April 2011 | VOL. 10, NO. 4 | www.McGowan.pitt.edu
William Wagner receives 2011 Clemson Award
McGowan Institute Deputy Director William R. Wagner, PhD, Professor of Surgery, Bioengineering and Chemical Engineering; Director of Thrombosis Research for the Artificial Heart and Lung Program; and Deputy Director of the NSF Engineering Research Center on "Revolutionizing Metallic Biomaterials," has been selected as the 2011 recipient of the Clemson Award for Applied Research. This award acknowledges the "significant utilization or application
of basic knowledge in science to accomplish a significant goal in
the biomaterials area… as evidenced by the development of a useful device or material which has achieved widespread usage
or acceptance, or expanded knowledge of biomaterials/host tissue relationships… and resulted in improvements in the clinical management of disease."
The award recognizes Dr. Wagner for his significant research, important original publications in the literature, and frequent reference to and reliance upon this work by subsequent researchers. His efforts range from in vitro studies of biomaterial properties to clinical studies and his work is published across the spectrum of basic science and engineering journals to the most respected clinical journals. His research emphasis has been upon tissue engineering of the heart and blood vessels, the development of materials targeted for vascular imaging, and the development of an advanced understanding of important principals related to medical device biocompatibility and design.
The Society for Biomaterials, which was established in 1974 and is the oldest scientific organization in the field of biomaterials, is a professional society that promotes advances in biomedical materials research and development by encouraging cooperative educational programs, clinical applications, and professional standards in the biomaterials field.
McGowan Institute for Regenerative Medicine affiliated faculty member Partha Roy, PhD, assistant professor of bioengineering and pathology at the University of Pittsburgh, and McGowan Institute for Regenerative Medicine faculty member Marina Kameneva, PhD, research professor of surgery at the University of Pittsburgh School of Medicine, professor of bioengineering, University of Pittsburgh, and director of the Artificial Blood Program at the McGowan Institute, are the principal investigator and co-investigator, respectively, on a recently awarded Department of Defense US Army Medical Research and Materiel Command (USAMRMC) grant entitled "Drag-reducing polymers (DRP) to curb breast cancer metastasis." The team's 1-year effort funded at $113,625 proposes a working postulate that "systemic administration of DRP is a novel interventional approach to reduce extravasation and metastasis of tumor cells." Their hypothesis will be tested by:
- Determining whether presence of DRP impairs the ability of circulating breast cancer cells to attach and transmigrate through endothelial monolayer in vitro, and
- Determining whether systemic administration of DRP reduces spontaneous metastasis of breast cancer cells in vivo.
Adhesion of circulating tumor cells to microvascular endothelial cells is key for extravasation of tumor cells and therefore an important step for tumor metastasis. There is growing evidence that systemic inflammation facilitates adhesion of circulating tumor cells to endothelial cells hence promoting metastasis and progression of cancer. It has been hypothesized that leukocytes enhance attachment of tumor cells to endothelial cells by creating formation of a tripartite linkage between these three different cell types. Presence of leukocytes in the tumor microenvironment also leads to local release of cytokines that further promotes junctional disruption of endothelial cells and extravasation of tumor cells. Current strategies to inhibit extravasation which involve molecular targeting of either a single adhesion receptor on tumor cells or a specific signaling pathway are therapeutically inefficient because of involvement of multiple adhesion receptors and signaling pathways in the extravasation process.
In complete contrast to these currently envisioned strategies, Drs. Roy and Kameneva propose a conceptually novel paradigm that hemodynamic perturbation that inhibits attachment of inflammatory cells to endothelial cells is an efficient way to impair tumor cell attachment to endothelium thereby reducing extravasation and metastasis. Systemic administration of so called DRP (long-chain viscoelastic polymers that are non-toxic and blood-soluble) at nanomolar concentrations was shown to reduce/eliminate the near-wall cell-free layer naturally existing in microvessels (Fåhraeus effect) and to increase blood flow in microcirculation. DRP-induced occupation of the near-wall space by red blood cells and increasing of near-wall shear rates may inhibit leukocyte rolling and attachment to blood vessel wall which can drastically reduce inflammatory responses (demonstrated in animals implanted with biodegradable scaffolds) and transendothelial migration of tumor cells.
