Total Joint Resurfacing Previous attempts to repair articular cartilage have focused on the repair of focal defects. One of the main complications of focal defect repair is that integration of the repair tissue with the surrounding native cartilage is inconsistent and generally poor, which renders the repair site biomechanically unstable not clinically efficacious. In the case of severe osteoarthritis where the entire joint surface has deteriorated, the procedures for repair of focal cartilage defects are no longer applicable. For severe arthritis, total joint replacement is the final option which, although it has a generally good outcome, there are still long-term complications including, erosion of the articulating surface of the prostheses, and breaking or loosening of the prosthetic stem. These problems necessitate revision surgery which is progressively more difficult and complicated. To obviate this problem, we propose to design and test a tissue engineered cell-matrix composite for the total resurfacing of a joint or joint compartment, which is designed to eliminate cartilage-tocartilage integration problems and provide a cell-based option for totally resurfacing joints without totally replacing them. The primary challenges for tissue engineering the total cartilage resurfacing of a joint are to produce viable cartilage tissue of sufficient thickness and surface area to cover an entire joint, to produce cartilage that has appropriate mechanical properties to support the in vivo mechanical demands, and to ensure the integration of the construct with underlying bone. The goal of this proposal is to produce functional autologous cartilage constructs using tissue engineering principles wherein autologous cells, such as Mesenchymal Stem Cells (MSCs), auricular or articular chondrocytes are used to produce full-thickness replacement cartilage and that is then fused and allowed to integrate onto sub-chondral bone, thus totally replacing the deteriorated cartilage with autologous engineered cartilage. This approach is based on the hypothesis that the production of full-thickness cartilage implants obviates the intractable difficulty of lateral cartilage integration, and functional long-term repair will be accomplished by producing biomechanically sound autologous cartilage.
The specific aims of this proposal are: 1. To produce implantation-ready tissue engineered cartilage constructs: In a rabbit model, MSCs and culture-expanded chondrocytes will be used to produce full-thickness (300 um) cartilage constructs of sufficient area to cover an entire humeral condyle. Variables to be tested include the use of auricular or articular chondrocytes or MSCs;hyaluronan- or collagen-based scaffolds;and variations in culture conditions such as cell seeding density, medium flow rate, and the addition of growth factors such as TGF-p1, TGFpS, BMPs, and omega-3 fatty acids. 1. To test implantation-ready constructs in an ex vivo model for cartilage resurfacing: Implant materials synthesized to the proper thickness and surface area will be fixed onto explanted rabbit humeral condyles using four adhesive methods: a calcium phosphate paste, fibrin glue, a final using the zero-length cross-linker1-Ethyl-3-{3-dimethylaminopropyl} carbodiimide, and APTMS-MBA (aminopropyltrimethoxysilanemethylenebisacrylamide), a non-toxic polymer adhesive. These adhesive materials will be tested for their biomechanical properties in vitro, in organ culture, and after implantation into athymic mouse hosts for up to 6 weeks. Biomechanical properties to be tested include a map of surface stiffness, and measures under uniaxial tension and horizontal shear (to failure). MRI imaging, histological examination, and immunochemistry will be used to determine the consistency of cartilage thickness and integration into subchondral bone. 2. To test constructs in an in vivo model of cartilage resurfacing in rabbits: Autologous engineered cartilage constructs will be used to resurface entire humeral condyles in rabbits. The implants will be harvested and examined for biomechanical properties and histology at 4, 12, 24 and 48 weeks post-implantation. Through the use of the Cell, Bioreactor and Imaging Cores, the goals of this proposal will be more easily and efficiently accomplished. The Core components are very appropriate for this project as there is a high demand for cells (chondrocytes and MSCs), bioreactors are need to fabricate cartilage tissue, and imaging is needed for outcome analysis. If these studies are successful, the follow-up study would be to reproduce these results in a large animal pre-clinical model such as in sheep or goats. The long-term objective of this study is to provide an alternative treatment for severe arthritis of diarthrodial joints that is composed of living autologous tissue which, hopefully, will provide many years of functional use before the need for total joint replacement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR053622-05
Application #
8380791
Study Section
Special Emphasis Panel (ZAR1-CHW-J)
Project Start
Project End
2014-04-30
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$68,118
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kean, Thomas J; Mera, Hisashi; Whitney, G Adam et al. (2016) Disparate response of articular- and auricular-derived chondrocytes to oxygen tension. Connect Tissue Res 57:319-33
Whitney, G A; Mansour, J M; Dennis, J E (2015) Coefficient of Friction Patterns Can Identify Damage in Native and Engineered Cartilage Subjected to Frictional-Shear Stress. Ann Biomed Eng 43:2056-68
Chung, Chen-Yuan; Mansour, Joseph M (2015) Determination of poroelastic properties of cartilage using constrained optimization coupled with finite element analysis. J Mech Behav Biomed Mater 42:10-8
Kean, Thomas J; Dennis, James E (2015) Synoviocyte Derived-Extracellular Matrix Enhances Human Articular Chondrocyte Proliferation and Maintains Re-Differentiation Capacity at Both Low and Atmospheric Oxygen Tensions. PLoS One 10:e0129961
Chung, Chen-Yuan; Heebner, Joseph; Baskaran, Harihara et al. (2015) Ultrasound Elastography for Estimation of Regional Strain of Multilayered Hydrogels and Tissue-Engineered Cartilage. Ann Biomed Eng 43:2991-3003
Correa, D; Somoza, R A; Lin, P et al. (2015) Sequential exposure to fibroblast growth factors (FGF) 2, 9 and 18 enhances hMSC chondrogenic differentiation. Osteoarthritis Cartilage 23:443-53
Mansour, Joseph M; Gu, Di-Win Marine; Chung, Chen-Yuan et al. (2014) Towards the feasibility of using ultrasound to determine mechanical properties of tissues in a bioreactor. Ann Biomed Eng 42:2190-202
Song, In-Hwan; Dennis, James E (2014) Simple evaluation method for osteoinductive capacity of cells or scaffolds using ceramic cubes. Tissue Cell 46:372-8
Motavalli, Mostafa; Akkus, Ozan; Mansour, Joseph M (2014) Depth-dependent shear behavior of bovine articular cartilage: relationship to structure. J Anat 225:519-26
Somoza, Rodrigo A; Welter, Jean F; Correa, Diego et al. (2014) Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations. Tissue Eng Part B Rev 20:596-608

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