Current methods to spatiotemporally modify stimuli response in hydrogels are typically subtractive and lead to a decrease in response. To increase the breadth of hydrogel applications and biomedical systems, new formulations are needed that can introduce and increase stimuli response spatiotemporally in hydrogels. In this work, the light induced thiol-norbornene click chemistry reaction was used to modify the stimuli response of robust hyaluronic acid hydrogels through an additive process in spatiotemporal fashion, overcoming this limitation. These stimuli responsive hydrogels were made from norbornene functionalized hyaluronic acid (NorHA) crosslinked with thermo-responsive dithiol-terminated poly(N-isopropylacrylamide) (DTPN).Varying crosslinker molecular weight and gelation conditions led to a range of compression modulus (5 to 54 kPa) and mass loss (9 to 33%) upon heating to 37 °C while retaining a majority NorHA in the hydrogel. The thermo-response of these hydrogels could not only be controlled by the crosslink density, but also by heating to 55 °C to increase the dewatering of the hydrogels.The stimuli response of the hydrogels were temporally increased by introducing additional DTPN and UV-initiator to an original hydrogel with subsequent irradiation. This modification was extended to spatiotemporally changing the stimuli response by photopatterning DTPN into a NorHA hydrogel, yielding a hydrogel that changed shape and topology through heating.Furthermore, human mesenchymal stem cells could adhere and proliferate on the DTPN patterned surface, demonstrating that the materials could be used for studies where cells are present.

Carboxymethyl cellulose (CMC) is functionalized with norbornene groups to undergo thiol-norbornene cross-linking reactions. Hydrogels synthesized from a single norbornene-modified carboxymethyl cellulose (NorCMC) via a light-initiated thiol-ene cross-linking reaction with a variety of dithiol cross-linkers yield hydrogels with a tunable compression modulus ranging from 1.7 to 103 kPa. Additionally, thermoresponsiveness is spatiotemporally imparted to NorCMC hydrogels by photopatterning a dithiol-terminated poly(N-isopropyl acrylamide) cross-linker, enabling swelling and topological control of the hydrogels as a function of incubation temperature. NorCMC hydrogels are cytocompatible as the viability of encapsulated human mesenchymal stem cells (hMSCs) is greater than 85% after 21 d while using a variety of cross-linkers. Moreover, hMSCs can remodel, adhere, and spread in the NorCMC matrix cross-linked with a matrix metalloproteinase-degradable peptide, further demonstrating the utility of these materials as a tunable biomaterial.

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