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Heart Valves & Large Blood Vessels for Pediatric Patients


Congenital and acquired diseases of the heart valves are significant causes of morbidity and mortality among children.  The current standards of care call for surgical correction by implanting either artificial mechanical valves or decellularized, non-living tissue valves.  However, multiple open heart surgeries are often required prior to adulthood for two reasons.  First, calcification and failure of the non-living tissue materials may necessitate replacement.  Secondly, both types of valves are unable to grow with the child and may therefore require replacement with larger conduits.  The tissue engineering approach to organ repair and regeneration offers the possibility of generating valve tissue that can grow, remodel and adapt as the child grows, thus eliminating most of the need for repeated surgeries.  Thus the long-term goal of this work is the development of methods for generating transplantable vascular tissue (large vessels and valves) for pediatric applications.

 


Bioreactor Expansion of Hematopoietic Stem Cells


The inadequate supply of hematopoietic stem cell (HSC) enriched cell populations severely limits the widespread use of HSC transplantation as an effective treatment of hematologic and malignant diseases.  In addition the success rate of hematopoietic transplant therapies could be significantly increased if large quantities transplant material with a high incidence of HSCs could be reliably generated.  The long term goal of this project is to address these deficiencies by developing a perfusion culture system capable of specifically expanding a population of primitive hematopoietic progenitors enriched in HSCs while inhibiting lineage differentiation.  In most hematopoietic expansion schemes, expansion and lineage differentiation proceed in parallel and HSC expansion per se is limited.  Recent published studies suggest that it may be possible to exert precise control over the differentiation vs. proliferation activities of hematopoietic populations in vitro by controlling both the soluble cytokines and the ECM substances to which the cells are exposed. In our laboratory, the effects of these factors on the expansion of human CD34+ cord blood stem cells are being evaluated. Delivery of promising molecular species in soluble vs. immobilized form is being optimized.  Results from these experiments are being incorporated into perfusion bioreactor systems suitable for optimization and scale up to achieve cost efficient, high yield expansion of either hematopoietic stem cells or therapeutically valuable blood cell lineages.

 


Liver Regeneration via Hepatocyte Transplantation


There is a current need to expand the quantity of liver tissue available for transplantation. This need is particularly pressing for the pediatric population given the much lower availability of pediatric organs. One approach to addressing these needs involves developing effective methods for hepatocyte transplantation. The ability to reliably re-assemble isolated hepatocytes into a functional, "neo-organ" would greatly facilitate the development of such systems. Hepatocyte transplantation also has great potential for providing cures for a variety of liver-based, metabolic and enzyme deficiency diseases. However, tissue engineering of sizeable implantable liver systems is currently limited by the difficulty of assembling three dimensional hepatocyte cultures of a useful size, while maintaining full cell viability. The main limitation stems from the high metabolic rates of these cells and the associated low rates of diffusive mass transfer in densely seeded tissue scaffolds. We are addressing these limitations by developing tissue scaffold designs that allow for superior nutrient and oxygen transport to the cell mass in the short term and enhanced angiogenesis in the long term. The long-term goal of this project is to design scaffold materials and procedures for assembling isolated hepatocytes into a functional, vascularized mini organ.