July 2004 | VOL. 7 | www.McGowan.pitt.edu

On the occasion of the third anniversary of the McGowan Institute for Regenerative Medicine, I would like to take this opportunity to extend my thanks and appreciation for the sincere and substantial contributions of our Team that has resulted in the sustained growth and maturation of the Institute. The visibility of Regenerative Medicine, and the role that the McGowan Institute is playing in the advancing the science and clinical translation of new technologies is growing rapidly. Pittsburgh is now a recognized destination for regenerative medicine research and we are working to make Pittsburgh also the destination of choice for regenerative therapies.

While we can all applaud the progress that has been made, I would like to take this opportunity to remind us that there is much left to do. I seek your participation in the realization of the goals of the Institute. Using the Institute's Mission Statement as a roadmap, the following are some thoughts on our status and future direction:

• To provide a national center of expertise in regenerative medicine focused on developing and delivering therapies that reestablish tissue and organ function impaired by disease, trauma or congenital abnormalities.
  
  Our progress to date is clearly attributable to the achievements of the individual teams lead by our distinguished faculty and by the collaborative activities amongst different faculty-lead teams. Collaboration between investigators continues to grow, and one example of a great team effort is the recent receipt of a $4.5 million dollar grant from NIH to develop a Pediatric Ventricular Assist Device (PediaFlow). This work, coupled with a $14.5 million grant from the National Heart, Lung, and Blood Institute (NHLBI) of NIH awarded to a team from Children's Hospital and the University of Pittsburgh to develop novel approaches that seek to improve the outcomes of pediatric heart transplant recipients, secures our place as a leading center for organ replacement design and discovery. The five-year grant at Children’s Hospital establishes the University of Pittsburgh as a Specialized Center of Clinically Oriented Research (SCCOR) in Pediatric Heart Development and Disease. Such a center encourages basic science research findings to be applied more rapidly to address specific clinical problems.
  
  
• To foster the generation of scientific knowledge in regenerative medicine and to share that knowledge with researchers, clinicians and the public through educational activities, training and publications.
  
  The Institute is strongly committed to promoting and facilitating inter-group collaboration. The seminars, annual retreat, McGowan Student Network, and the Institute intranet support these initiatives; the two new grants referenced above are products of improved networking, but we must be ever-vigilant for new opportunities in this area. Public education continues to move forward through our collaboration with the Pittsburgh Tissue Engineering Initiative. The “planetarium shows ” developed under PTEI leadership have received “rave” reviews.
  
  
• To educate and train scientists and engineers to pursue technologies related to regenerative medicine, and train a generation of clinicians in the implementation of regenerative therapies.
  
  This is the only region in the Country that has training grants for Undergraduates (PTEI), Pre-Doctoral (CATER) and Post-Doctoral (PTEI). The T-32 CATER Training Grant (Cellular Approaches to Tissue Engineering and Regeneration) was successfully implemented this past year.
  
  
• To support the commercialization of technologies in regenerative medicine and thereby accelerate the translation of research discoveries to clinical implementation and patient benefit.
  
  Progress to date has been slow but steady; in the past year we have begun to develop partnerships and collaborative efforts with industrial organizations. As our projects continue to mature, this will be an increasingly important area, and must be one of our high-priority focus areas for the coming year. Our partnership with the Limbach Entrepreneurial Center is designed to facilitate progress in this area.

The Institute has grown to 30 core faculty and 150 member faculty and nearly 600 students and staff. As the collaborative efforts grow, the distinction between core faculty and member faculty continues to diminish. As our personnel and programs continue to grow, we have acquired additional lab space in the Bridgeside Point building. I look forward to another exciting year of advances in science and progress toward the movement of our emerging technologies to clinical/commercial use. As noted above, this progress is directly attributable to all of the McGowan Team; I trust that next year collectively we will be able to look back and say that we have made more progress along the road we jointly travel.

Thanks and best wishes for continued success!

Alan J. Russell, Ph.D.
Director

 

 

The University of Pittsburgh Medical Center (UPMC) discharged its first patient on July 20, 2004 who was successfully implanted, on July 2nd with the Heartmate XVE Left Ventricular Assist System (LVAS). In the past, such a device was used as a bridge to transplantation; in this case it was implanted as a permanent implant in lieu of a heart transplant. The patient, 58-year-old John Didion, has recovered well enough to be discharged to his home in Allison Park, PA.

The Heartmate XVE (LVAS) is a long-term permanent assist device approved by the U.S. Food and Drug Administration (FDA) for “destination therapy” in patients with end-stage heart failure who, despite receiving optimal treatment, have a life expectancy of less than two years and are not viable candidates for heart transplantation.