McGowan Institute for Regenerative Medicine affiliated faculty members William Anderson, MD, director of Interventional Cardiology at University of Pittsburgh Medical Center (UPMC), and Thomas Gleason, MD, director of the Center for Thoracic Aortic Disease of the UPMC Department of Cardiothoracic Surgery, recently performed heart implants in the first patient in the Medtronic CoreValve® U.S. Clinical Trial. The purpose of the trial is to evaluate a non-surgical, less-invasive procedure as a treatment alternative to open-heart surgery for patients who suffer from a serious narrowing of the heart's aortic valve. Drs. Anderson and Gleason are co-principal investigators of the UPMC trial.
UPMC is one of 40 hospitals across the U.S. to participate in the trial for patients with severe aortic stenosis, which prevents the heart's aortic valve from opening completely and in turn hampers healthy blood flow from the aorta to the rest of the body. Untreated, it can lead to serious heart problems.
"Aortic stenosis frequently occurs in elderly patients who have a higher risk of complications from standard valve-replacement surgery. This growing patient population may then have the most to gain from new, less invasive, catheter-based approaches to the implantation of a new aortic valve. The trial will allow us to explore this possibility," Dr. Anderson said.
"Because open-heart surgery is currently the only available treatment option for these patients, and because the risks of surgery can be significant for many patients, the medical community is enthusiastic about the less-invasive option," Dr. Gleason said.
Worldwide, approximately 300,000 people have been diagnosed with this condition (100,000 in the U.S.), and approximately one-third of these patients are deemed at too high a risk for open-heart surgery, the only therapy with significant clinical effect that currently is available in the United States.
In the U.S., the CoreValve System will not be commercially available until the successful completion of this clinical trial and approval by the U.S. Food and Drug Administration. The CoreValve System received CE (Conformité Européenne) Mark in Europe in 2007.
For more information about the Medtronic CoreValve U.S. Clinical Trial, visit their site here.
Information about the clinical trial is available here.
The University of Pittsburgh and the University of Michigan (U-M) Cardiovascular Center have been awarded $13.3 million to explore the potential benefits of heart devices for the large and growing group of Americans with heart failure. Principal investigators of the 5-year effort include:
- McGowan Institute for Regenerative Medicine faculty member Robert Kormos, MD, director of the UPMC Artificial Heart Program, co-director of the UPMC Heart Transplantation Program, and Medical Director of Vital Engineering,
- Keith Aaronson, M.D., M.S., medical director of the heart transplant program and Center for Circulatory Support at the U-M Cardiovascular Center, and
- Francis A. Pagani, M.D., Ph.D., surgical director of the heart transplant program and the Center for Circulatory Support at the U-M.
The National Heart, Lung and Blood Institute (NHLBI) and HeartWare, a maker of left ventricular assist devices (LVAD), are sponsoring the study of earlier access to these devices that support the circulation of patients with failing hearts.
In REVIVE-IT (Randomized Evaluation of VAD InterVEntion before Inotropic Therapy), researchers will compare whether patients with heart failure less advanced than that of current LVAD recipients and are not eligible for a heart transplant do better with implanted devices than with current medical therapy.
"The new study allows us to examine the use of heart devices earlier in the cascade of heart failure," says Dr. Aaronson, associate professor of medicine at the U-M Medical School.
For most patients, either a past heart attack or certain conditions such as hypertension, heart muscle diseases, abnormal heart valves, or diabetes has lead to heart failure.
LVADs are currently used in patients with very advanced heart failure as a last resort to help them survive the wait for a heart transplant, or serve as a permanent alternative to heart transplantation.
"Ventricular assist devices have been shown to improve both the quality and length of life of late-stage heart failure patients," says J. Timothy Baldwin, Ph.D., REVIVE-IT trial project officer, Division of Cardiovascular Sciences, NHLBI. "This trial promises to help us learn if there are advantages to providing these devices before patients reach late-stage heart failure."
The pilot study will include 100 patients from selected hospitals across the United States, including the U-M and Pittsburgh. Site selection for the study will begin later this year. The U M's Michigan Institute for Clinical and Health Research will coordinate the study.
