April 2006 | VOL. 5, NO. 4 | www.McGowan.pitt.edu

Recognizing the need for novel approaches that can restore, even partially, the structure and function of lost or damaged tissues, the Defense Advanced Research Projects Agency (DARPA) has awarded a $3.7 million grant to the University of Pittsburgh’s McGowan Institute for Regenerative Medicine to oversee an ambitious, multi-center research program to better understand the intricate processes involved in wound healing and tissue restoration. A large part of the team’s effort will involve examining the cellular and molecular systems that allow certain animals to completely regenerate lost tissue. The ultimate goal of the research is to identify ways for enhancing the capacity for wound healing and tissue restoration in humans. 

The need for such technologies is paramount; while U.S. soldiers fighting in Iraq and Afghanistan are surviving injuries that in previous conflicts likely would have been fatal, the number of wounded with major tissue loss has never before been so high. Such injuries – the partial or complete loss of digits or limbs and deforming facial injuries – have profoundly affected the quality of life of the wounded as well as presented a new set of challenges for the medical community faced with treating them.

Coordinating the effort is Stephen Badylak, D.V.M., M.D., Ph.D., research professor in the department of surgery at the University of Pittsburgh School of Medicine and Director of the Center for Pre-clinical Tissue Engineering at the McGowan Institute. In addition to the University of Pittsburgh, five other centers are involved. The investigators from these institutions offer diverse, yet complementary, research interests. They are:
• 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

“We sincerely believe that the ability to promote tissue restoration in humans is not only possible, it will in fact be a reality some day. By working as a team and capitalizing on our collective expertise and experience, we’re in a better position to succeed at unlocking the regenerative potential of mammals than would be possible working in the silos of our individual labs,” said Dr. Badylak. The investigators believe their goal is attainable due to a convergence of recent discoveries made in their labs as well as at other institutions in the areas of stem cell research, extracellular matrix biochemistry and the regulation of gene expression. 

The researchers aim to prove that mammals can form the required progenitor cells for regeneration just as a salamander does. By studying salamanders and MRL mice, the researchers hope to identify the specific types of cells, molecular signals, genes and cellular scaffolding required for regenerative cell growth. In essence, they seek as comprehensive an understanding as possible of the mechanisms and processes – to obtain the blueprint for regenerative growth.

With such information in hand, the researchers will turn their attention to studies using another mouse model incapable of tissue restoration – a model more representative of mammals, including humans. Specifically, they will attempt to orchestrate the formation of a blastema in response to an injury at the site where nature would normally direct the accumulation of scar tissue.

The $3.7 million DARPA grant supports the project for one year. The agency could provide additional funding for up to three more years.

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Based on the requests of faculty and graduate students for more and different types of networking sessions, the 3rd Moleculart project will be held on May 10, 2006. Our goal is to have a scientific gathering that fosters networking in a different environment. The artists for the third session are:

• Mrs. Ruth Levine
• Dr. Robert Kormos

Please save the date and join us on May 10th
Time: 4:30 – 6:30 PM
Place: S-100 BST

The prior sessions featured Lena and Horacio Vodovotz, daughter and uncle of Yoram Vodovotz (Center for Inflammation and Regenerative Modeling), and Veronica Garcia, wife of Alejandro Nieponice and Makiko Sakamoto (Vorp Lab).

 

During the week of April 25th, the McGowan Institute was the host to nearly 1,000 scientists, clinicians, business leaders, entrepreneurs and military and government officials from around the world attending the 2006 Regenerate World Congress on Tissue Engineering and Regenerative Medicine, the first ever meeting of the Tissue Engineering and Regenerative Medicine International Society (TERMIS). McGowan Institute-affiliated researchers were also amongst those presenting new research.

Alan Russell, PhD served as the chairman of the Regenerate World Congress and William Wagner, Ph.D., McGowan Institute deputy director, and an associate professor of surgery, chemical engineering and bioengineering, was the scientific chairman.

The Regenerate World Congress provides a forum for the latest research on tissue engineering/regenerative medicine approaches to restoring the function of damaged or diseased tissues and organs. It will be held every three years, with the next congress in Korea in 2009.

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Under the leadership of David Vorp, PhD, the Center for Vascular Remodeling and Regeneration (CVRR) at the McGowan Institute is forming.

By way of background, the blood vessel is arguably the most important organ in the body, since no other organ or tissue can be sustained without a viable vasculature.  Though vascular dysfunction is most often linked to heart disease, the leading cause of death in the US, other significant diseases and their treatment are directly affected by a deficient vasculature.  This includes peripheral vascular disease, stroke, renal insufficiency, and other maladies. 

Vascular remodeling – the response (good and bad) of blood vessels to various types of stresses – is an important consideration in both disease process and prevention. It is widely felt that regeneration approaches (including tissue engineering and cell therapy) will greatly influence vascular medicine by leading to new therapeutic approaches. 

