Genipin crosslinking promotes biomechanical reinforcement and pro-regenerative macrophage polarization in bioartificial tubular substitutes

Traumatic nerve injuries are nowadays a significant clinical challenge and new substitutes with adequate biological and mechanical properties are in need. In this context, fibrin-agarose hydrogels (FA) have shown the possibility to generate tubular scaffolds with promising results for nerve repair....

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Bibliographic Details
Published in:	Biomedicine & pharmacotherapy Vol. 174; p. 116449
Main Authors:	Berasain, Jone, Ávila-Fernández, Paula, Cárdenas-Pérez, Rocío, Cànaves-Llabrés, Antoni Ignasi, Etayo-Escanilla, Miguel, Alaminos, Miguel, Carriel, Víctor, García-García, Óscar Darío, Chato-Astrain, Jesús, Campos, Fernando
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-05-2024 Elsevier
Subjects:	Animals Anti-inflammatory response Biocompatible Materials - chemistry Biocompatible Materials - pharmacology Biomechanical Phenomena Biomechanical properties Cell Survival - drug effects Cross-Linking Reagents - chemistry Cross-Linking Reagents - pharmacology Fibrin - metabolism Fibrin-agarose Genipin Hydrogels - chemistry Hydrogels - pharmacology Iridoids - pharmacology Macrophage polarization Macrophages - drug effects Macrophages - metabolism Mice Peripheral nerve RAW 264.7 Cells Sepharose - chemistry Sepharose - pharmacology Tissue Engineering - methods Tissue Scaffolds - chemistry Anti-inflammatory response Peripheral nerve Biomechanical properties Macrophage polarization Fibrin-agarose Genipin
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Summary:	Traumatic nerve injuries are nowadays a significant clinical challenge and new substitutes with adequate biological and mechanical properties are in need. In this context, fibrin-agarose hydrogels (FA) have shown the possibility to generate tubular scaffolds with promising results for nerve repair. However, to be clinically viable, these scaffolds need to possess enhanced mechanical properties. In this line, genipin (GP) crosslinking has demonstrated to improve biomechanical properties with good biological properties compared to other crosslinkers. In this study, we evaluated the impact of different GP concentrations (0.05, 0.1 and 0.2% (m/v)) and reaction times (6, 12, 24, 72 h) on bioartificial nerve substitutes (BNS) consisting of nanostructured FA scaffolds. First, crosslinked BNS were studied histologically, ultrastructurally and biomechanically and then, its biocompatibility and immunomodulatory effects were ex vivo assessed with a macrophage cell line. Results showed that GP was able to improve the biomechanical resistance of BNS, which were dependent on both the GP treatment time and concentration without altering the structure. Moreover, biocompatibility analyses on macrophages confirmed high cell viability and a minimal reduction of their metabolic activity by WST-1. In addition, GP-crosslinked BNS effectively directed macrophage polarization from a pro-inflammatory (M1) towards a pro-regenerative (M2) phenotype, which was in line with the cytokines release profile. In conclusion, this study considers time and dose-dependent effects of GP in FA substitutes which exhibited increased biomechanical properties while reducing immunogenicity and promoting pro-regenerative macrophage shift. These tubular substitutes could be useful for nerve application or even other tissue engineering applications such as urethra. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0753-3322 1950-6007
DOI:	10.1016/j.biopha.2024.116449