title: Hyaluronan dermal fillers via crosslinking with 1,4-butandiol diglycidyl ether: Exploitation of heterogeneous reaction conditions.
abstract: Most of hyaluronan (HA)-based dermal fillers currently available on the market are produced through biopolymer crosslinking with 1,4-butandiol diglycidyl ether (BDDGE). Chemical modification is usually performed on the biopolymer dissolved in a highly alkaline aqueous medium (homogeneous conditions). Heterogeneous conditions for HA reaction with BDDGE were exploited here to obtain competitive HA fillers and to assess potential improvements in production process. Optimal parameters for effective reaction accomplishment were evaluated (e.g., medium composition, temperature and time of reaction). HA was modified with increasing BDDGE/HA equivalents (7-14%) achieving 66-74% (w/w) biopolymer insolubility. Hydrogels exhibited high swelling extent and outstanding resistance to enzymatic degradation decreasing and improving according to crosslinking degree, respectively. Once suspended in physiological solution (20 mg/mL), these products directly formed easy-to-extrude gels through 27-29 G needles. Gel particle dimensions were in the range 10-1000 µm. Rheological analyses revealed decreasing viscosity with the shear rate and G' values in the range 1200-1700 Pa. Overall, results of the in vitro characterization demonstrated the attainment of crosslinked HA particles suitable for application as dermal fillers. These new gels proved superior to similar commercialized products in terms of stability to enzymatic hydrolysis. Further, the protocol assessed allowed interesting improvements over conventional manufacturing procedures.
authors.affiliation: Department of Experimental Medicine, Faculty of Medicine, Second University of Naples, Via L. De Crecchio 7, 80138, Naples, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: La Gatta
authors.affiliation: Department of Experimental Medicine, Faculty of Medicine, Second University of Naples, Via L. De Crecchio 7, 80138, Naples, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Papa
authors.affiliation: Department of Experimental Medicine, Faculty of Medicine, Second University of Naples, Via L. De Crecchio 7, 80138, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Schiraldi
authors.affiliation: Department of Experimental Medicine, Faculty of Medicine, Second University of Naples, Via L. De Crecchio 7, 80138, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: De Rosa
mesh_terms: D000818:Animals; D002417:Cattle; D003432:Cross-Linking Reagents / Q000737:chemistry*; D000067548:Dermal Fillers / Q000737:chemistry*; D006820:Hyaluronic Acid / Q000737:chemistry*; D006821:Hyaluronoglucosaminidase / Q000737:chemistry*; D006868:Hydrolysis; D008297:Male
chemical_list: D003432:Cross-Linking Reagents; D000067548:Dermal Fillers; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase
keywords: crosslinking; dermal filler; enzymatic degradation, injectable gels; hyaluronan