Abstract
Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials.
Highlights
Silk fibroin (SF) made from Bombyx mori silkworm have been extensively studied as a versatile biomaterial for tissue engineering as it possess superior mechanical properties and biodegradable[13,14]
We describe that the silk fibroin (SF) hydrogel system, which was developed in our group by horseradish peroxidase (HRP) catalyzed crosslinking, can undergo spontaneous conformational change under physiological conditions
SF hydrogel conformation was analysed by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR, Fig. 1a)
Summary
Silk fibroin (SF) made from Bombyx mori silkworm have been extensively studied as a versatile biomaterial for tissue engineering as it possess superior mechanical properties and biodegradable[13,14]. Aeschbach et al studied the formation of dityrosine in SF and other 14 proteins via oxidation of tyrosine residues by HRP and hydrogen peroxide catalysis in basic pH22. These studies neither showed detailed physicochemical properties nor the biomedical application of the formed SF hydrogels. We describe that the SF hydrogel system, which was developed in our group by HRP catalyzed crosslinking, can undergo spontaneous conformational change (after 7 days) under physiological conditions. The hydrogels displayed dual ionic strength and pH responses We found that these biomimetic hydrogels acquire a β-sheet conformation after 10 days under physiological conditions in vitro. A chick chorioallantoic membrane (CAM) model was used to assess the effect of SF conformational changes in encapsulated HeLa cells within the hydrogel
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