide for this purpose. More specifically, their potential to be homogeneously distributed in the peritoneal cavity by high pressure nebulization and prevent peritoneal adhesions was evaluated. Solutions of each polymer type could be successfully nebulized while retaining their responsive gelation behavior in vitro and in vivo. Furthermore, none of the polymers caused in vitro toxicity on SKOV3-IP2 cells. Following intraperitoneal administration, both the PLGA-PEG-PLGA and the hexapeptide hydrogels resulted in local inflammation and fibrosis and failed in preventing peritoneal adhesions 7 days after adhesion induction. In contrast, the pH sensitive UPy-PEG formulation was well tolerated and could significantly reduce the formation of peritoneal adhesions, even outperforming the commercially available Hyalobarrier® as positive control. To conclude, local nebulization of the bioresponsive UPy-PEG hydrogel can be considered as a promising approach to prevent postsurgical peritoneal adhesions.

Keywords: Intraperitoneal drug delivery; Nebulization; PIPAC; Peritoneal adhesions; Postoperative adhesions; Smart hydrogels.