title: 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.
authors.affiliation: Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box1188, New York, NY 10029, USA.James.iatridis@mssm.edu.
authors.forename: M
authors.initials: M
authors.lastname: Likhitpanichkul
authors.forename: M
authors.initials: M
authors.lastname: Dreischarf
authors.forename: S
authors.initials: S
authors.lastname: Illien-Junger
authors.forename: B A
authors.initials: BA
authors.lastname: Walter
authors.forename: T
authors.initials: T
authors.lastname: Nukaga
authors.forename: R G
authors.initials: RG
authors.lastname: Long
authors.forename: D
authors.initials: D
authors.lastname: Sakai
authors.forename: A C
authors.initials: AC
authors.lastname: Hecht
authors.forename: J C
authors.initials: JC
authors.lastname: Iatridis
mesh_terms: D000818:Animals; D019149:Bioreactors; D002417:Cattle; D020219:Chondrogenesis; D019245:Compressive Strength; D015718:Fibrin Tissue Adhesive / Q000494:pharmacology* / Q000627:therapeutic use; D020100:Hydrogels / Q000494:pharmacology* / Q000627:therapeutic use; D007403:Intervertebral Disc / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D055959:Intervertebral Disc Degeneration / Q000601:surgery; D039823:Iridoids / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques / Q000295:instrumentation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D013314:Stress, Mechanical; D013718:Tensile Strength; D019415:Torque
chemical_list: D015718:Fibrin Tissue Adhesive; D020100:Hydrogels; D039823:Iridoids; D009569:Nitric Oxide; C007834:genipin