"Our work may advance the treatment of heart failure by evaluating whether technology now reserved for very severe heart failure is ready for application to a broader group of patients in need," says Dr. Pagani, a cardiac surgeon and professor of surgery at the U-M Medical School.
In 1985, the first artificial heart device – the Jarvik Artificial Heart – was implanted at the University of Pittsburgh Medical Center (UPMC). Five years later, UPMC became the first medical center ever to discharge a patient on a VAD. Since these milestones, UPMC's Artificial Heart Program has treated more than 600 patients with mechanical circulatory support devices and has continued to uphold its long history as an international leader in this field.
U-M's Center for Circulatory Support is a multidisciplinary team of physicians, surgeons, and allied health care providers dedicated to the care of patients with advanced heart failure or cardiogenic shock. Center clinicians and researchers have provided leadership in the clinical investigation of most of the implantable circulatory support devices in use today.
"The University of Michigan and University of Pittsburgh have been leaders in exploration and development of new technologies for mechanical circulatory support," says Doug Godshall, president and chief executive officer of HeartWare International. "We look forward to supporting their efforts, as they direct this first-of-its-kind clinical study."
Ergin Kocyildirim, MD, assistant professor, Department of Cardiothoracic Surgery, University of Pittsburgh, and leader of the Team Pittsburgh-Fontan Study Group, and his colleagues recently received a $100,000 grant through Texas A&M Institute for Preclinical Studies (TIPS) for an exciting and novel project which will lead to a significantly enhanced understanding of Fontan circulation and venous assist options. The project will not only allow validation of the multi-disciplinary team's previous research on failing Fontan circulation, venous assist options, and enhanced external counterpulsation (EECP), but will also provide the relevant EECP data in Fontan circulation. The project data is projected to pave the way to a clinical study.
Single ventricle anomalies are the fifth most common heart defect and the leading cause of death from all structural birth defects in the United States. In a normal biventricular heart, the systemic and pulmonary circulations are in series and each circulation is supported by a ventricle. In patients born with a single ventricular chamber, the two circulations are in parallel and patients only survive because the systemic and pulmonary venous bloods mix.
In 1971, Francis Fontan and Eugene Baudet first described a procedure that diverted all systemic venous blood into the pulmonary arteries, without the interposition of a ventricle, as a surgical palliation for tricuspid atresia. The introduction of this eponymous 'Fontan operation' 40 years ago revolutionized the treatment of complex congenital heart defects and remains the treatment of choice for patients born with one functional ventricle.
A large number of children continue to benefit from the Fontan operation. However, despite many refinements of the surgical procedure in the past 20 years, a relatively high proportion of patients demonstrate a gradual decline in functional capacity and premature death.
In addition to Dr. Kocyildirim, local Pittsburgh team members on the project include:
- Ozlem Soran, MD, MPH, director of EECP Research Lab, research associate professor of medicine, associate professor of epidemiology/research, Division of Cardiology, University of Pittsburgh
- Victor Morell, MD, associate professor of surgery, Department of Cardiothoracic Surgery, chief, Pediatric Cardiothoracic Surgery, co-director, Heart Center, Division of Cardiac Surgery of the Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine
- Peter Wearden, MD, PhD, McGowan Institute for Regenerative Medicine faculty member, assistant professor of cardiothoracic surgery, University of Pittsburgh School of Medicine, cardiothoracic surgeon, Division of Pediatric Cardiothoracic Surgery, Children's Hospital of Pittsburgh of UPMC
- Kerem Pekkan, PhD, assistant professor with Carnegie Mellon University's Biomedical and Mechanical Engineering Departments
TIPS faculty members Terry Fossum, PhD, professor, Veterinary Medicine & Biomedical Sciences, Texas A&M University, and Egemen Tuzun, MD, scientific director, TIPS, recently joined the team and will also work as collaborators on the project.
Additionally, the Team Fontan Study Group's research will be presented at the World Society for Pediatric and Congenital Heart Surgery Annual Meeting in 2011, which will provide an opportunity to share this novel research.
