November 2004 | VOL. 11 | www.McGowan.pitt.edu

As The Society for Biomaterials has announced that Stephen Badylak, DVM, MD, PhD is the 2005 recipient of the prestigious Clemson Award for Applied Research. The selection is based on the work of the candidate that has resulted in significant utilization or application of basic knowledge in science to accomplish a significant goal in the biomaterials area. The achievement will be 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 which have received widespread acceptance and resulted in improvements in the clinical management of disease.

Dr. Badylak discovered that a strong, pliable tissue harvested from porcine small intestine provides an inductive scaffold for host cells to replace and repair damaged tissue. This biomaterial is called small intestinal submucosa, or SIS, and it is a naturally-occurring, complex matrix that is easy to handle, yet strong enough to hold sutures and provide support for weakened tissue.

As a naturally-derived, extracellular matrix (ECM) material, SIS is not chemically cross-linked. Since SIS is taken from a biological source and is processed to remove all cells, it is biocompatible and safe for human use. It is sterilized to eliminate pathogens and provide a long shelf life.

The initial SIS science developed by Dr. Badylak and his colleagues was subsequently licensed to DePuy, Inc. and Cook Biotech, Inc. These companies today market a variety of products whose origin is the Badylak SIS technology.

Success is measured in the significance and the frequency of outcomes. In the case of SIS-based clinical procedures, success has clearly arrived. SIS-clinical tissue engineering procedures have now assisted over 250,000 patients.

In terms of his continuing commitment, more exciting results are emerging from the Badylak laboratories. Using extracellular matrix technologies he will soon be ready to launch a clinical trial for the repair of damaged esophagus. Typically corrective action is required due to cancer or traumatic injury. Currently, the only means to address esophageal repair is to remove the damaged section of the esophagus and then pull the stomach up so that the shortened esophagus can be reconnected. The illustration shows the procedure to use a section of SIS extracellular matrix (ECM) material that replaces the damaged section of the esophagus; in preclinical trials, the ECM translates to esophageal-like tissue within several months. Soon, Dr, Badylak will be able to help patients who need esophageal repair, where the current “solution” means a significantly reduced quality of life.

Dr. Badylak’s pioneering research and his commitment to clinical translation has had a profound impact on over a quarter of million patients, and his continued pursuit of other challenging clinical needs reaffirms his selection as the recipient of the 2005 Clemson Award for Applied Research.

 

If you are seriously ill and have health insurance, the United States is the best country in the world in which to live. The American public not only embraces medical technology and medical advances, but has come to expect the best that clinical care and medical research can offer.

And why shouldn't they? The average American has come of age with remarkable medical advances, from the polio vaccine to multi-organ transplants, both of which were pioneered right here at the University of Pittsburgh and the University of Pittsburgh Medical Center. And our knowledge base about how to cure disease doubles every 10 years or so.
One of the hopes for the future is customized cures through regenerative medicine. If we can understand how the body heals itself, and accelerate that pace of healing to a clinically acceptable timescale, we will be able to grow nerves, regenerate hearts and heal wounds. We no longer have to imagine injecting cells into damaged hearts, growing whole human bladders in the laboratory and treating burn victims with artificial living skin.

This is the reality of today's patient- focused cell-based therapy. Every region in our country will use these therapies as they become commonplace for our grandchildren, but very few will manufacture these living pharmaceuticals. Pittsburgh needs all the regeneration it can get and cell-based therapies can regenerate our health and our economy.

Unfortunately, in today's politically energized environment, cell therapy has too often become a struggle between those who believe in embryonic stem cell research and those who do not. Re- searchers who believe in the potential of embryonic stem cells are neither evil nor foolish, and those who advocate against the research are sincere and absolutely confident that they are on the right side of the issue.

Whether one believes in the research or not, the study of embryonic stem cells will change the course of medicine and its underpinning science forever. So California's decision to invest billions (that it must borrow to do so) in embryonic stem cell science is marvelous news for researchers and venture capitalists.

