Synthesis and Spatiotemporal Modification of Biocompatible and Stimuli‐Responsive Carboxymethyl Cellulose Hydrogels Using Thiol‐Norbornene Chemistry

Abstract

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.

Modulation of Thiol–Ene Coupling by the Molecular Environment of Polymer Backbones for Hydrogel Formation and Cell Encapsulation

“…Functionalized CMC-NB (P6) was synthesized following a protocol adapted from the literature. 41 In brief, 0.25 g (1.2 mmol of repeat units) of sodium CMC (CMC 90 kDa was used for NMR experiments, whereas CMC 250 kDa was used for rheology and gelation studies) were dissolved in 25 mL of deionized water. 0.148 g (0.77 mmol) EDC and 89 mg (0.77 mmol) NHS were added to the solution, prior to 0.1 mL (0.8 mmol) of 5-norbornene-2-ethylamine.…”

New Developments in Medical Applications of Hybrid Hydrogels Containing Natural Polymers

“…The presence of thiol-bearing CMC into hydrogel structure determined pH sensitivity of the gels, demonstrating improved swelling and faster release of loaded BSA protein at basic pH [140]. Moreover, thermo-responsive CMC-Nor hydrogels was developed by its crosslinking with a dithiol end functionalized PNIPAAm, determining temperature-induced shrinkage of the gel, at temperatures above the lower critical phase transition temperature (LCST) (around 32 • C) [179].…”

Thiol-Mediated Chemoselective Strategies for In Situ Formation of Hydrogels

“…A unique capacity of photo-initiated crosslinking methods (as well as degradation) mentioned above is to allow temporal and spatial control over the hydrogel structure and properties in order to generate complex bioactive scaffolds [108,109,110]. For instance, the thiol-ene photocrosslinking was used to fabricate ultrathin, micro-patterned hydrogel films on solid substrates and 3D-patterned peptide-presenting hydrogels with tunable crosslinking density and biochemical cues for cell encapsulation [92,111,112,113,114]. Again, as new methods for photo crosslinking advance toward the use of light in the visible and near IR range [78,115] and initiators with low toxicity [95,116,117], these hydrogels will find even wider applications in developing responsive biomaterials and creating complex 3D microenvironments for tissue engineering.…”