Robert E. Guldberg, PhD, (School of Mechanical Engineering, Georgia Institute of Technology)
Todd C. McDevitt, PhD, Gladstone Institutes
Johnna S. Temenoff, PhD (Department of Biomedical Engineering, Georgia Institute of Technology)
Krishnendu Roy, PhD (Department of Biomedical Engineering, Georgia Institute of Technology)
Tom Koob, PhD (MiMedx Group, Inc.)
Engineering an Improved Cartilage Repair Strategy Combining Cells and ECM-derived Materials
Osteoarthritis (OA) is the leading cause of disability in the United States and one in two people are expected to develop symptomatic knee OA by age 85. The avascularity, low cellularity, and slow proliferation of chondrocytes all limit the natural regenerative capacity of cartilage in addition to the inflammation prevalent in the joint space. Cell therapies, such as autologous chondrocyte implantation (ACI), offer promising options for treating persistent cartilage lesions, but the inability to expand chondrocytes to sufficient numbers without adversely affecting their phenotype remains a significant problem for graft success. ACI is not indicated for cartilage damage associated with osteoarthritis (OA) or other inflammatory diseases, however, and this lack of efficacy is attributed to the inflammatory environment cells are exposed to, since multiple inflammatory mediators have been shown to play a pivotal role in the initiation and perpetuation of OA. Anti-inflammatory therapies with single molecular inhibitors are unable to effectively modulate the complex inflammatory environment presented in OA. Thus, novel therapies that are capable of modulating multiple signaling pathways and cell types are an attractive alternative to address OA-associated inflammation.
Therefore, the objective of this proposal was to engineer an improved cartilage repair strategy by combining cells and ECM materials to address problems with both cartilage repair and OA-associated inflammation. We developed decellularized cartilage microcarriers that retain endogenous extracellular matrix proteins to both expand and deliver chondrocytes while retaining their phenotype. We also characterize the effects of aggregation, culture conditions, and donor variability on the ability of mesenchymal stem cell (MSC) immunomodulation of OA. To this end, we quantified MSC paracrine factor production, suppression of activated synoviocyte inflammation, and therapeutic efficacy in the rat medial meniscal transection (MMT) rat model of OA. Furthermore, we investigated the interaction between MSCs and human amniotic membrane and the influence of cell-cell and cell-ECM therein on the modulation of inflammation, both in vitro and in vivo. Overall, this work broadens current understanding of cartilage tissue engineering and immunomodulation via ECM and stem cell-based therapies, providing valuable information that can be used to develop strategies to improve efficacy of osteoarthritis treatments.