McGowan Institute for Regenerative Medicine affiliated faculty member James Luketich, MD, FACS, the Henry T. Bahnson Professor of cardiothoracic surgery, chief of the division of thoracic and foregut surgery at the University of Pittsburgh School of Medicine, and director of the Heart, Lung and Esophageal Surgery Institute at the University of Pittsburgh Medical Center, along with researchers at the University of Pittsburgh Cancer Institute (UPCI) recently reported that patients with advanced non-small cell lung cancer can safely take an experimental oral drug intended to protect healthy tissue from the effects of radiation.
The team's findings support further clinical testing of the agent, called manganese superoxide dismutase (MnSOD) plasmid liposome, to determine if giving it alongside chemotherapy and radiation will prevent damage to normal cells that is the typical cause of side effects in cancer treatment, said senior investigator Joel S. Greenberger, M.D., professor and chair, Department of Radiation Oncology, Pitt School of Medicine, and co-director of the lung and esophageal cancer program at UPCI.
"If we can sufficiently protect tissues that are normal, we should be able to deliver our cancer treatments more effectively and perhaps even at higher doses," he explained. "Our aim is to improve the quality of life of patients by minimizing side effects while providing the best treatment for their cancers."
For the safety study, 10 patients with inoperable stage III non-small cell lung cancer took oral doses of MnSOD plasmid liposome twice weekly for a total of 14 doses during 7 weeks of conventional chemotherapy and radiation treatment. The agent, which boosts levels of an antioxidant the body makes naturally, is made of fat droplets containing the gene that produces MnSOD. When swallowed, it is absorbed by cells in the esophagus, which is a common site for severe side effects during radiation treatment for lung cancer.
"The results of this initial trial indicate that MnSOD plasmid liposome can be safely administered," Dr. Greenberger said. "It did not linger in normal cells after treatment, nor did it protect cancer cells from radiation treatment. The next study, which is underway at UPCI, is to determine whether it protects normal tissue, particularly the esophagus, from radiation exposure."
A common toxicity of lung cancer radiation therapy is esophagitis, or inflammation of the esophagus, he explained. Within a few weeks of treatment, patients typically experience painful swallowing that over time can become so severe that narcotics or a break from radiotherapy may be necessary for patient comfort.
Preclinical testing has shown that generating higher levels of MnSOD in healthy cells can suppress the production of inflammatory molecules and reduce cell death, micro-ulceration, and esophagitis. Because the agent is delivered to healthy tissue, it does not protect tumor cells from radiation treatment. In fact, Dr. Greenberger noted, experiments hint that when it is given to cancer cells, it actually encourages cell death because of abnormalities in their cellular metabolism.
He and his team plan to investigate the use of MnSOD plasmid liposome for other cancers, such as protecting the rectum from radiotherapy for prostate cancer and protecting the bladder during ovarian or endometrial cancer treatment.
AWARDS AND RECOGNITIONS
McGowan Institute for Regenerative Medicine faculty member Robert Kormos, MD, the director of the Artificial Heart Program, co-director of Heart Transplantation at University of Pittsburgh Medical Center, and the medical director of Vital Engineering, has been named by Allezoe Medical Holdings as a member of its wholly-owned subsidiary Organ Transport Systems' Medical Advisory Board (MAB). Organ Transport Systems (OTS) revealed that it is in preparations for clinical trials of its LifeCradle®, beginning with applications of its technology to donor heart preservation. OTS has selected the heart as the first focus of its clinical trials due to the pressing need for heart sharing in light of the prevalence of heart disease.
OTS, through its LifeCradle®, aims to directly address the discrepancy between available donor organs and those actually transplanted, by improving the preservation technology. The MAB provides guidance and recommendations for interacting with all the parties of the cardiac transplant community and providing insights into the donor organ procurement process and how the LifeCradle® should fit seamlessly into that process. OTS selected the MAB after evaluating their experience and passion for improving the donor organ procurement process and their willingness to share and be a part of the OTS team.
Dr. Kormos says that, "The OTS donor heart preservation technology incorporated in the LifeCradle® is based on very sound scientific research and is the best documented research for any donor heart preservation technology to date."
