Musculoskeletal disease and injury can commonly result in damage to articular cartilage. These cartilage defects have little inherent ability to repair. Current clinical treatments are inadequate as they often lead to fibrocartilage formation and joint pain. The goal of this proposal is to develop chondrocytes specifically for superficial zone cartilage regeneration. The premise of this strategy is to provide clinicians with an early stage intervention approach, and one that would also prevent the formation of more debilitating defects. This group has recently demonstrated the ability to derive osteochondroprogentior cells (OPCs) from primary mesenchymal stem cells (MSCs) and shown these OPCs to be responsive to insulin-like growth factor-1 (IGF-1), an anabolic growth factor associated with functional articular cartilage. It has been shown that hyaluronic acid (HA) can lead to up-regulate chondrocytic expression of superficial zone protein (SZP), a key phenotypic marker for superficial zone chondrocytes. These results led to the development of the following hypotheses. It is hypothesized that the dynamic culture of human mesenchymal stem cells within chondrogenic media will provide an environment conducive for rapid chondrocytic differentiation. Specifically, enhanced oxygen and nutrient transport, provided by the dynamic culture conditions, will promote hMSC viability and proliferation, while TGF-beta3 delivery and shear forces imparted the by perfusing chondrogenic media will promote chondrocytic differentiation. To examine this hypothesis, dynamic culture parameters will be developed so as to direct MSC differentiation into OPCs. Second, it is hypothesized that controlled delivery of IGF-1 to osteochondroprogenitor cells will encourage their maturation to differentiated superficial zone chondrocytes, as demonstrated by up-regulated PRG4 and type II collagen expression. In addition, it is hypothesized that engineered superficial zone cartilage can effectively treat superficial articular cartilage defects in a rat model. To examine these hypotheses, delivery exogenous IGF-1 to osteochondroprogenitor cells within the TPS bioreactor environment will be performed and their maturation into superficial zone chondrocytes will be assessed as well, as indicated by PRG4 and type II collagen production, and then utilize this engineered construct to regenerate superficial zone cartilage in a rat model.
Broader Impacts The broader impacts of this project include the development of an engineered tissue and the elucidation of new strategies and technologies within regenerative medicine. In addition, enhancing biomedical engineering research at multiple education levels is a key aspect of the work's impact. The key activity related to this proposal will be the development and execution of a new series of projects associated with the Engineering World Health (EWH) chapter at the University of Maryland. EWH aims to create and distribute readily implementable biomedical technologies to developing countries. The PI has worked with the EWH chapter at Maryland during it inaugural year in 2011-2012 to realize these goals. The PI will also continue many activities that impact undergraduate and graduate education. For example, the PI currently instructs an undergraduate Modeling Physiological Systems and Laboratory course, and an undergraduate / graduate Tissue Engineering course. Since 2007, the PI has directed the Molecular & Cellular Bioengineering Research Experiences for Undergraduates Site. To date, the Molecular & Cellular Bioengineering REU site has brought approximately 60 students from around the country to work in the laboratories of faculty associated with the Fischell Department of Bioengineering. Finally, the PI currently acts as the Associate Chair and Director of Undergraduate Studies in the Fischell Department of Bioengineering. In this position, the PI has a direct influence in fostering undergraduate bioengineering education at the curriculum, program, and research levels.
Jointly funded by Biomedical Engineering (CBET) and Instrument Development for Biological Research (BIO Directorate)
