The bone marrow produces nearly 500 billion blood cells per day in an adult human. Each type of blood cell is required for life: red blood cells deliver oxygen, white blood cells provide immunity, and platelets prevent bleeding, among other functions of these cells. Dysregulation of blood cell production leads to severe anemia, leukopenia, and thrombocytopenia, and produces substantial morbidity and mortality. Approximately 15 million red blood cell units, 9 million platelet units and thousands of stem cell units are transfused annually in the United States. Transfusion of donor-derived blood cells, however, raises many concerns, including the lack of control over quality and quantity, and the risk of infectious and bacterial contamination during storage and transfusion. New strategies to stimulate thrombopoiesis in vivo, or to produce sufficient numbers of blood cells in vitro would revolutionize the management of anemia and cytopenias. Important progress has been made towards tailoring the molecular biology and biochemical regulation of hematopoietic cells in culture. These approaches, however, are limited by their failure to reproduce the complexity of bone marrow architecture. Here we propose to develop an in vitro microfluidic bone marrow niche that recapitulates the bone marrow in its cellular and matrix components, but which can also be manipulated to determine the roles of each component in the functioning of a normal bone marrow, and allow us to elucidate and control hematopoiesis. Ideally, this system will be scalable, with the ultimate goal of generating blood cells in vitro for transfusion. Although much information has been learned about the mechanisms of hematopoiesis over the last several decades, a great deal remains unknown, particularly regarding the role of specific marrow niches in blood cell production. Recent advances in tissue engineering and vascular biology make it an opportune time to unravel these mysteries. The creation of the microfluidic bone marrow niche will represent the first in vitro system that recapitulates the complex architecture of the bone marrow, and functions to generate blood cells. Uniquely, this system allows the stepwise addition or removal of individual components of the niche to reveal their individual functions in blood cell production. The proposed work will not only be an important step towards understanding and controlling the hematopoietic development in both healthy and diseased states, but could also revolutionize preclinical testing for therapies to increase blood cell count in diseases where they are low, either because of the disease itself or its therapy. This system will also allow for optimization of the conditions for ex vivo production of blood cells. Once thes conditions are determined, the system can be scaled up to generate quantities sufficient for transfusion.
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