DEVELOPMENT OF BIOMIMETIC MICRODEVICES TO RECONSTITUTE BONE MARROW FUNCTION
The Hakubi Center for Advanced Research, Kyoto University, Japan; AMED-PRIME, Japan Agency for Medical Research and Development
Studies on hematopoiesis are usually conducted in animals because in vitro methods for culturing blood cells do not accurately model bone marrow physiology. Given the complexity of the bone marrow microenvironment necessary to support the viability and function of the hematopoietic system, there is currently no method to recapitulate the bone marrow microenvironment as well as blood forming functions in vitro. To overcome this challenge, we used a tissue engineering approach to first induce formation of new bone containing marrow in vivo, and then we surgically removed it whole and maintained it in a microfluidic device in vitro. New bone containing marrow was engineered by implanting a polymer device containing a cylindrical hole filled with bone-inducing materials subcutaneously on the back of a mouse. The engineered bone marrow was virtually identical to bone marrow isolated from a mouse femur and could be surgically removed intact and maintained viable in a microfluidic system in vitro. This bone marrow-ona-chip microdevice continues to produce blood cells which are released into microfluidic circulation, while maintaining hematopoietic stem and progenitor cells in normal in vivo-like proportions inside the device. This microdevice could be used to mimic complex organlevel marrow responses to radiation toxicity normally only observed in vivo, and to detect the therapeutic responses of countermeasure agents that have been shown to accelerate recovery from radiation-induced toxicity in animals, whereas these responses could not be replicated by conventional bone marrow culture methods. It is because conventional culture methods do not recapitulate the bone marrow microenvironment which plays an important role in hematopoiesis as well as radiation responses. Therefore, the ability to engineer a complex hematopoietic niche that is capable of maintaining functional hematopoietic stem cells offers a new approach for evaluation of drug efficacy and toxicities and study of hematopoiesis and hematologic diseases.