title: Induced collagen cross-links enhance cartilage integration.
abstract: Articular cartilage does not integrate due primarily to a scarcity of cross-links and viable cells at the interface. The objective of this study was to test the hypothesis that lysyl-oxidase, a metalloenzyme that forms collagen cross-links, would be effective in improving integration between native-to-native, as well as tissue engineered-to-native cartilage surfaces. To examine these hypotheses, engineered cartilage constructs, synthesized via the self-assembling process, as well as native cartilage, were implanted into native cartilage rings and treated with lysyl-oxidase for varying amounts of time. For both groups, lysyl-oxidase application resulted in greater apparent stiffness across the cartilage interface 2-2.2 times greater than control. The construct-to-native lysyl-oxidase group also exhibited a statistically significant increase in the apparent strength, here defined as the highest observed peak stress during tensile testing. Histology indicated a narrowing gap at the cartilage interface in lysyl-oxidase treated groups, though this alone is not sufficient to indicate annealing. However, when the morphological and mechanical data are taken together, the longer the duration of lysyl-oxidase treatment, the more integrated the interface appeared. Though further data are needed to confirm the mechanism of action, the enhancement of integration may be due to lysyl-oxidase-induced pyridinoline cross-links. This study demonstrates that lysyl-oxidase is a potent agent for enhancing integration between both native-to-native and native-to-engineered cartilages. The fact that interfacial strength increased manifold suggests that cross-linking agents should play a significant role in solving the difficult problem of cartilage integration. Future studies must examine dose, dosing regimen, and cellular responses to lysyl-oxidase to optimize its application.
authors.affiliation: Department of Biomedical Engineering, University of California Davis, Davis, California, United States of America.
authors.forename: Aristos A
authors.initials: AA
authors.lastname: Athens
authors.forename: Eleftherios A
authors.initials: EA
authors.lastname: Makris
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Hu
mesh_terms: D000818:Animals; D002356:Cartilage / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002358:Cartilage, Articular / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D003094:Collagen / Q000378:metabolism*; D048091:Guided Tissue Regeneration; D008297:Male; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism / Q000494:pharmacology; D013718:Tensile Strength
chemical_list: D003094:Collagen; D008249:Protein-Lysine 6-Oxidase