High throughput platforms for studying dynamic cellular mechanobiology




Lee, Jason, Ph. D. in biomedical engineering

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Cardiovascular disease is one of the most common causes of death in the US and the world. On average, $312 billion is spent every year in drug development and treatment for more than 200 drugs in development by 2013. Despite the resources available, no therapy exists that can effectively treat vascular disease. The chronic nature of the disease renders various treatment methods ineffective on the long term. Drugs with promising preliminary results often fail to succeed in clinical trials. Those that do pass the clinical trial stages require an average of 12 years of development time before they are commercially available. Many of these treatments fail from the poor representation of the dynamic mechanical forces that direct tissue behavior in the body. Previous studies have shown that mechanobiology plays a significant role from a cellular level. These studies have revealed a variety of mechanisms through which mechanical forces can alter cardiovascular biology. Mechanical forces can interact with cellular structures through the transmission of force to other elements and through transduction to turn mechanical forces into a chemical event. The search for potential molecular mechanotransducers has revealed a variety of complex and fascinating mechanisms through which stretch- and flow-induced forces can alter arterial biology. Although these pathways are known to be involved in sensing forces, much remains to be understood as to how these pathways work together to guide its downstream effects or how to engineer efficient therapies for disease. The lack of tools to accurately capture these mechanical forces is a major barrier in anticipating treatment response in vivo. Thus, there is a large disconnect between in vitro and in vivo results. Consequently, there is a high demand to effectively mimic the mechanical environment of the body. Development of in vivo techniques that can produce the necessary strains and stresses can be the key in expediting the transition from preliminary research into clinical trials. Preemptively exposing the cells to the complex physiological forces at high throughput could screen out for multitude of small molecule treatments that can be ineffective in vivo before beginning clinical trials. The results could also reveal potential therapeutic targets that affect disease progression and also condition mesenchymal stem cells and vascular cells to the mechanical stresses to promote proper differentiation and remodeling. Here we have designed and developed a device that is capable of depicting the physiological forces at high throughput with high accuracy and flexibility. Throughout the course of this research we have demonstrated its capability to explore cellular response to ranges of dynamic mechanical strain. Using this advantage, we have examined the changes in vascular smooth muscle cells, and studied the potential to use mechanical strain to condition human mesenchymal stem cell to have endothelial phenotypes and endothelial cells to have mesenchymal phenotypes.


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