Fibrin-genipin adhesive hydrogel for annulus fibrosus repair: performance evaluation with large animal organ culture, in situ biomechanics, and in vivo degradation tests

Abstract

Annulus fibrosus (AF) defects from annular tears, herniation, and discectomy procedures are associated with painful conditions and accelerated intervertebral disc (IVD) degeneration. Currently, no effective treatments exist to repair AF damage, restore IVD biomechanics and promote tissue regeneration. An injectable fibrin-genipin adhesive hydrogel (Fib-Gen) was evaluated for its performance repairing large AF defects in a bovine caudal IVD model using ex vivo organ culture and biomechanical testing of motion segments, and for its in vivo longevity and biocompatibility in a rat model by subcutaneous implantation. Fib-Gen sealed AF defects, prevented IVD height loss, and remained well-integrated with native AF tissue following approximately 14,000 cycles of compression in 6-day organ culture experiments. Fib-Gen repair also retained high viability of native AF cells near the repair site, reduced nitric oxide released to the media, and showed evidence of AF cell migration into the gel. Biomechanically, Fib-Gen fully restored compressive stiffness to intact levels validating organ culture findings. However, only partial restoration of tensile and torsional stiffness was obtained, suggesting opportunities to enhance this formulation. Subcutaneous implantation results, when compared with the literature, suggested Fib-Gen exhibited similar biocompatibility behaviour to fibrin alone but degraded much more slowly. We conclude that injectable Fib-Gen successfully sealed large AF defects, promoted functional restoration with improved motion segment biomechanics, and served as a biocompatible adhesive biomaterial that had greatly enhanced in vivo longevity compared to fibrin. Fib-Gen offers promise for AF repairs that may prevent painful conditions and accelerated degeneration of the IVD, and warrants further material development and evaluation.

Enhancing cell migration in shape-memory alginate–collagen composite scaffolds: In vitro and ex vivo assessment for intervertebral disc repair

“…Risk of implant migration and extrusion must be assessed, and sealant materials (i.e. fibrin glue, (75,76) genipin crosslinking (77) or biodegradable glue (78) ) warrant further investigations. However, further investigations will be required to determine if the addition of collagen into the alginate scaffold will elicit a beneficial response in vivo in terms of tissue integration, without fibrosis and scar tissue formation, as has previously been observed for collagen based scaffolds.…”

Organ Culture Bioreactors – Platforms to Study Human Intervertebral Disc Degeneration and Regenerative Therapy

“…One approach is the injection of fibrin-genipin adhesive hydrogel to seal large AF defects [86,87]. In a bovine organ culture model, bovine-derived fibrin cross-linked with genipin successfully closed an AF wound that was induced by a stab with a scalpel blade [86,87].…”

“…One approach is the injection of fibrin-genipin adhesive hydrogel to seal large AF defects [86,87]. In a bovine organ culture model, bovine-derived fibrin cross-linked with genipin successfully closed an AF wound that was induced by a stab with a scalpel blade [86,87]. The hydrogel with gelation times of less than 15 min successfully sealed large AF defects, promoted functional restoration with improved motion segment biomechanics, and served as a biocompatible adhesive biomaterial that had greatly enhanced in vivo longevity compared to fibrin alone.…”

“…The hydrogel with gelation times of less than 15 min successfully sealed large AF defects, promoted functional restoration with improved motion segment biomechanics, and served as a biocompatible adhesive biomaterial that had greatly enhanced in vivo longevity compared to fibrin alone. The authors concluded that fibrin-genipin would offer promise for AF repair strategies and would warrant further material development and evaluation for clinical application [86]. Thus, hydrogels might find their way into the operation rooms as commercially available products are already FDA-approved such as Tisseel© from Baxter, inc. Another approach is the combination of genipin reinforced hydrogels with adherence molecules or anti-inflammatory drugs such as anti-TNFα.…”

“…Implantation of MSC-seeded scaffolds with a sutured membrane could preserve the disc height and prevent NP protrusion under bioreactor guided mechanical load [94]. Modified fibrin was also able to seal the AF defects and restore disc height following substantial compressive loading in a one week organ culture experiment [86]. …”