Tissue engineering therapies for repair or regeneration of articular cartilage typically involve grafting cells alone, cells within engineered scaffolds, or tissues containing cells. A major unresolved problem is the inconsistent integration between the implant and the host articular cartilage. The long- term goal of this project is to develop a quantitative understanding of cellular and molecular processes leading to integrative cartilage repair and to apply this information to improve medical, surgical, and physical therapies for stimulating successful cartilage healing. Our working general hypothesis is: functional integrative repair can result from a local sequence of events at a cartilage surface that includes: (a) cellular biosynthesis of molecular components of collagen fibrils and molecules that regulate fibrillogenesis, (b) coordinated extracellular deposition of these molecules and associated remodeling of the fibrillar collagen meshwork. A corollary of this hypothesis is: transplanted chondrocytes can mediate and accelerate this process if these cells remain adherent at the defect site and contribute appropriate molecular products. Our recent studies (i) implicated collagen biosynthesis by endogenous chondrocytes, and subsequent deposition and crosslinking of collagen, as critical factors for the modest biomechanical integration that occurs between apposing surfaces of bovine cartilage in vitro, (2) developed a method to transplant chondrocytes quantitatively onto a cartilage surface and thereby provide metabolically active cells at a cartilage-cartilage interface, and (3) developed a system to characterize adhesiveness of chondrocytes to articular cartilage (e.g., the surrounding host tissue). We now propose to test two specific hypotheses. (i) The ability of transplanted chondrocytes to adhere to articular cartilage depends on the extent of interactions between the cartilage matrix substrate and the surface receptors or pre-formed pericellular matrix of the transplanted cells. (2) The ability of endogenous and transplanted chondrocytes to promote integrative repair of articular cartilage in vitro depends on their ability to locally deposit molecules that contribute to remodeling of the collagen meshwork. The approaches proposed include (a) relating biomechanical function to the metabolism of specific molecules, (b) making quantitative measurements to characterize collagen synthesis, diffusion, and crosslinking, and (c) investigating manipulations that are of potential clinical utility and provide insight into underlying molecular mechanisms.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-M (02))
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Panagis, James S
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University of California San Diego
Engineering (All Types)
Schools of Arts and Sciences
La Jolla
United States
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Hwang, Jennifer; Bae, Won C; Shieu, Wendy et al. (2008) Increased hydraulic conductance of human articular cartilage and subchondral bone plate with progression of osteoarthritis. Arthritis Rheum 58:3831-42
Nugent-Derfus, G E; Takara, T; O'neill, J K et al. (2007) Continuous passive motion applied to whole joints stimulates chondrocyte biosynthesis of PRG4. Osteoarthritis Cartilage 15:566-74
Jadin, Kyle D; Bae, Won C; Schumacher, Barbara L et al. (2007) Three-dimensional (3-D) imaging of chondrocytes in articular cartilage: growth-associated changes in cell organization. Biomaterials 28:230-9
Masuda, K; Pfister, B E; Sah, R L et al. (2006) Osteogenic protein-1 promotes the formation of tissue-engineered cartilage using the alginate-recovered-chondrocyte method. Osteoarthritis Cartilage 14:384-91
McGowan, Kevin B; Sah, Robert L (2005) Treatment of cartilage with beta-aminopropionitrile accelerates subsequent collagen maturation and modulates integrative repair. J Orthop Res 23:594-601
Chia, Stanley H; Homicz, Mark R; Schumacher, Barbara L et al. (2005) Characterization of human nasal septal chondrocytes cultured in alginate. J Am Coll Surg 200:691-704
Allen, R Todd; Robertson, Catherine M; Pennock, Andrew T et al. (2005) Analysis of stored osteochondral allografts at the time of surgical implantation. Am J Sports Med 33:1479-84
Ahsan, T; Harwood, F; McGowan, K B et al. (2005) Kinetics of collagen crosslinking in adult bovine articular cartilage. Osteoarthritis Cartilage 13:709-15
Chia, Stanley H; Schumacher, Barbara L; Klein, Travis J et al. (2004) Tissue-engineered human nasal septal cartilage using the alginate-recovered-chondrocyte method. Laryngoscope 114:38-45
Masuda, Koichi; Sah, Robert L; Hejna, Michael J et al. (2003) A novel two-step method for the formation of tissue-engineered cartilage by mature bovine chondrocytes: the alginate-recovered-chondrocyte (ARC) method. J Orthop Res 21:139-48

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