Microenvironment mimicry is crucial for the success of many biomedical applications. 3D organoid culture, local cell delivery and explant time-lapse imaging are as many examples of applications that depend heavily on properly designed scaffolds. Chemically crosslinked hydrogels are ideal materials in that matter as they allow tunable composition and stiffness. However, most of the crosslinking reactions are either toxic to the cells and tissues, or incompatible with physiological conditions (e.g., pH, medium). In the past, using the furan/maleimide Diels-Alder reaction, we developed and used hyaluronan (HA)-based hydrogels to investigate cell survival and migration, with much success. However, in the initial system, the slow crosslinking reaction and the maleimide degradation required an overnight pre-gelation step at acidic pH, and extensive washes with medium; limiting these hydrogels to 2D culture. To expand their potential, we systematically studied three key factors of the physicochemistry of Diels-Alder HA hydrogels, at physiological pH: polymer entanglement, diene substituents and degrees of substitution. Using HA with different molecular weights (240 kDa vs 1.5 MDa), we showed that an increase in polymer chain entanglement considerably decreases the gelation time, the initial swelling and the overall swelling rate of the HA gels, while minimally increasing the stiffness of the material and not affecting its injectability. The comparison of methylfuran and furan groups confirmed that electron-donating substituents on dienes can dramatically decrease the gelation time (down to minutes), at the cost, however, of the hydrogel stability. Finally, to investigate the effect of the degree of substitution of the crosslinker, we synthesized various HA-maleimide crosslinkers (10, 20, 40, 60 kDa), and showed that increasing the number of maleimide per chain can lead to much faster gelation and more stable gels. Overall, these newly designed furan/maleimide Diels-Alder HA hydrogels can gel within minutes at physiological pH, and are stable for months; paving the way towards successful cell encapsulation and transplantation.

Bringing furan/maleimide Diels-Alder HA hydrogel chemistry to physiological conditions, for biomedical applications

255th National Meeting (2018)

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