title: Comparative stability of the bioresorbable ferric crosslinked hyaluronic acid adhesion prevention solutions.
abstract: The Intergel® ferric crosslinked hyaluronate (FeHA) adhesion prevention solution (APS) (FDA) is associated with serious post-operative complications (Henley, http://www.lawyersandsettlements.com/features/gynecare-intergel/intergel-timeline.html, 2007; FDA, 2003; Roman et al., Fertil Steril 2005, 83 Suppl 1:1113-1118; Tang et al., Ann Surg 2006;243(4):449-455; Wiseman, Fertil Steril 2006;86(3):771; Wiseman, Fertil Steril 2006;85(4):e7). This prompted us to examine the in situ stability of crosslinked HA materials to hyaluronidase lyase degradation. Variables such as ferric ionic crosslink density, HA concentration, gel geometry, and molecular weight (MW) of HA polymer were studied. Various formulations of the crosslinked "in house" [Isayeva et al., J Biomed Mater Res: Part B - Appl Biomater 2010, 95B (1):9-18] FeHA (0.5%, w/v; 30, 50, 90% crosslinked), the Intergel® FeHA (0.5%, w/v; 90%), and the non-crosslinked HA (0.05-0.5%, w/v) were degraded at a fixed activity of hyaluronidase lyase from Streptomyces hyalurolyticus (Hyase) at 37°C over time according to the method [Payan et al., J Chrom B: Biomed Sci Appl 1991;566(1):9-18]. Under our conditions, the data show that the crosslink density affects degradation the most, followed by HA concentration and then gel geometry. We found that MW has no effect. Our results are one possible explanation of the observations that the Intergel® FeHA APS (0.5%, w/v; 90%) material persisted an order of magnitude longer than expected [t1/2 = 500 hrs vs. t1/2 = 50 hrs (FDA; Johns et al., Fertil Steril 1997;68(1):37-42)]. These data also demonstrate the sensitivity of the in vitro hyaluronidase assay to predict the in situ stability of crosslinked HA medical products as previously reported [Sall et al., Polym Degrad Stabil 2007;92(5):915-919].
authors.affiliation: Division of Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland, USA. Hoan-My.Luu@fda.hhs.gov
authors.forename: Hoan-My Do
authors.initials: HM
authors.lastname: Luu
authors.forename: Angela
authors.initials: A
authors.lastname: Chen
authors.forename: Irada S
authors.initials: IS
authors.lastname: Isayeva
mesh_terms: D001672:Biocompatible Materials / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents; D004355:Drug Stability; D005290:Ferric Compounds / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D005782:Gels; D006801:Humans; D006820:Hyaluronic Acid / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D006821:Hyaluronoglucosaminidase; D008422:Materials Testing; D008970:Molecular Weight; D012996:Solutions; D000267:Tissue Adhesions / Q000517:prevention & control*
chemical_list: D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D005290:Ferric Compounds; D005782:Gels; D012996:Solutions; C550243:intergel; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase
keywords: FeHA APS); FeHA adhesion prevention solution (Intergel®; HA clearance; HA digests; Intergel®; abdominal tissue adhesions (ATA); adhesion; adhesion barriers (AB); enzymatic degradation; ferric crosslinking hyaluronic acid (FeHA); gel; half life (t1/2); hexasaccharides (6S); high pressure liquid chromatography (HPLC); hyaluronic acid (HA); hyaluronidase (Hyase); tetrasaccharides (4S)