Interplay Between Stiffness and Degradation of Architectured Gelatin Hydrogels Leads to Differential Modulation of Chondrogenesis In Vitro and In Vivo

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Melika Sarem, Neha Arya, Miriam Heizmann, Axel T. Neffe, Andrea Barbero, Tim P. Gebauer, Ivan Martin, Andreas Lendlein, V. Prasad Shastri
The limited capacity of cartilage to heal large lesions through endogenous mechanisms has led to extensive effort to develop materials to facilitate chondrogenesis. Although physical-chemical properties of biomaterials have been shown to impactin vitro chondrogenesis, whether these findings are translatable in vivo is subject of debate. Herein, architectured 3D hydrogel scaffolds (ArcGel) (produced by crosslinking gelatin with ethyl lysine diisocyanate (LDI)) were used as a model system to investigate the interplay between scaffold mechanical properties and degradation on matrix deposition by human articular chondrocytes (HAC) from healthy donorsin vitroandin vivo. Using ArcGel scaffolds of different tensile and shear modulus, and degradation behavior; in this study, we compared the fate ofex vivoengineered ArcGels-chondrocytes constructs, i.e. the traditional tissue engineering approach, with thede novoformation of cartilaginous tissue in HAC laden ArcGels in an ectopic nude mouse model. While the softer and fast degrading ArcGel (LNCO3) was more efficient at promoting chondrogenic differentiationin vitro, upon ectopic implantation, the stiffer and slow degrading ArcGel (LNCO8) was superior in maintaining chondrogenic phenotype in HAC and retention of cartilaginous matrix. Furthermore, surprisingly thede novoformation of cartilage tissue was promoted only in LNCO8. Since HAC cultured for only three days in the LNCO8 environment showed upregulation of hypoxia-associated genes, this suggests a potential role for hypoxia in the observed in vivo outcomes. In summary, this study sheds light on how immediate environment (in vivoversusin vitro) can significantly impact the outcomes of cell-laden biomaterials.Statement of SignificanceIn this study, 3D architectured hydrogels (ArcGels) with different mechanical and biodegradation properties were investigated for their potential to promote formation of cartilaginous matrix by human articular chondrocytesin vitroandin vivo.Two paradigms were explored (i)ex vivoengineering followed byin vivoimplantation in ectopic site of nude mice and (ii) shortin vitroculture (3 days) followed by implantation to inducede novocartilage formation. Softer and fast degrading ArcGel were better at promoting chondrogenesisin vitro,while stiffer and slow degrading ArcGel were strikingly superior in both maintaining chondrogenesisin vivoand inducingde novoformation of cartilage. Our findings highlight the importance of the interplay between scaffold mechanics and degradation in chondrogenesis.

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