National Engineers Week seeks to increase public awareness and appreciation of the engineering profession and technology by emphasizing engineers' positive contributions to society. To help students better understand the practical applications of mathematical and scientific principles, the National Engineers Week Committee sponsors the Annual National Engineers Week Future City Competition. Since the National Engineers Week Future City Competition began, the education and engineering communities have recognized it as an innovative learning program. Excitement abounds throughout the classroom. Students are responsible for solving problems while creating their future city. This year, the 2010-2011 Pittsburgh Regional Future City Competition offered students a resourceful way to learn about engineering. An unusual aspect of this year's competition was to design a future city that would improve treatment or prevention of human disease or injury. Brandon Reines, DVM, a recent guest and medical historian on McGowan Institute for Regenerative Medicine's podcast site, Regenerative Medicine Today, coached a group of 7th and 8th grade students from The Ellis School in Pittsburgh to design a city that would have maximal capacity for high tech regenerative medicine.
The seven Ellis School girls won first prize in the Annual National Engineers Week Future City Competition 2011 for Western Pennsylvania. The Ellis students chose traumatic limb loss and built their future city around tissue engineering principles aimed at regrowing lost limbs. The students named their city "Crescimus" which is Latin for "we grow." Read the students' prize-winning project essay here.
A critical component of the students' tissue engineering project was the use of extracellular matrix (ECM)—a primary focus of the research and scientific work of McGowan Institute for Regenerative Medicine deputy director Stephen Badylak, DVM, PhD, MD, professor in the University of Pittsburgh's department of surgery, and director of the Center for Pre-Clinical Tissue Engineering within the McGowan Institute. Work in Dr. Badylak's lab often begins with tissue or organ decellularization—the process of removing all of the cells from a tissue or an organ leaving only the ECM, the framework between the cells, intact. Dr. Badylak has reported through his efforts over the years that decellularized tissues and organs have been successfully used as bioscaffolds derived from xenogeneic (derived or obtained from an organism of a different species, as a tissue graft) ECM and have been used in numerous tissue engineering applications. The safety and efficacy of such scaffolds when used for the repair and reconstruction of numerous body tissues including musculoskeletal, cardiovascular, urogenital, and skin structures has been shown in both preclinical animal studies and in human clinical studies.
More than 2 million human patients have been implanted with xenogeneic ECM scaffolds. These ECM scaffolds are typically prepared from porcine organs such as small intestine or urinary bladder, which are subjected to decellularization and terminal sterilization without significant loss of the biologic effects of the ECM. The composition of these bioscaffolds includes the structural and functional proteins that are part of native mammalian extracellular matrix. The three-dimensional organization of these molecules distinguishes ECM scaffolds from synthetic scaffold materials and is associated with constructive tissue remodeling instead of scar tissue formation.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Lee KW, Stolz DB, Wang Y.
Substantial expression of mature elastin in arterial constructs.
Mature elastin synthesis is a key challenge in arterial tissue engineering. Most engineered vessels lack elastic fibers in the medial layer and those present are poorly organized. The objective of this study is to increase mature elastin synthesis in small-diameter arterial constructs. Adult primary baboon smooth muscle cells (SMCs) were seeded in the lumen of porous tubular scaffolds fabricated from a biodegradable elastomer, poly(glycerol sebacate) (PGS) and cultured in a pulsatile flow bioreactor for 3 wk. We tested the effect of pore sizes on construct properties by histological, biochemical, and mechanical evaluations. Histological analysis revealed circumferentially organized extracellular matrix proteins including elastin and the presence of multilayered SMCs expressing calponin and α-smooth muscle actin. Biochemical analysis demonstrated that the constructs contained mature elastin equivalent to 19% of the native arteries. Mechanical tests indicated that the constructs could withstand up to 200 mmHg burst pressure and exhibited compliance comparable to native arteries. These results show that nontransfected cells in PGS scaffolds in unsupplemented medium produced a substantial amount of mature elastin within 3 wk and the elastic fibers had similar orientation as those in native arteries. The 25-32 μm pore size supported cell organization and elastin synthesis more than larger pore sizes. To our knowledge, there was no prior report of the synthesis of mature and organized elastin in arterial constructs without exogenous factors or viral transduction.
Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2705-10. Epub 2011 Jan 31..
Miniature Biofuel Cell from Gold Microfiber Electrodes
National Science Foundation
05/01/11 – 04/30/13
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