title: An in situ cross-linking hybrid hydrogel for controlled release of proteins.
abstract: There is a clear need for methods to provide a safe controlled release of therapeutic proteins, either to achieve and maintain high local protein concentrations, or for sustained systemic delivery. We have developed a protein delivery system that combines in situ cross-linkable polysaccharide hydrogels with gelatin. This formulation is injectable, easy to apply, and obviates the need for organic solvents or potentially toxic cross-linking agents in the formulation process. The cross-linked polysaccharides themselves (comprising hyaluronic acid, dextran and/or carboxymethylcellulose) provided prolonged release of fluorescently labeled albumin (FITC-albumin). The duration of release was markedly extended by the incorporation of gelatin into the formulation: FITC-albumin and interleukin-2 (IL-2) were released over the course of more than 3 weeks. The IL-2 maintained >70% activity throughout that time. Gelatin also accelerated the gelation time of the hydrogels, and reduced their swelling in phosphate-buffered saline. The composite hydrogel (dextran-carboxymethylcellulose-gelatin) showed minimal cytotoxicity in vitro, and benign tissue reaction after subcutaneous injection in rats.
authors.affiliation: Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hila
authors.initials: H
authors.lastname: Epstein-Barash
authors.forename: Cristina F
authors.initials: CF
authors.lastname: Stefanescu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kohane
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis*; D004058:Diffusion; D004339:Drug Compounding / Q000379:methods; D020100:Hydrogels / Q000737:chemistry*; D007279:Injections, Subcutaneous; D008297:Male; D008422:Materials Testing; D051379:Mice; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D020100:Hydrogels; D011506:Proteins