The passage of Proposition 71 in California, providing $3 billion in state funds over 10 years for stem-cell research, also is a seismic wake-up call to all states that are serious about participating in the regenerative medicine economy of the 21st century. People predict that the business of selling these therapies will be a $5 billion to $50 billion business within our lifetime.

While every state in the country with any appreciable investment in cell-based scientific inquiry and commercialization is hurrying to analyze the potential impact of Prop 71, what is certain is that California's ambitious legislation - backed by unprecedented levels of funding (the National Institutes of Health, by comparison, spent only about $25 million on research on human embryonic stem cells in 2003) - will fundamentally reshape biomedical research and economic development initiatives in many regions.

But even as it likely "seals the deal" for California as the nexus for embryonic stem cell research, Prop 71 could well open doors in other sectors of cellular research and regenerative medicine. Those with the most to gain and the most to lose are the regions which are in the lead now in the race to deliver safe therapies to patients - regions such as Pittsburgh. This year, we ranked first in the world as a center of excellence in the exciting new field of cellular and regenerative medicine.

So while we may have the most to lose from California's bold move, there is a silver lining in this cloud. Our region has been investing in regenerative medicine for a decade and we have built a world class environment through inspired research and translation to patient needs.
Pitt, in partnership with UPMC, started the McGowan Institute for Regenerative Medicine long before it was trendy.

If there in Pittsburgh the focus is on delivering therapies to patients through world class science rather than vilifying those with opposing opinions, there is a path forward which everyone can support and through which we can continue to lead. When Pittsburgh dominated the steel industry, we did so by excelling across the spectrum of research and manufacturing. We did not focus exclusively on just one method of extracting rid processing ore.

In other words, when California pumps $3 billion into embryonic stem research, patients will only be cured if someone also answers other critical questions surrounding how to use cells in patients, most notably how to keep cells alive outside the body and then somehow return the cells to a diseased tissue to facilitate restoration of function in a patient. In Pennsylvania, we have been answering these two questions for early a decade, and the marketplace is well aware of what we are doing.

So now that California has thrown down the gauntlet, this is a time to act boldly to secure the lead that we have already built. The urgency of this needed action cannot be overstated. Many other states are developing active responses to Prop 71. These include New Jersey, which has invested $95 million to date and is moving toward a goal of total investment of $l billion, and Wisconsin, which has committed $750 million over five years.

Pittsburgh made transplants commonplace, is home to the country's most successful academic health care system (UPMC) and has two world class universities (Carnegie Mellon and Pitt) that collaborate closely at the interface between life science, engineering and medicine. Our region is the perfect place from which to take on California.

When we accept the challenge of capturing a $50 billion market, the stakes will be high and Prop 71 will mean that the price of entry to the competition has sharply increased. Clearly, we will need to work hard to market what we have already built. This is inexpensive. But we must also continue to invest significantly and publicly in infrastructure for continuing research, business development and patient care. This will cost less than the price of a stadium, but much more than we spend now. And we must work quickly and boldly.

The rewards from this struggle lie ahead of us and not behind, so like the sprinters who never look back as they approach the finishing line, we must increase our momentum and be confident that the same passion that has brought us this far will drive us to where we need to go. Yes, Prop 71 raises the stakes, but it also focuses the mind and provides a marvelous opportunity to continue to lead from the front.

(1) OpEd by Alan J. Russell, PhD, published in the Pittsburgh Post Gazette, November 28, 2004, page F-2

Traditionally a heart ventricular assist device (VAD) is used as a bridge to organ transplantation, maintaining a patient's cardiac function until a donor organ becomes available. In some cases, the device rests the heart and allows it to heal without the need for heart transplantation. The frequency of this occurrence and the patients most likely to benefit from VAD implantation as a bridge to heart recovery has been poorly defined prior to a University of Pittsburgh Medical Center (UPMC) study that was presented at the American Heart Association's Scientific Sessions 2004 in New Orleans. Marc A. Simon, M.D., fellow in transplantation cardiology at the University of Pittsburgh School of Medicine, reported on the long-term outcome of patients successfully weaned from VADs at (UPMC).

