title: pH effect on the synthesis, shear properties, and homogeneity of iron-crosslinked hyaluronic acid-based gel/adhesion barrier.
abstract: Iron-crosslinked hyaluronic acid hydrogel (FeHA) has been used to reduce postsurgical adhesions in patients undergoing open, gynecological surgery. The performance of FeHA gel as an adhesion barrier device is influenced by many factors, including the physicochemical gel properties, which, in turn, depend on the chemistry and conditions of the device manufacturing. In this work, we demonstrate the effect of reaction pH on rheology and homogeneity of FeHA gels formulated in house and also compare the viscoelastic properties of FeHA gels with that of uncrosslinked HA solution of similar HA concentration and ionic strength. Dynamic mechanical analyses provide evidence that the reaction of HA with Fe(III) ions leads to the formation of "weak" gels. The viscoelastic properties and homogeneity of FeHA gels vary depending on the pH at which crosslinking was initiated. When solution pH, at the start of crosslinking, varied between 1.5 and 3, the low-shear rate viscosity of FeHA varied between 10,000 and 40,000 cPoise (10-40 Pa s). The highest steady-state shear viscosity and viscoelasticity were measured when pH was around 2.6, which is similar to the pH-dependent viscoelasticity of pure HA solution. Initiating HA crosslinking at pH ≤ 3 led to relatively homogenous solutions, while crosslinking higher pH > 3 caused instantaneous gel precipitation and inhomogeneities. Sensitivity of FeHA gel properties to small variations in reaction pH clearly supports the need for a tight manufacturing control during medical device fabrication.
authors.affiliation: Division of Chemistry and Materials Science (DCMS)/Office of Science and Engineering Laboratories (OSEL)/Center for Devices and Radiological Health (CDRH)/Food and Dug Administration (FDA), Silver Spring, Maryland 20903, USA. irada.isayeva@fda.hhs.gov
authors.forename: Irada
authors.initials: I
authors.lastname: Isayeva
authors.forename: Srilekha
authors.initials: S
authors.lastname: Sarkar Das
authors.forename: Andrew
authors.initials: A
authors.lastname: Chang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Defoe
authors.forename: Hoan-My Do
authors.initials: HM
authors.lastname: Luu
authors.forename: Katherine
authors.initials: K
authors.lastname: Vorvolakos
authors.forename: Dinesh
authors.initials: D
authors.lastname: Patwardhan
authors.forename: Joyce
authors.initials: J
authors.lastname: Whang
authors.forename: Steven
authors.initials: S
authors.lastname: Pollack
mesh_terms: D003432:Cross-Linking Reagents; D004548:Elasticity; D005782:Gels / Q000737:chemistry* / Q000627:therapeutic use; D006820:Hyaluronic Acid / Q000737:chemistry / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000737:chemistry; D008422:Materials Testing / Q000379:methods*; D011182:Postoperative Care / Q000379:methods; D000267:Tissue Adhesions / Q000517:prevention & control*; D014783:Viscosity
chemical_list: D003432:Cross-Linking Reagents; D005782:Gels; D006820:Hyaluronic Acid; D007501:Iron