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Thiol-Ene Click Reaction Initiated Rapid Gelation of PEGDA/Silk Fibroin Hydrogels.

ABSTRACT: In this work, poly(ethylene glycol) diacrylate (PEGDA) molecules were grafted to silk fibroin (SF) molecules via a thiol-ene click reaction under 405 nm UV illumination for the fabrication of a PEGDA/SF composite hydrogel. The composite hydrogels could be prepared in a short and controllable gelation time without the use of a photoinitiator. Features relevant to the drug delivery of the PEGDA/SF hydrogels were assessed, and the hydrogels were characterized by various techniques. The results showed that the prepared PEGDA/SF hydrogels demonstrated a good sustained-release performance with limited swelling behavior. It was found that a prior cooling step can improve the compressive strength of the hydrogels effectively. Additionally, the MTT assay indicated the prepared PEGDA/SF hydrogel is non-cytotoxic. Subcutaneous implantation of the PEGDA/SF hydrogel in Kunming mice did not induce an obvious inflammation, which revealed that the prepared PEGDA/SF hydrogel possessed good biocompatibility. Furthermore, the mechanism of the gelation process was discussed.

SUBMITTER: Liang J

PROVIDER: S-EPMC6960922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer - gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). This unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment. STATEMENT OF SIGNIFICANCE: Hydrogels permitting on-demand and secondary crosslinking are ideal for mimicking a stiffening tumor microenvironment (TME). However, none of the current dynamic hydrogels account for both stiffening and accumulation of hyaluronic acid (HA), a major extracellular matrix component increasingly deposited in tumor stromal tissues, including pancreatic ductal adenocarcinoma (PDAC). The current work addresses this gap by developing a dynamic hydrogel system capable of simultaneously increasing stiffness and HA accumulation. This is achieved by a new gelatin macromer permitting sequential thiol-norbornene (for primary network crosslinking) and hydrazone click chemistry (for bioinert or biomimetic stiffening with oxidized dextran (oDex) or oHA, respectively). The results of this study provide new insights into how dynamically changing physicochemical matrix properties guide cancer cell fate processes.

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Thiol-Ene Click Reaction Initiated Rapid Gelation of PEGDA/Silk Fibroin Hydrogels.

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