Osteoarthritis (OA), the most prevalent form of arthritis, affects up to 15% of the adult population and is principally characterized by degeneration of the articular cartilage component of the joint, often with accompanying subchondral bone lesions. Understanding the mechanisms underlying the pathogenesis of OA is important for the rational development of disease modifying OA drugs (DMOADs). While most studies on OA have focused on the investigation of either the cartilage or the bone components of the articular joint, the osteochondral complex represents a more physiologically relevant target as the disease ultimately is a disorder of osteochondral integrity and function. In this application, we propose to construct an in vitro 3-dimensional microsystem that models the structure and biology of the osteochondral complex of the articular joint. Osteogenic and chondrogenic tissue components will be produced using adult human mesenchymal stem cells (MSCs) derived from bone marrow and adipose seeded within biomaterial scaffolds photostereolithographically fabricated with defined internal architecture. A 3D-printed, perfusion-ready container platform with dimensions to fit into a 96-well culture plate format is designed to house and maintain the osteochondral microsystem that has the following features: (1) an anatomic cartilage/bone biphasic structure with a functional interface;(2) all tissue components derived from a single adult mesenchymal stem cell source to eliminate possible age/tissue type incompatibility;(3) individual compartments to constitute separate microenvironment for the """"""""synovial"""""""" and """"""""osseous"""""""" components;(4) cell-seeded envelopes to represent """"""""synovium"""""""" and """"""""endothelium"""""""";(5) accessible individual compartments that may be controlled and regulated via the introduction of bioactive agents or candidate effector cells, and tissue/medium sampling and compositional assays;(6) compatibility with the application of mechanical load and perturbation;and (7) imaging capability to allow for non-invasive functional monitoring. The robustness and physiological relevance of the osteochondral microsystem will be tested on the basis of: (1) structural integrity and potential connectivity of the separate """"""""synovial"""""""" and """"""""osseous"""""""" compartments;(2) maintenance of distinct cartilage and bone phenotypes and the development of a histologically distinct osteochondral junction or tidemark;(3) applicability and tissue responsiveness to mechanical loading;and (4) imaging and analytical capabilities. The consequences of mechanical injury, exposure to inflammatory cytokines, and compromised bone quality on degenerative changes in the cartilage component will be examined in the osteochondral microsystem as a first step towards its eventual application as an improved and high-throughput in vitro model for prediction of efficacy, safety, bioavailability, and toxicology outcomes for candidate DMOADs.
Osteoarthritis, a degenerative joint disease that affects up to 15% of adults, is initiated by degeneration of the articular cartilage that covers the joint surfac. Development of disease modifying drugs for osteoarthritis requires a clear understanding of the underlying mechanisms, responsible for the failed interaction between cartilage and bone. This proposal aims to establish an in vitro 3-dimensional microsystem based on adult stem cells to simulate this bone-cartilage interface, which may be used in the future to identify and test candidate therapeutics for osteoarthritis.
|Hofer, Heidi R; Tuan, Rocky S (2016) Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 7:131|
|Jiang, Yangzi; Cai, Youzhi; Zhang, Wei et al. (2016) Human Cartilage-Derived Progenitor Cells From Committed Chondrocytes for Efficient Cartilage Repair and Regeneration. Stem Cells Transl Med 5:733-44|
|Jiang, Yangzi; Hu, Changchang; Yu, Shuting et al. (2015) Cartilage stem/progenitor cells are activated in osteoarthritis via interleukin-1?/nerve growth factor signaling. Arthritis Res Ther 17:327|
|Jiang, Yangzi; Tuan, Rocky S (2015) Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat Rev Rheumatol 11:206-12|
|Diederichs, Solvig; Tuan, Rocky S (2014) Functional comparison of human-induced pluripotent stem cell-derived mesenchymal cells and bone marrow-derived mesenchymal stromal cells from the same donor. Stem Cells Dev 23:1594-610|
|Lin, Hang; Cheng, Anthony Wai-Ming; Alexander, Peter G et al. (2014) Cartilage tissue engineering application of injectable gelatin hydrogel with in situ visible-light-activated gelation capability in both air and aqueous solution. Tissue Eng Part A 20:2402-11|
|Alexander, Peter G; Gottardi, Riccardo; Lin, Hang et al. (2014) Three-dimensional osteogenic and chondrogenic systems to model osteochondral physiology and degenerative joint diseases. Exp Biol Med (Maywood) 239:1080-95|
|Lin, Hang; Lozito, Thomas P; Alexander, Peter G et al. (2014) Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1?. Mol Pharm 11:2203-12|
|Yang, Guang; Rothrauff, Benjamin B; Lin, Hang et al. (2013) Enhancement of tenogenic differentiation of human adipose stem cells by tendon-derived extracellular matrix. Biomaterials 34:9295-306|
|Lozito, Thomas P; Alexander, Peter G; Lin, Hang et al. (2013) Three-dimensional osteochondral microtissue to model pathogenesis of osteoarthritis. Stem Cell Res Ther 4 Suppl 1:S6|