NOVEL DIFFUSION TYPE BIOARTIFICIAL ORGAN

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The immune exclusion devices containing viable cells (a bioartificial organ ) have broad application to treating a variety of diseases caused by the loss of specific vital metabolic functions. The cells which produce the desired therapeutic substances are separated from immune lymphocytes and immunoglobulins by semipermeable membranes which pass only small molecules such as the specific therapeutic substance as well as oxygen, nutrients and metabolites. As immune lymphocytes and antibodies are excluded by the membrane, the requirement for chronic immunosuppression is eliminated. The cells contained within the bioartificial organ could be freshly isolated cells such as pancreatic islets and hepatocytes which replace dysfunctioning cells as well as cell lines and genetically engineered cells which are custom-made to produce the desired molecules. An ideal bioartificial organ would 1) be introduced into recipients with a minimally invasive procedure, 2) be structurally stable, 3) be biocompatible, 4) be fully retrievable, and 5) require no immunosuppression when allogeneic or xenogeneic cells are used. Although three types of immune exclusion devices, i.e. microcapsules, diffusion chambers and vascularized devices, have been extensively studied for treatment of various metabolic diseases, none has yet fulfilled the above requirements completely. We have recently conceived a novel diffusion-type bioartificial organ (an "ultra-thin pouch") which was successfully used in a pilot study to ameliorate experimental diabetes when pancreatic islets were included within the device. The innovative feature of our diffusion pouch is that the thickness of the islet chamber (distance between the two membranes) is reduced to the size of a large islet, so that all the islets within the pouch are close to the membrane and exposed to the same degree of oxygen supply. The present proposal will determine the optimal configuration and conditions of the ultra-thin pouch for maximal production of insulin and long-term survival of the islets and determine whether the ultra-thin bioartificial pancreas containing xenogeneic islets achieves long-term normalization of hyperglycemia without immunosuppression. We believe that successful development of the ultra- thin pouch for treatment of diabetes will pave a way to a broad application of the device for treatment of various other diseases and thus will achieve a long-term impact on biomedical research.