The study included 147 patients who underwent VAD implantation at UPMC from 1996 through 2003. Of the patients, 70 were ischemic and 77 non-ischemic. Of these, 10 were weaned from the VAD as a bridge to recovery (BTR).

"We found that seven percent of patients implanted with heart assist devices were successfully weaned from the devices without the need for a heart transplant," said Dr. Simon. "Our study found that when utilized in acute inflammatory cardiomyopathy or post-partum cardiomyopathy (PPCM), VAD support appears to allow long-term restoration of cardiac function. VAD support as a bridge to recovery (BTR) should be an important component of the care of acute inflammatory myocarditis."

"With the availability of VADs, no patient should die from acute myocarditis or severe peripartum cardiomyopathy. This study demonstrates that ventricular support can facilitate dramatic recovery even in patients who are gravely ill," said Dennis McNamara, M.D., associate professor of medicine at the University of Pittsburgh School of Medicine and senior author of the study.

"Successful therapeutic strategies for end-stage congestive heart failure now include not only cardiac replacement with assist devices or transplantation, but the true opportunity for repair and recovery of myocardial function through the synergy between advanced medical therapy and ventricular assist devices," said Robert L. Kormos, M.D., director of Heart Transplantation, director of the Artificial Heart Program at UPMC, and Medical Director of the McGowan Institute.

UPMC's Artificial Heart Program is one of the most experienced and active in the United States. Since its inception in 1985, the program has supported nearly 250 patients on assist devices for a period of time that equates to more than 50 years. It often serves as both a proving ground for manufacturers and a training center for surgeons from around the world.

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The University of Pittsburgh School of Medicine has established a department of computational biology, making it one of the first U.S. medical schools to assign this newest of disciplines the same status as more traditional clinical and basic science departments. Taking advantage of a growing body of knowledge about the human genome and protein structure, the department’s primary mission is the creation of efficient computational models that aim to identify more rational approaches to our understanding of human biology and disease processes, and to the development of new therapies, including drugs and vaccines.

Computational biology brings together disparate fields of study – computer science and biological science, as well as physical and mathematical sciences – by developing physically inspired computational models and methods to address key biological questions, and assist in gaining better understanding of the molecular basis of complex cellular events. Such insight can help pinpoint the specific flaws in biomolecular structure and dynamics that are associated with genetic disorders and disease so that more effective therapies can be designed.

Ivet Bahar, Ph.D., who was recruited to the University of Pittsburgh four years ago to direct the Center for Computational Biology and Bioinformatics (CCBB), has been named the chairman of the new department as well as professor of computational biology. Until now, Dr. Bahar has been a professor in the department of molecular genetics and biochemistry, and the founding director of the CCBB.

The department will focus on three areas of research that will become increasingly important and promising with advances in molecular biology and computational technology. These are computational structural biology, computational genomics and systems biology with applications to cell signaling and regulation.
Last year, the National Institute of General Medical Sciences, one of the National Institutes of Health (NIH), awarded funding to Dr. Bahar to plan the Pittsburgh Center for Biomedical Computation. The center includes the University of Pittsburgh School of Medicine, the Pittsburgh Supercomputing Center, Carnegie Mellon University and Duquesne University, and brings together their collective expertise in biological sciences, computer science, mathematics, engineering, physics and chemistry.

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A study lead by James D. Luketich, M.D found that gastric bypass is feasible and effective in controlling gastroesophageal reflux disease (GERD) in patients who had previous antireflux surgery and who have subsequently gained significant weight, and in obese patients who have had previous antireflux procedures and continued to have problems with GERD.

As reported in the November issue of the journal Obesity Surgery, the study involved seven patients who underwent laparoscopic gastric bypass after having antireflux surgery to control GERD. Patients’ co-morbid medical conditions included sleep apnea, diabetes mellitus, hypertension, degenerative joint disease, depression, hypercholesterolemia, polycystic ovarian syndrome and lower extremity edema.