There is clearly a critical mass of scientists and clinicians in place at the University of Pittsburgh and UPMC who are actively engaged in studying various aspects of vascular remodeling and regeneration.   What is missing is a facilitating vehicle to unite this critical mass and to provide a means of accelerating the clinical translation of the science. 

With this in mind, we have created the CVRR in hopes that it will become such a vehicle.  The long-term benefits of the CVRR would be to accelerate the “bedside-to-bench-to-bedside” process of vascular-based therapies.  Moreover, a formal unifying and facilitating Center focusing on vascular remodeling and regeneration would position us to be competitive for program project grants, center grants, training grants, and other collaborative synergies.

If interested, please contact Dr. David Vorp regarding an inaugural CVRR retreat and organizational meeting that will be held on May 26, from 11am to 6pm. Though this is co-sponsored by the Departments of Surgery and Bioengineering, and the McGowan Institute for Regenerative Medicine, this is not an exclusive Center. Rather, we wish to encourage participation by anyone who has an interest, from clinician-scientists, to applied scientists to basic scientists, all with a common objective: building a bedside-to-benchtop-to-bedside pipeline for the improvement of vascular medicine.

You will soon be hearing from Dr. David Vorp regarding an inaugural CVRR retreat and organizational meeting that will be held on May 26, from 11am to 6pm.  Please put a hold on that date now so that you may attend this exciting event. 

 

The University of Pittsburgh Medical Center is the largest volume lung transplantation center in the United States. In 2005, a record 91 such surgeries were performed, according to new data from the United Network for Organ Sharing (UNOS). UPMC surgeons performed 61 lung transplants in 2004. Since 1982, they have performed 903 lung transplants (115 of which were combined heart/lung).

The program is under the leadership of Kenneth R. McCurry, M.D., assistant professor of surgery at the University of Pittsburgh School of Medicine and director of cardio-pulmonary transplantation at the UPMC Heart, Lung, and Esophageal Surgery Institute.

As lung transplant volumes at UPMC have increased, outcomes also have improved. The medical center’s one-year survival rate of 88 percent far exceeds the national average of 81 percent; experiences with re-transplanting patients who experience chronic rejection after transplantation also have produced better than average results. For example, 18 lung re-transplants at UPMC completed during the past three years have generated a 100 percent one-year survival rate.

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Results of Maple Syrup Urine Disease study published in American Journal of Transplantation

Liver transplants cured the metabolic symptoms of 11 patients with a rare but devastating genetic condition known as Maple Syrup Urine Disease (MSUD), according to a study by researchers from Children’s Hospital of Pittsburgh and the Clinic for Special Children.

MSUD is a metabolic disease which causes amino acids from proteins to accumulate in the body. The disease gets its names from the sweet smell of the urine. The accumulation of amino acids in the blood can cause metabolic crisis at any age, which can lead to brain swelling, stroke and even sudden death. Over a patient’s lifetime, chronic instability of blood amino acids can result in serious learning disabilities and mental illness.

Before transplant, the only treatment was strict adherence to a diet almost devoid of protein. Despite adherence to this diet, patients were still at risk of metabolic crisis from something as simple as a common cold, which can disrupt the body’s metabolism and cause rapid neurological deterioration.

In 1997, an MSUD patient at another hospital received a liver transplant due to an unrelated medical condition and physicians noticed the symptoms of her MSUD were alleviated.

Based on this serendipitous result, physicians from Children’s and the Clinic for Special Children, located in Strasburg, Pa., began working collaboratively to develop a liver transplant protocol for MSUD which optimized patient safety. With a comprehensive, multidisciplinary protocol established, Children’s transplant surgeons began performing liver transplants on MSUD patients in May 2004. Children’s has performed 18 MSUD liver transplants since then.

 “The development of liver transplantation as a treatment for MSUD has dramatically improved our patients’ quality of life,” said George V. Mazariegos, director of Pediatric Transplantation at Children’s and one of the study authors. “Our MSUD patients and their families had lived in fear of everything from a chicken nugget to a common cold. Liver transplantation is not without risks, but for some patients, it is the best option and it has allowed these recipients and their families to live without fear of simple things most people take for granted.”

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In the 2006 Top Doctors survey published by Pittsburgh magazine, 14 McGowan faculty were amongst the UPMC physicians that were named in 38 areas of expertise, from adolescent medicine to urology.

The list was compiled by Castle Connolly Medical Ltd., a physician-led research team that scrutinizes a doctor’s medical education, training, and experience. The result is a rigorously screened selection of highly ranked doctors on the national and regional levels.

