Grant of the Month

Title Temporal Delivery of Growth Factors for Wound Healing Using Porous Hollow Fibers

Description Our objective is to optimize wound healing through temporal delivery of growth factors using porous hollow fibers extending into a wound site. As an extension to the wound-cap technology (artificial capillary bed delivery system), these fibers can be made from materials that dissolve in the presence of a chemical or temperature-based trigger following the wound healing process. Because angiogenesis is, in many cases, one of the first steps towards wound healing, we propose to demonstrate enablement of this technology by mimicking the natural sequence of stimuli that directs angiogenesis. Our hypothesis is that sequential delivery of appropriate angiogenesis-promoting factors from our externally-regulated delivery system, as opposed to simultaneous delivery of multiple factors, will result in more mature and integrated neo-vasculature.

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Co-Investigators Kimimasa Tobita, MD, PhD and Stephen Badylak, DVM, MD, PhD

Title Cardiac Remodeling with Organ Specific Extracellular Matrix Scaffolds

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Title Tissue Engineered Skeletal Muscle (TESM) from Muscle Progenitor Cells: A Model for Studying Insulin Resistance and Muscle Metabolism

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Co. Investigator: Robert Carithers, Adrian Di Bisceglie, Michael Fried, Marc Ghany, Steven Han, E. Jenny Heathcote, W. Ray Kim, Daryl Lau, William Lee, Anna Lok, Mitchell Shiffman, KathleenSchwarz, and Norah Terrault

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Title: Regenerative Medicine Approach to the Treatment of Abdominal Compartment Syndrome in a Dog Model

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Co. Investigator: Sharon Marx and Gabriel Amitai

Title: Temperature responsive modification of microfiber tissue perfusion devices.

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Co-PIs: Marina Kameneva, William Wagner, Jörg Gerlach, Mark Yazer

Title: Large Scale Human Placenta Progenitor Cell-Derived Erythrocyte Production – Continuous Red Blood Cell Production

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Co-PIs: Eric Lagasse, William Saunders, and Youjun Li

Title: Function of a Glycoprotein Ibα, a Subunit of the Von Willebrand’s Factor Receptor as a Transforming Oncoprotein

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Co-PIs: Alan Russell, PhD and William Wagner, PhD

Title: Percutaneous Respiratory Assist Catheter

Description: Each year several hundred thousand Americans suffer short term lung failure requiring respiratory support within the intensive care unit. The objective of this proposal is to develop a percutaneous respiratory assist catheter (PRAC) that can be inserted into the venous system to provide supplemental breathing support, independent of the lungs, for patients requiring short-term (~ 4-7 day) respiratory assistance.

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Co-PIs: Gregory M. Constantine, PhD (Pitt—Mathematics); Steve Chang (CEO of Immunetrics); Drs. Gary Nieman and Kris Maier (SUNY-Syracuse)

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Co-PIs: William Wagner, PhD

Title: Engineered Early Embryonic Cardiac Tissue

Description: We have developed an Engineered Early Embryonic Cardiac Tissue, termed EEECT, using embryonic cardiac cells isolated during the period of primary morphogenesis in order to investigate the regulation of embryonic CM proliferation and differentiation and to generate tissues with optimal properties for cardiac repair. Our EEECT construct uses a simple cylindrical geometry which is reproducible, scalable, and preserves the unique proliferative and contractile properties of developing myocardium. Using EEECT we can investigate the regulation of CM proliferation and maturation within a functioning in vitro 3D environment. EEECT proliferation and force production increases in response to cyclic mechanical stretch. With prolonged culture EEECT acquires a post-natal myocardial phenotype (reduced proliferation, increased calcium and β-adrenergic sensitivity, and increased force production). Preliminary data show that cylindrical EEECT can be implanted onto recipient injured adult myocardium as part of a cardiac repair/recovery strategy. Implanted EEECT survive, proliferate, and functionally contribute to recipient cardiac functional recovery.

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Title Research Training Group Award

Summary Will provide resources to develop training programs for mathematics students to work with physicians and biologists to help resolve complicated medical problems through mathematics. A variety of computer models will be produced based on differential equations to create immune system models to plot the various chemical and physical changes that occur as the body battles influenza, inflammation, sepsis, necrosis, and wounds. The researchers hope to be able to plot and pinpoint the origin of uncontrollable inflammation and infection that can occur as complications following surgery.
Source

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Title Four Projects Funded by CR Bard, Inc.

