Title Metastatic Colon Cancer, Stem Cells, and Artificial Bioreactors
Summary This study will focus on the cellular characterization of metastatic colon cancer in the liver and a 3-D perfusion culture instrument that recapitulates hepatic vasculature and microenvironment. Colon cancer is a very common cancer second only to lung cancer. Distant metastases are one of the worst prognostic signs as this places the patient in the most advanced staging category. Colon cancers generally spread through the lymphatics or through the portal venous system to the liver. The liver is the most frequent visceral site of metastatic dissemination and is the initial site of distant spread in one-third of recurring colon cancers, with two-thirds of patients having liver involvement at the time of death. The median survival after the detection of distant metastases range from 6 to 9 months (with heavy liver involvement) to 24 to 30 months (with initially small liver nodules).
Summary The aim of this proposal is to design solutions for vascular, cardiac, and pulmonary organ failure by building interactive teams of researchers focused on specific aspects of cardiopulmonary organ engineering. Our efforts will address a tissue engineered blood vessel, and a myocardial patch. The assembled research teams will function as cores of expertise that address common tasks associated with each of the projects. Five research cores will be established in the following areas:
Summary The PediaFlow™ is a miniature magnetically levitated turbodynamic VAD for pediatric patients ranging from birth weight to 15 kg. Our design is based on extensive computational modeling. CFD analysis was used to optimize the flow field for efficiency and hemocompatibility and reach a design point of 0.5 L/min at a 110 mm Hg pressure head.
The current (1st generation) PediaFlow™ design is 51 mm in length with a diameter of 28 mm. Its total mass is approximately 100 g. Prototypes are currently undergoing in vitro performance tests and flow path visualization and quantification. In vivo evaluation is planned during the current grant year.
Susan Braunhut, Ph.D., professor of biological sciences at the University of Massachusetts at Lowell
Lorraine Gudas, Ph.D., chairman of the pharmacology department and Revlon Pharmaceutical Professor of Pharmacology and Toxicology, Weill Medical College of Cornell University, New York City
Ellen Heber-Katz, Ph.D., professor, molecular and cellular oncogenesis program, The Wistar Institute in Philadelphia
Shannon Odelberg, Ph.D., assistant professor, departments of internal medicine and neurobiology and anatomy, University of Utah, Salt Lake City
Hans-Georg Simon, Ph.D., a developmental biologist and assistant professor of pediatrics, Children’s Memorial Research Center and Northwestern University in Chicago
Title Mammalian Limb Restoration
Summary The regenerative ability of adult human tissues, organs, and appendages is typically very limited. The default mechanism of wound repair in humans and most other mammals is characterized by scar tissue formation. However, there is evidence for some site-specific regeneration-like processes during mammalian embryologic development and during the early postnatal period. In addition, there is lifelong self-renewal capability for selected cell populations such as hematopoietic cells, intestinal epithelium, and hepatocytes.
PI J. Peter Rubin, MD; Kacey Marra, PhD; Albert Donnenberg, PhD; Vera Donnenberg, PhD; Stephen Badylak, DVM, PhD, MD
Title Injectable Engineered Tissue for Cancer Reconstruction
Summary Breast cancer is endemic in the United States, with nearly 216,000 new cases expected this year (American Cancer Society statistics). For patients undergoing mastectomy, the loss of one or both breasts can cause significant discomfort and psychosocial distress.
PI Jörg Gerlach, M.D., Ph.D
Title 3D Culture of mES Cells in Four-Compartment Bioreactors
Summary Embryonic stem (ES) cell research and scale-up for development of possible clinical therapies is limited by the existing 2D dish culture methods. Our proposed studies present a new approach, in which ES cells are expanded under 3D medium perfusion conditions within four-compartment hollow fiber-based bioreactors. The design of the bioreactors allows integral oxygenation and efficient transfer of nutrients and waste products to and from the cells, cultured at high density involving minimal solute gradients within the cell compartment. Additionally, the interwoven fibers provide a scaffold allowing the cells to form 3D structures where the size of cellular aggregates is limited by the spacing between the hollow fibers. We propose that the well-controlled and versatile culture environment provided by our bioreactor is ideal for both large-scale expansion of undifferentiated ES cells and directed differentiation of ES cells using numerous strategies, including controlled exposure of the cells to molecular reagents and compartmentalized co-culture with mature cells.