“Despite a morbidity rate of 42.8 percent, this study showed that all patients did well with zero mortality and were satisfied with their condition during the follow-up period, suggesting that the long-term outcome of laparoscopic gastric bypass in obese patients who had previous antireflux surgery is promising. There also was a significant improvement of GERD symptoms following the laparoscopic gastric bypass, which was maintained during follow-up,” said Ioannis Raftopoulos, M.D., Ph.D., assistant professor of surgery in the division of thoracic & foregut surgery at the University of Pittsburgh School of Medicine, and principal author of the study. In addition, 70 percent of associated co-morbid medical conditions were either resolved or improved significantly. GERD is a significant public health problem affecting up to 40 percent of the American adult population.

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McGowan Faculty contributed to a paper that describes how the antigen-rich particles receive cozy welcome by recipient cells…bubble-like nano-scale particles that are shed by dendritic cells may hold the key to achieving transplant tolerance – the long-term acceptance of transplanted organs without the need for drugs. The study was published in the November 15th issue of the journal Blood.
The results provide some of the first information about what these structures called exosomes actually do.

Exosomes are no larger than 65-100 nanometers – 1,000 times smaller than the diameter of a human hair – yet each contains a potent reserve of major histocompatibility complex (MHC) molecules. MHC molecules are gene products that cells use to determine self from nonself. Millions of exosomes scurry about within the bloodstream, and while their function has been somewhat of a mystery, researchers are beginning to surmise that they play an important role in immune regulation and response.

The function and mechanisms for dendritic cell-derived exosomes had never before been elucidated, so in a study led by In a study led by Adrian Morelli, M.D., Ph.D., of the University’s Thomas E. Starzl Transplantation Institute, Dr. Morelli and colleagues sought to do so by following the fate of exosomes that they extracted from dendritic cells of one mouse strain and injected into the bloodstream of mice of a different strain. The exosomes were labeled with a dye, and methods such as flow cytometry, confocal microscopy and immuno-electron microscopy helped the researchers track their every movement and activity within the mouse.

Very quickly and efficiently, the donor exosomes were captured by one of three recipient immune system cell types: antigen-presenting dendritic cells and macrophages, both originating in the spleen, and Kupffer cells of the liver.

Of particular interest to the researchers were those exosomes that were caught by the dendritic cells of the spleen, the site where dendritic cells typically present antigens as bounty to T cells that do their part to destroy the foreign invaders. Yet, what the researchers discovered was that these dendritic cells internalized the exosomes instead of displaying them to T cells, this despite the exosomes’ rich endowment of donor MHC molecules.
Once internalized, the exosomes were ushered inside larger vesicles, special endosomes called MHC-II enriched compartments, where they were processed with the dendritic cell’s own MHC molecules. This hybrid MHC-II molecule, now loaded with a peptide of donor MHC, was then expressed on the cell’s surface. As one family of MHC molecules, MHC-II serves as a beacon for a specific population of T cells called CD4+ T cells. Such cells are activated during chronic rejection in a process associated with the indirect pathway of immune recognition.

Additional research will be required to determine whether donor-derived exosomes will enhance the likelihood that an organ transplant from the same donor will be accepted. Under a recently awarded National Institutes of Health grant, Dr. Morelli plans to address this question with studies involving mice that receive heart transplants following infusion with exosomes from the same donor. A recent French study in rats, while offering no clues as to why, suggests the approach will be successful. In addition, animal studies conducted at Pitt by Paul Robbins, Ph.D., professor of molecular genetics and biochemistry, provide evidence that exosomes can reverse arthritis. Drs. Morelli and Robbins plan to collaborate in future research.

In addition to Drs. Morelli and Thomson, other authors of the study published in Blood include Adriana T. Larregina, M.D., Ph.D.; William J. Shufesky; Mara G. Sullivan; Donna Beer Stolz, Ph.D.; Glenn D. Papworth, Ph.D.; Alan F. Zahorchak; Alison J. Logar; Zhiliang Wang, M.D.; Simon C. Watkins, Ph.D.; and Louis D. Falo, Jr., M.D., Ph.D.

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