Combined use of chondroitinase-ABC, TGF-β1, and collagen crosslinking agent lysyl oxidase to engineer functional neotissues for fibrocartilage repair.
Patients suffering from damaged or diseased fibrocartilages currently have no effective long-term treatment options. Despite their potential, engineered tissues suffer from inferior biomechanical integrity and an inability to integrate in vivo. The present study identifies a treatment regimen (including the biophysical agent chondroitinase-ABC, the biochemical agent TGF-β1, and the collagen crosslinking agent lysyl oxidase) to prime highly cellularized, scaffold-free neofibrocartilage implants, effecting continued improvement in vivo. We show these agents drive in vitro neofibrocartilage matrix maturation toward synergistically enhanced Young's modulus and ultimate tensile strength values, which were increased 245% and 186%, respectively, over controls. Furthermore, an in vitro fibrocartilage defect model found this treatment regimen to significantly increase the integration tensile properties between treated neofibrocartilage and native tissue. Through translating this technology to an in vivo fibrocartilage defect model, our results indicate, for the first time, that a pre-treatment can prime neofibrocartilage for significantly enhanced integration potential in vivo, with interfacial tensile stiffness and strength increasing by 730% and 745%, respectively, compared to integration values achieved in vitro. Our results suggest that specifically targeting collagen assembly and organization is a powerful means to augment overall neotissue mechanics and integration potential toward improved clinical feasibility.
Department of Biomedical Engineering, University of California Davis, United States; Department of Orthopaedic Surgery and Musculoskeletal Trauma, University of Thessaly, Greece.
Eleftherios A
EA
Makris
Department of Biomedical Engineering, University of California Davis, United States.
Regina F
RF
MacBarb
Department of Biomedical Engineering, University of California Davis, United States.
Nikolaos K
NK
Paschos
Department of Biomedical Engineering, University of California Davis, United States.
Jerry C
JC
Hu
Department of Biomedical Engineering, University of California Davis, United States; Department of Orthopaedic Surgery, University of California Davis, United States. Electronic address: athanasiou@ucdavis.edu.
Kyriacos A
KA
Athanasiou
D000818:Animals; D001696:Biomechanical Phenomena; D019765:Chondroitin ABC Lyase / Q000737:chemistry*; D003094:Collagen / Q000737:chemistry*; D051445:Fibrocartilage / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008422:Materials Testing; D051379:Mice; D008819:Mice, Nude; D019736:Prostheses and Implants; D008249:Protein-Lysine 6-Oxidase / Q000737:chemistry*; D013718:Tensile Strength / Q000187:drug effects; D023822:Tissue Engineering / Q000379:methods*; D053773:Transforming Growth Factor beta1 / Q000737:chemistry*; D014945:Wound Healing / Q000187:drug effects
D053773:Transforming Growth Factor beta1; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D019765:Chondroitin ABC Lyase
Collagen crosslinking; Fibrocartilage; Integration; Lysyl oxidase; Tissue engineering