Summary In vivo and in vitro evaluation of porcine dermal product for pelvic floor and body wall (hernia) reconstruction. ($90,000)
Manufacturing process review and modification. ($96,000)
In vitro characterization of porcine dermis ECM and products in development. ($118,000)
Evaluation of gel form of porcine dermal matrix. ($60,130)

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Title Function of a Glycoprotein lba, a Subunit of the von Willebrand’s Factor Receptor as a Transforming Oncoprotein

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Co-PI(s) Joerg Gerlach

Title Ovarian Cancer, Stem Cells and Bioreactors

Summary Addressing the needs of new approaches for anti-cancer therapies by combining stem cell biology, cancer biology and bioengineering. Our central hypothesis is that cancer stem cells are initiating and sustaining the growth of ovarian cancer. In consequence, the identification of the cancer stem cells represents a major step forward in the elucidation of ovarian cancer hierarchy and could hold the key to understanding the origin and maintenance of ovarian cancer, the relapses and possibly the metastases in advanced cases. Another problem facing cancer cell biology is the access of in vitro culture models for research and study of cancer development and its pathophysiology. Here we propose to adopt bioreactors used for bioartificial livers (BAL) to provide tumor cells with a 3-D perfusion culture instrument that recapitulate vasculature and microenvironment.

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Title Armed Forces Institute for Regenerative Medicine

Summary The University of Pittsburgh’s McGowan Institute for Regenerative Medicine and the Institute for Regenerative Medicine at Wake Forest University Baptist Medical Center have been selected as co-leaders of a national $85 million program to use the science of regenerative medicine to develop new treatments for wounded soldiers.

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Title Advanced Regenerative Medicine (ARM) Therapies for Combat Injuries

Summary Badylak: Digit regeneration using porcine derived scaffolds
Gerlach: Wound cap for tissue regeneration
Gerlach: Skin gun for burn therapy

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Title Levitronix Phase II SBIR

Summary Development of a magnetically levitated, bearingless pump for a pediatric ventricular assist device.

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Title: Cardiopulmonary Organ Engineering

Description: Researchers are currently working to develop tissue constructs that could be utilized to repair congenital heart defects and to recover function lost to myocardial infarction. The general approach involves optimizing the combination of precursor cells with synthetic scaffolds and culturing methods to achieve the functionality required for the given application. The research team working on this project includes cardiothoracic surgeons, bioengineers, polymer chemists, cell biologists and electrophysiologists.

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Title: Beta-catenin in the growth of hepatocellular cancer

Description: Hepatocellular cancer (HCC) is a disease of poor prognosis. Identifying novel molecular aberrations might present opportunities to identify new therapeutic targets. Due to the similarities between the processes of development and cancer, we used early developing livers to identify genes that might play a primary role in HCC. Platelet-derived growth factor receptor-alpha (PDGFRalpha) was identified from microarray using early developing mouse livers. Expression of PDGFRalpha and its upstream effectors, PDGF-AA and PDGF-CC, were examined in HCC tissues (n = 43) by Western blot, real-time PCR, and immunohistochemistry. Finally, effect of anti-PDGFRalpha antibody (mAb 3G3, ImClone Systems, Inc.) was examined on human hepatoma cells. A high expression of PDGFRalpha was observed during early liver development. HCCs (17 of 21) revealed cytoplasmic PDGFRalpha and activated PDGFRalpha (phospho-Tyr(754)) by immunohistochemistry. Additional HCCs (14 of 22) showed elevated PDGFRalpha levels when compared with the adjacent normal livers by Western blots. Of these 14 patients, 3 showed increased PDGFRalpha gene expression, 3 showed elevated PDGF-AA, and 4 had higher PDGF-CC levels in the tumors compared with adjacent livers. Multiple hepatoma cell lines, when treated with mAb 3G3, showed significant decreases in cell proliferation and survival (P < 0.05). In conclusion, approximately 70% of HCC tissues had elevated PDGFRalpha levels due to diverse mechanisms. PDGFRalpha inhibition in hepatoma cells led to diminution of tumor cell survival and proliferation and thus might be of therapeutic significance.

