A pH-driven genipin gelator to engineer decellularized extracellular matrix-based tissue adhesives

Decellularized extracellular matrix (dECM) derived from natural ECM is receiving considerable interest as a promising component of tissue adhesives because of its high biocompatibility and tissue regenerative ability. However, the availability of dECM as a tissue adhesive is limited because of the lack of a gelator that can crosslink low concentrations of dECM to form hydrogels. Here, we report dECM-based tissue adhesives using a genipin gelator. Based on the pH-dependent reactivity of genipin, genipin-terminated 4 arm-poly(ethylene glycol) (GeniPEG) was synthesized. dECM-based hydrogels were formed within a few seconds of mixing GeniPEG and dECM at an optimum pH through crosslinking of dECM and self-crosslinking between GeniPEG molecules. The hydrogels crosslinked with GeniPEG exhibited greater tissue adhesive strength to porcine-derived aorta tissue than those crosslinked with genipin. Moreover, GeniPEG can be applied to various dECMs, including those from the urinary bladder, heart, liver, pancreas, and small intestine. In vivo implantation experiments demonstrated biocompatibility and biodegradability of the dECM-GeniPEG hydrogels. Therefore, this dECM-based hydrogel may extend the possibility and availability of dECM as an organ-specific tissue adhesive and contribute to successful minimally invasive surgery. STATEMENT OF SIGNIFICANCE: There is a strong need to develop highly functional tissue adhesives with high biocompatibility, tissue adhesive strength, and tissue regenerative ability. In this report, dECM-based tissue adhesives were reported using a pH-driven genipin-gelator. Focusing on the pH-dependent reactivity of genipin, genipin-based gelators were synthesized to form dECM-based hydrogels in response to pH changes. The crosslinking reaction proceeded within a few seconds to form hydrogels. The hydrogels obtained had greater tissue adhesion to aorta tissue than that of the free genipin crosslinker. This gelator can be applied to various types of dECMs. This dECM-based hydrogel had high biocompatibility and tissue adhesive properties and is useful for sealing wounds and preventing postoperative complications.