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) cross-linked with thermoresponsive dithiol-terminated poly(N-isopropylacrylamide) (DTPN). Variation of the cross-linker 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 of NorHA in the hydrogel. The thermoresponse of these hydrogels could be controlled not only by the cross-link density but also by heating to 55 °C to increase the dewatering of the hydrogels. The stimuli response of the hydrogels was 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.
Keywords: hyaluronic acid; hydrogels; spatiotemporal modification; stimuli-responsive; thiol−norbornene click chemistry.