Tyrosinase is a common crosslinker used in the formation of in situ hydrogels, often resulting in significantly longer gelation times. The rate-determining step for the interconversion between the four discrete states of the enzyme is characterized by a lag phase, which contributes to its slow gelation kinetics. In this study, we report, for the first time, the use of a catalytic amount of iron(II) to produce fast in situ-gellable tyramine-conjugated hyaluronic acid hydrogels (HATA), which are prospectively applicable for nasal drug delivery. We observed gelation times ranging from 886 to 538 seconds, depending on the polymer and enzyme concentrations, irrespective of the pH level tested. The presence of iron(II) significantly reduced the gelation time by an order of magnitude, ranging from 86 seconds to 25.46 seconds, depending on the polymer concentration, pH, and enzyme activity. Based on our findings, we propose a double crosslinking mechanism involving catechol-catechol coupling and catechol-iron(II) complex formation, as evidenced by improvements in the rheological properties of the hydrogels. These novel hydrogels can encapsulate antibodies and provide prolonged release for up to two weeks. Additionally, we confirmed that the crosslinking chemistry did not affect the bioactivity of the antibodies. Given their improved mucoadhesive properties, we envision these hydrogels as promising candidates for the formulation of bioadhesive drug delivery systems.

Centre de Recherche du CHU de Québec Université Laval Axe Médecine Régénératrice Québec Québec City Canada

Contipro a s Dolní Dobrouč 401 56102 Dolní Dobrouč Czech Republic

Department of Biomedical Research University of Bern 3010 Bern Switzerland

Department of Molecular Medicine Faculty of Medicine Laval University Quebec City Qc Canada

Department of Neurology Inselspital Bern University Hospital University of Bern 3010 Bern Switzerland

Department of Pharmaceutical Technology Faculty of Pharmacy Charles University Akademika Heyrovského 1203 8 500 03 Hradec Králové 3 Czech Republic

Experimental Neurology Center Bern University Hospital University of Bern 3010 Bern Switzerland

Graduate School for Cellular and Biomedical Sciences University of Bern 3010 Bern Switzerland

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