Gastroenterology David C. Whitcomb, MD, PhD Neurology Steven T. DeKosky, MD Orthopaedic Surgery Freddie H. Fu, MD Otolaryngology Clark A. Rosen, MD Barry Hirsch, MD Physical Medicine and Rehabilitation Ross Zafonte, DO Plastic Surgery - Hand W.P. Andrew Lee, MD

Plastic Surgery - Reconstructive  Ernest Manders, MD Psychiatry David J. Kupfer, MD   Surgery  Michael T. Lotze, MD, PhD Surgery - Oncology Howard D. J. Edington, MD Transplantation Robert L. Kormos, MD Ron Shapiro, MD   Urology Michael B. Chancellor, MD

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As part of his collaborative efforts, Dr. Anthony Atala, has formally associated with the McGowan Institute as an Adjunct Professor of Surgery at the University of Pittsburgh. Dr. Atala's primary appointment is at Wake Forest University where he is the Director of the Wake Forest Institute for Regenerative Medicine.

In The Lancet, Dr. Atala describes long-term success in children and teenagers who received bladders grown from their own cells. The engineered bladders were grown from the patients' own cells, so there is no risk of rejection. Scientists hope that laboratory-grown organs can one day help solve the shortage of donated organs available for transplantation. Atala reported that the bladders showed improved function over time – with some patients being followed for more than seven years.

The study involved patients from 4 to 19 years old who had poor bladder function because of a congenital birth defect that causes incomplete closure of the spine. Their bladders were not pliable and the high pressures could be transmitted to their kidneys, possibly leading to kidney damage. They had urinary leakage, as frequently as every 30 minutes.

The main goal of the surgery was to reduce pressures inside the bladder to preserve the kidneys. In addition, urinary incontinence, which was a problem before the surgery, improved in all patients.

The report involves children who were treated at Boston Children's Hospital when Atala was director of the Tissue Engineering and Cellular Therapeutics at Harvard Medical School. In 2004, Atala's program moved to Wake Forest.

"We have shown that regenerative medicine techniques can be used to generate functional bladders that are durable" said Atala. "This suggests that regenerative medicine may one day be a solution to the shortage of donor organs in this country for those needing transplants."

Atala said the approach needs further study before it can be widely used. Additional clinical trials of the bladders are scheduled to begin later this year.

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Being able to witness the precise events that form the heart's orchestral rhythm or the rat-a-tat-tat of irregular heartbeats could enable researchers to better understand the underlying causes of arrhythmias and sudden cardiac death. A team, lead by Guy Salama, Ph.D., professor of cell biology and physiology at the University of Pittsburgh School of Medicine and colleagues from Carnegie Mellon University report they have developed unique chemical dyes that have made it possible to see what the naked eye has never seen before: action potentials, or voltage changes, of cardiac cells – including those deep inside the heart, which trigger and determine the pace of heartbeats.

"What exactly causes arrhythmias and sudden cardiac death remains an important question we hope to answer through our studies that make use of a combination of novel imaging approaches. Toward this end, these dyes have proved to be particularly important for recording membrane potential changes and capturing in detail, and in real time, the synchronicity or asynchronicity of the heart. Obtaining such images had long been a challenge due to confounding motions of the heart," said lead author Dr. Salama.

Like a light switch that's quickly flipped on and off, a heart beat begins in similar fashion. A rapid change in electrical charge – from negative to positive and back again – occurs within each cell, producing a current that takes about 3/10 of a second to spread in a staccato yet fluid motion across the heart. As these voltage changes occur, so do the traffic patterns of potassium, sodium and calcium, each of these ions entering and leaving cells through their designated portals called channels. Should any of these channels be blocked, or open too fast or too slow, the entire orchestral rhythm of the heart can at once become chaotic, causing irregular heartbeats. Of the different types of arrhythmias, those originating in the heart's ventricles are the most common underlying cause of sudden cardiac death.

To create a method capable of yielding images of a cell as its voltage changes, Dr. Salama teamed up with Alan Waggoner, Ph.D., and Lauren Ernst, Ph.D., of Carnegie Mellon's Molecular Biosensor and Imaging Center (MBIC). Together, they developed the long wavelength, voltage-sensitive dyes described in the paper.

The new voltage-sensitive dyes, together with novel optical techniques, have greatly enhanced the understanding of how the heart works. Research will continue toward the development of a high-speed, depth-resolved 3-D imaging system that makes use of what may be the fastest camera at 100x100 pixels, with the ability to capture 10,000 images per second.

In addition to Drs. Salama, Waggoner and Ernst, other authors of the paper are Bum-Rak Choi, Ph.D., Ghassan Azour and Mitra Lavasani, all of the University of Pittsburgh School of Medicine; Brian M. Salzberg, Ph.D., of the University of Pennsylvania; and Michael J. Patrick, from Carnegie Mellon University.

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