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Eight-armed poly(ethylene glycol) was functionalized with furyl and maleimide groups. The two macromonomers were cross-linked by Diels-Alder (DA) reactions and the degradation behavior of the formed hydrogels was investigated. UV spectroscopy showed that maleimide groups were subject to ring-opening hydrolysis above pH 5.5, with the reaction rate depending on the pH and temperature. As a result of this, the gelation kinetics and stiffness of DA hydrogels were dependent on the temperature and the pH of the cross-linking medium, as demonstrated by rheological experiments. The gel time varied between 87.8 min (pH 3.0, 37 C) and 374.7 min (pH 7.4, 20 C). Values between 420 Pa (pH 9.0, 37 C) and 3327 Pa (pH 3.0, 37 C) were measured for the absolute value of the complex shear modulus. Hydrogel swelling and degradation were influenced by the same parameters. With increasing pH and temperature the degradation time was reduced from 98 days (pH 7.4, 20 C) to 2 days (pH 7.4, 50 C); no degradation was observed at pH 3.0 and 5.5. Molecular modeling studies of the DA and retro-Diels-Alder (rDA) moieties revealed that hydrogel degradation occurred by rDA reaction followed by OH Àcatalyzed ring-opening hydrolysis of maleimide groups to unreactive maleamic acid derivatives.

Eight-armed PEG, molecular mass 10 kDa, was functionalized with furyl and maleimide groups, respectively; the obtained macromonomers were cross-linked via Diels-Alder chemistry. The mesh size (ξ) of the prepared hydrogels was determined by swelling studies, rheology, and low field NMR spectroscopy. The in vitro release of fluorescein isothiocyanate labeled dextrans (FDs) and bevacizumab was investigated. The average mesh size (ξavg) increased from 5.8 ± 0.1 nm to 56 ± 13 nm during degradation, as determined by swelling studies. The result of the rheological measurements (8.0 nm) matched the initial value of ξavg. Low field NMR spectroscopy enabled the determination of the mesh size distribution; the most abundant mesh size was found to be 9.2 nm. In combination with the hydrodynamic radius of the molecule (Rh), the time-dependent increase of ξavg was used to predict the release profiles of incorporated FDs applying an obstruction-scaling model. The predicted release profiles matched the experimentally determined release profiles when Rh < ξavg. However, significant deviations from the theoretical predictions were observed when Rh ≥ ξavg, most likely due to the statistical distribution of ξ in real polymer networks. The release profile of bevacizumab differed from those of equivalently sized FDs. The delayed release of bevacizumab was most likely a result of the globular structure and rigidity of the protein. The observed correlation between ξ and the release rate could facilitate the design of controlled release systems for antibodies.

Tethering drug substances to a gel network is an effective way of controlling the release kinetics of hydrogel-based drug delivery systems. Here, we report on in situ forming, biodegradable hydrogels that allow for the covalent attachment of peptides or proteins. Hydrogels were prepared by step-growth polymerization of branched poly(ethylene glycol). The gel strength ranged from 1075 to 2435 Pa; the degradation time varied between 24 and 120 h. Fluorescence recovery after photobleaching showed that fluorescently labeled bovine serum albumin (FITC-BSA) was successfully bound to the gel network during gel formation. Within 168 h, the mobility of the tethered molecules gradually increased due to polymer degradation. Using FITC-BSA and lysozyme as model proteins, we showed the potential of the developed hydrogels for time-controlled release. The obtained release profiles had a sigmoidal shape and matched the degradation profile very well; protein release was complete after 96 h.

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