New insights into the cross-linking and degradation mechanism of Diels–Alder hydrogels

Abstract

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.

Diels–Alder Hydrogels for Controlled Antibody Release: Correlation between Mesh Size and Release Rate

“…18, 19 The mesh size of 8armPEG10k-hydrogels was determined using swelling studies, rheology and low field NMR spectroscopy. The calculated values of ξ allowed us to estimate the release 15 rate of fluorescein isothiocyanate-labeled dextran (FD); four different molecular masses (4 kDa, 20 kDa, 150 kDa and 500 kDa) were studied.…”

“…Since the D g values can be calculated from eqn. (19) and (20) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 21 where M t and M ∞ represent the absolute cumulative amounts of FD released at time t and infinity, respectively; q n are the roots of the Bessel function of the first kind of zero order, and r and h denote the radius and height of the gel cylinder. The increase in r and h due to swelling is taken into account, and the predicted release profiles are shown in Figure 5B.…”

“…In eqn. (19), k is the Boltzmann constant, T is the temperature (310.16 K), and η is the viscosity of water (0.69 mPa s). within DA hydrogels during the release period ( Figure 5A).…”

“…(18) where M r is the relative molecular mass of the FD. The hydrodynamic radii and the diffusion coefficients in water (D 0 ), calculated from the Stokes-Einstein equation: 15 (19) are listed in Table 3. In eqn.…”

Design of hydrogels for delayed antibody release utilizing hydrophobic association and Diels–Alder chemistry in tandem

“…Finally, the degradation rate of DA hydrogels is governed by the hydrolytic stability of the involved maleimide groups. 25 It has been shown that degradation occurs by retro-Diels-Alder (rDA) reaction and subsequent ring-opening hydrolysis of the newly generated maleimide groups. The rate of the rDA reaction is low at 37 1C; however, ring-opening hydrolysis of maleimide to unreactive maleamic acid shifts the DA/rDA equilibrium and significantly accelerates the degradation rate.…”