title: Modeling Hematopoiesis and Responses to Radiation Countermeasures in a Bone Marrow-on-a-Chip.
abstract: Studies on hematopoiesis currently rely on animal models because in vitro culture methods do not accurately recapitulate complex bone marrow physiology. We recently described a bone marrow-on-a-chip microfluidic device that enables the culture of living hematopoietic bone marrow and mimics radiation toxicity in vitro. In the present study, we used this microdevice to demonstrate continuous blood cell production in vitro and model bone marrow responses to potential radiation countermeasure drugs. The device maintained mouse hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture. Increases in the number of leukocytes and red blood cells into the microfluidic circulation also could be detected over time, and addition of erythropoietin induced a significant increase in erythrocyte production. Exposure of the bone marrow chip to gamma radiation resulted in reduction of leukocyte production, and treatment of the chips with two potential therapeutics, granulocyte-colony stimulating factor or bactericidal/permeability-increasing protein (BPI), induced significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow. In contrast, BPI was not found to have any effect when analyzed using static marrow cultures, even though it has been previously shown to accelerate recovery from radiation-induced toxicity in vivo. These findings demonstrate the potential value of the bone marrow-on-a-chip for modeling blood cell production, monitoring responses to hematopoiesis-modulating drugs, and testing radiation countermeasures in vitro.
authors.affiliation: 1 Wyss Institute for Biologically Inspired Engineering, Harvard University , Boston, Massachusetts.|2 Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital Boston and Harvard Medical School , Boston, Massachusetts.
authors.forename: Yu-Suke
authors.initials: YS
authors.lastname: Torisawa
authors.affiliation: 2 Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital Boston and Harvard Medical School , Boston, Massachusetts.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.affiliation: 2 Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital Boston and Harvard Medical School , Boston, Massachusetts.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jiang
authors.affiliation: 2 Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital Boston and Harvard Medical School , Boston, Massachusetts.
authors.forename: Amanda
authors.initials: A
authors.lastname: Jiang
authors.affiliation: 2 Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital Boston and Harvard Medical School , Boston, Massachusetts.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
authors.affiliation: 1 Wyss Institute for Biologically Inspired Engineering, Harvard University , Boston, Massachusetts.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Watters
authors.affiliation: 1 Wyss Institute for Biologically Inspired Engineering, Harvard University , Boston, Massachusetts.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bahinski
authors.affiliation: 1 Wyss Institute for Biologically Inspired Engineering, Harvard University , Boston, Massachusetts.|2 Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital Boston and Harvard Medical School , Boston, Massachusetts.|3 School of Engineering and Applied Science, Harvard University , Cambridge, Massachusetts.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage; D001798:Blood Proteins / Q000008:administration & dosage; D001853:Bone Marrow / Q000473:pathology* / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006410:Hematopoiesis / Q000502:physiology* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation*; D008954:Models, Biological; D022423:Myeloid Cells / Q000166:cytology* / Q000528:radiation effects
chemical_list: D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; C021623:bactericidal permeability increasing protein; D016179:Granulocyte Colony-Stimulating Factor