#16-Dr. William Federspiel is developing devices that do some of the lungs’ critical work of adding oxygen to blood and removing carbon dioxide. These aren’t ventilators, which mechanically inflate the lungs with air, but small devices that can be inserted into a vein through an incision in the femoral artery.  Known as respiratory assist catheters, they can unburden the lungs for a short time while they recover from disease or injury, and:
Dr. Marina Kameneva, meanwhile, has found a compound derived from aloe vera that boosts survival rates during episodes of massive blood loss. Known as a drag reducing polymer, the compound seems to help oxygen-carrying red blood cells reach needy tissues even when there’s not a lot of blood to go around.

#15-Dr. Kevin Shakesheff of the University of Nottingham. He is developing new scaffolds from a familiar material: polylactic acid, the same stuff that makes up absorbable sutures. Dr. Shakesheff imagines outfitting surgeons with a syringe full of polylactic acid that is enhanced with growth factors -- or even the patient’s own cells -- to inject into an area that needs help to heal, and:
Dr. Nicholas Rhodes, of the University of Liverpool would like to do away with scaffolds altogether. Rather than introduce bioengineered materials into patients, he’d rather persuade a patient’s cells to do their own bioengineering. Dr. Rhodes is prompting regeneration by harnessing and directing the body’s natural inflammatory response.

#14-Dr. Malla Padidam of the biotech company RheoGene describes their gene switch, a molecule that can turn a gene on or off at a particular time to precisely guide the growth of transplanted tissues or cells. Another RheoGene product uses engineered enzymes that recognize certain sequences of DNA, so that when a scientist introduces a new gene it inserts into just one location. This is an improvement over current genetic engineering technology that can't control where in a chromosome a gene inserts itself, possibly hindering whether or not it functions, and:
David S. Smith of the Pittsburgh office of Pepper Hamilton LLP is a corporate lawyer who helps scientists transform their work from laboratory investigations into clinical products. Mr. Smith focuses on intellectual property transactions, regulatory issues, and licensing.

Satdarshan P.S. Monga*, Mariah S. Hout, Matt J. Baun, Amanda Micsenyi*, Peggy Muller*, Lekha Tummalapalli*, Aarati R. Ranade, Jian-Hua Luo*, Stephen C. Strom* and Jörg C. Gerlach¶

From the Departments of Pathology,* Medicine (Gastroenterology), and Surgery and Bioengineering, McGowan Institute for Regenerative Medicine, and the Department of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and the Department of Surgery,¶ Charité-Campus Virchow, Humboldt University, Berlin, Germany

Mouse Fetal Liver Cells in Artificial Capillary Beds in Three-Dimensional Four-Compartment Bioreactors

Bioreactors containing porcine or adult human hepatocytes have been used to sustain acute liver failure patients until liver transplantation. However, prolonged function of adult hepatocytes has not been achieved due to compromised proliferation and viability of adult cells in vitro. We investigated the use of fetal hepatocytes as an alternative cell source in bioreactors. Mouse fetal liver cells from gestational day 17 possessed intermediate differentiation and function based on their molecular profile. When cultured in a three-dimensional four-compartment hollow fiber-based bioreactor for 3 to 5 weeks these cells formed neo-tissues that were characterized comprehensively. Albumin liberation, testosterone meta-bolism, and P450 induction were demonstrated. Histology showed predominant ribbon-like three-dimensional structures composed of hepatocytes between hollow fibers. High positivity for proliferating cell nuclear antigen and Ki-67 and low positivity for terminal dUTP nick-end labeling indicated robust cell proliferation and survival. Most cells within these ribbon arrangements were albumin-positive. In addition, cells in peripheral zones were simultaneously positive for -fetoprotein, cytokeratin-19, and c-kit, indicating their progenitor phenotype. Mesenchymal components including endothelial, stellate, and smooth muscle cells were also observed. Thus, fetal liver cells can survive, proliferate, differentiate, and function in a three-dimensional perfusion culture system while maintaining a progenitor pool, reflecting an important advance in hepatic tissue engineering. matrix (ECM), a tissue-engineered scaffold, recently demonstrated cardiomyocyte population after myocardial implantation. Surgical restoration of myocardium frequently uses Dacron as a myocardial patch. We hypothesized that an ECM-derived myocardial patch would provide a mechanical benefit not seen with Dacron.

American Journal of Pathology. 2005;167:1279-1292

Eric Lagasse

Metastatic Colon Cancer, Stem Cells, and Artificial Bioreactors

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).

Our hypothesis, based on the current cancer stem cells model, is that metastatic colon cancer of the liver is a clonogenic event initiated by cancer stem cells which are optimally adapted to proliferate under the prevailing conditions in the primary tumor and emerges to form the metastatic cancer. Our goal will be to characterize the cancer cells isolated from metastatic colon cancer in the liver by identifying the cancer-initiating cell leading to the metastatic tumor and determine if this cell have the characteristic of a stem cell.

Finally, we propose to reconstitute in vitro tumor growth environment similar to what is found in patient affected with metastatic colon cancer using artificial liver bioreactors.

The specific aims pertaining to the main goal and its hypotheses are listed below:

Aim 1: Identification of colon cancer stem cells.
Aim 2: Expansion of human metastatic colon cancer stem cell populations using bioreactors.

Our approach will be to integrate the fields of stem cell biology, cancer biology, tissue engineering, and clinical treatment of patients to develop promising new therapies for patients with metastatic colon cancer. The overall goal of this project is to use cancer stem cells to create a diagnostic bioreactor using a novel 3-D culture model, which would allow tumor cells to recapitulate their in vivo geno- and phenotype diversity. This “in vitro” regeneration of the patient tumors in bioreactors would allow a new individualized chemotherapy planning and the discovery of novel approaches to effectively target cancer stem cells.