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Co-PIs: Dr. Joyce Bischoff, Dr. David Brown, Dr. Danielle Gottlieb, Dr. John Mayer, Dr. Robert Padera, Dr. Andrew Powell, Dr. Virna Sales, Dr. Frederick Schoen, Dr. George Stetten

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Co-PIs: Stephen Grant and Michael Epperly

Title: Biomarkers of invasiveness using isogenic and progressive human ductal carcinoma in situ cell lines

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Co-PIs: Douglas Weber, PhD

Title: Surface Modified Polymer Conduits for Peripheral Nerve Repair

Description: The project seeks to increase the understanding of the effects of biomaterial surface properties on nerve regeneration, and also to enhance the integrated research and education activities of graduate, undergraduate and pre-college students. The plan includes outreach programs and innovative research in the exciting areas of biomaterials and tissue engineering. Specifically, the research plan is focused on developing biodegradable conduits with modified inner luminal surfaces that enhance peripheral nerve repair over long gaps, and the educational plan is focused on enhancing and maintaining the involvement of women and underrepresented minorities in engineering.

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Co-PI(s) 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

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Title “Quantitative proteomics of nuclear matrix proteins in novel human ductal carcinoma in situ model systems”
Summary Background: Ductal carcinoma in situ (DCIS) is the earliest identifiable breast cancer lesion. Because DCIS is a pre-invasive malignancy, a better understanding of if and how it may progress to invasive disease will allow determination of which patients to treat aggressively and avoid unnecessary aggressive procedures. Once determined, these differentially expressed proteins may be used as biomarkers or therapeutic targets, as well as help determine the paths by which normal cells progress to DCIS plus provide a better understanding of breast carcinogenesis and ways to prevent it. Tumor grade, size and presence of necrosis are currently used to make clinical decisions regarding DCIS.

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Title Biomechanical Soldier Treatment and Regeneration Consortium (STRaC): Preclinical Study to evaluate the use of UBM-ECM for Partial Thickness Skin Wounds

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Co-PI(s) William Wagner, PhD

Title Biomechanical Optimization of Tissue Engineered Heart Valves
Summary The focus of this competitive renewal grant is a comprehensive biomechanical evaluation of the in-vitro phase of engineered tissue heart valve development.

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Co-PI(s) Donald M. Yealy, M.D and Mitchell P. Fink, M.D.

Title Protocolized Care for Early Septic Shock (ProCESS)

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Title National Tissue Engineering Center (Multiple Awards)

Summary Regenerative Medicine Approach to the Treatment of Abdominal Compartment Syndrome in a Dog Model

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Title Biological Markers of Recovery for the Kidney (BioMaRK)

Summary Investigate the role of inflammation, as well as other factors in recovery from acute renal failure (ARF). This project, called Biological Markers of Recovery for the Kidney, or BioMaRK, will examine how such factors influence survival as well as recovery of kidney function. The study will assess how certain inflammation markers relate to clinical outcomes and build a risk-prediction model based on clinical variables and those biomarkers. The results of this study could potentially lay the foundation for the development of ARF treatment therapies, particularly those designed to enhance organ recovery.

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Co-PI(s) Michael Chancellor, MD; Douglas Chew, BS; Johnny Huard, PhD; Naoki Yoshimura, MD, PhD

Title Bioengineered Urethral Augmentation

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Co-PIs Michael Chancellor, MD; Douglas Chew, BS; Johnny Huard, PhD; Naoki Yoshimura, MD, PhD

Title Bioengineered Urethral Augmentation

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Co-PIs Kacey G. Marra, Ph.D., Albert D. Donnenberg, Ph.D., Vera S. Donnenberg, Ph.D., Stephen Badylak, D.V.M., M.D., Ph.D., and Howard D. Edington, M.D.

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Co-PI(s) Marina V. Kameneva, PhD and Alan J. Russell, PhD

Title Next Steps in the Development of Drag Reducing Polymers for Treatment of Life-Threatening Hemmorrhagic Shock in Combat Casualties Using Small Volumes of Resuscitation Fluid

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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).

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Title Cardiopulmonary Organ Engineering

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:

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Title Pediatric Circulatory Support

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.

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• 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.

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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.

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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.

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