MASSACHUSETTS GENERAL HOSPITAL, THE
Grant: $98,847 - National Science Foundation - Aug. 19, 2009
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Award Description: Liver Reengineering
Project Description: Project not started.
Jobs Summary: There is a critical shortage of organs, with the organ waiting list currently at 100,000 requests and increasing by 5% every year. This study focuses on the liver: 27,000 die in the US annually due to liver disease, 3,000 while on the organ transplant list. Given that only organs in pristine condition are transplantable, orthotopic transplantation will always remain a limited pool. A more elegant, long-term solution is using stem cells to develop tissue-engineered replacements. However, while many in vitro successes have been demonstrated, clinical success has been very limited due to low cell viability and functionality in the long term in vivo. The major gap is the lack of an ideal transplantable scaffold that has all the necessary microstructure and extracellular cues for cell attachment, differentiation, function and vascularization, which has so far proven difficult to manufacture in vitro. Our long-term goal is to engineer transplantable liver grafts for curing or treating relevant liver diseases. The objective of the proposed study is to develop functional liver grafts. The central hypothesis to be tested here is that the naturai liver scaffold derived from discarded livers can be extensively repopulated, can provide an adequate maturation environment for stem cell derived liver cells, and that these grafts perform the essential hepatic functions. The rationate of the study is that while most research focuses on producing the ideal scaffold from the ground up using synthetic biomaterials, the native ECM is likely to contain the necessary architecture and environrhental cues, hence presents a promising, little explored alternative approach for producing organ grafts that can vertically advance the field of tissue engineering. As a resulf we expect to i) establish decellularized liver matrices as a viable scaffold for llepatic tissue engineering, ii) generate a liver ECM-based maturation protocol to generate hepatocytelike cells, and iii) introduce a novel graft engineering approach to provide auxiliary hepatic support. lntellectual merits of the proposed approach will be very tangible both scientifically and clinically. ln the scientific scene, the recellularized grafts can provide a feasible model to study liver development and hepatic maturation processes as well as a model to study the complex parenchymal and nonparenchymal liver cell interactions. The methods could be applied for other tissues, such as pancreatic grafts for treating diabetes. -lhe graft could also be used as a tool to accurately assess metabolism or toxicity in human liver grafts in vitro, by providing a natural environment for the hepatocytes. Finally, this work is expected to establish the basis of future sophisticated organ reengineering techniques that incorporates several different cell types and may ultimately lead to development of entire organs in vitro. Clinically, the ability to practically engineer auxiliary grafts would go far beyond treating liver failure, and could be used as a method to prevent failure in patients in risk. For instance, availability-of liver grafts would enable performing much more aggressive hepatic resections to patients with malignancies, which is currently not possible due to the likelihood of developing hepatic failure as a consequence of insufficient hepatic mass. The grafts could also be used to treat patients with inborn enzymatic liver diseases, possibly allowing the repopulation of the patient liver with healthy hepatocytes. Moreover, these grafts could revolutionize living-donor liver transplantation in that left-lateral grafts - currently not deemed sufllcient for adult recipients - could be sufficient to support the patient when performed in tandem with the hepatic support provided by the liver grafts. (Total jobs reported: 0)
Project Status: Not Started
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