The application's long-term objective is to use a cogent and comprehensive tissue engineering approach to successfully address meniscus regeneration, which remains one of the most elusive problems in musculoskeletal medicine. The study's main hypothesis is that the meniscus can be regenerated by a series of steps that involve the use of a scaffold with bioactive agents, cells, a bioreactor, mechanical stimuli, and an animal model. To test this hypothesis, we propose the following specific aims: 1) To design, fabricate, and characterize meniscus-specific biodegradable scaffolds. 2) To engineer the meniscus. 3) To test the meniscus in an animal model. The methodology involves an analysis and a synthesis phase: In the analysis phase, topographical and spatial properties of the meniscus will be identified using biomechanics, biochemistry, ultrastructural methods, and cell culture. The objective is to define 'gold standard' properties against which the properties of the regenerated meniscus will be compared. In the synthesis phase, fibrochondrocytes will be seeded onto meniscus-specific scaffolds and exposed to mechanical forces. The scaffolds, made of poly(propylene fumarate-co-ethylene glycol), are designed to be bioabsorbable, biocompatible, have mechanical integrity, allow for directed attachment of cells through the use of the GRGD peptide, and provide biosynthetic signals through the use of a growth factor. A hydrodynamic focusing bioreactor, operating in a low-shear environment, will then be used to enhance nutrient transport and to modulate mechanical signals. Furthermore, the effects of hydrostatic pressure and direct compression/tension will also be examined using custom-made instruments. At various time points, the properties of the engineered constructs will be quantified and compared to native tissue properties. The tissue engineered constructs will then be implanted in rabbits to evaluate the in vivo functional characteristics of the new meniscus. The clinical significance of the approach described in this proposal is enormous, since meniscal problems continue to be some of the most vexing in orthopaedics.
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