“I never thought this day would be possible,” said Mr. Didion. "I am so grateful to the dedicated staff at UPMC. If it weren't for them, I wouldn't be here today. I am living proof that this works."

Last fall, UPMC was among the first centers to receive approval from the Centers for Medicare & Medicaid Services (CMS) to implant left ventricular assist systems approved by the FDA, and UPMC is only one of two approved centers in western Pennsylvania to implant the Heartmate XVE.

“We are pleased to be able to bring this new technology and therapeutic approach to our patients,” said Robert L. Kormos, M.D., Professor of Surgery at the School of Medicine, Director of UPMC's Artificial Heart and Heart Transplant programs, and Medical Director-McGowan Institute of Regenerative Medicine. “Heart transplantation is still the best option for long-term survival, but unfortunately, it is not feasible for everyone. This new therapy allows us to return people to productive lives at home as an alternative to dying from end-stage congestive heart failure.”

“The Heartmate XVE has been developed to be a viable therapy and is giving new hope to people,” said Dennis McNamara, M.D., Associate Professor of Medicine and Director of the Heart Failure/Transplantation Program at the UPMC Cardiovascular Institute. “As the technology improves, this may someday, in conjunction with heart transplantation and other new therapies, help us to provide a full spectrum of choices for heart failure therapy.”

As the use of destination therapy expands, the long-term vision for mechanical support is to assist the heart while it repairs itself using novel new cellular therapies. These goals include promoting recovery from the mechanical effects of heart failure and availability as a viable replacement option when all other choices fail. These goals encompass the broader mission of the McGowan Institute and are a result of the collaboration among scientists, engineers and clinicians.

UPMC's Artificial Heart Program, in collaboration with UPMC's Congestive Heart Failure Program, is one of the most experienced and active in the United States. The program was established in 1985 and has supported nearly 300 patients on various assist devices for a period of time that equates to more than 65 patient-years. It often serves as both a proving ground for new technologies and clinical procedures and as a training center for surgeons from around the world. [More]

 

Results suggest the fluid could increase survival in trauma patients and wounded soldiers

A novel resuscitation fluid derived from aloe vera that was developed by researchers at the McGowan Institute has the potential to save the lives of patients with massive blood loss, according to results of an animal study published in the August edition of the medical journal Shock. The findings could have a significant impact on the treatment of hemorrhagic shock caused by both civilian and military trauma.

In a rodent model of hemorrhagic shock, animals that were given a very small amount of the fluid, an aloe vera-derived drag reducing polymer (DRP), had significantly longer survival time and increased systemic whole body oxygen consumption, even in the absence of resuscitation with blood or other fluids, compared to animals that did not receive DRP.

“We hope this fluid will offer a viable solution to a significant problem, both on and off the battlefield. Typically, hemorrhagic shock is treated by controlling ongoing bleeding and restoring blood volume by infusing a lactate solution and packed red blood cells. Soldiers wounded in combat often lose significant amounts of blood, and there is no practical way to replace the necessary amount of blood fast enough on the front lines. When this happens, there is inadequate perfusion of the organs which quickly leads to a cascade of life-threatening events,” said senior author Mitchell P. Fink, M.D., Professor and Chair, Department of Critical Care Medicine and Watson Professor of Surgery at the School of Medicine. “Medics would need only carry a small amount of this solution, which could feasibly be administered before the soldier is evacuated to a medical unit or facility,” he added.

The central ingredient of Pitt’s resuscitation fluid comes from the slick substance inside the leaves of the aloe vera plant. A so-called mucilage, it is rich in polysaccharides and has a high molecular mass and specific “visco-elastic” properties that allow it to reduce resistance to turbulent flow when added to a fluid at minute concentrations.

“As a drag reducing polymer, it may provide better diffusion of oxygen molecules from red blood cells to tissues because of its ability to better mix in the plasma surrounding red blood cells,” explained Marina Kameneva, Ph.D., Research Associate Professor of Surgery and Bioengineering and Director of the Artificial Blood Program at the McGowan Institute who developed the fluid and has been researching its potential for the past several years.

In the current study, lead by Carlos A. Macias, M.D., a Visiting Research Associate in the Department of Critical Care Medicine, five of 10 rats that were injected with a small amount of a normal saline solution survived four hours after hemorrhagic shock. Of the animals treated with a same amount of saline and the aloe-derived DRP, eight of 10 survived. The animals treated with DRP also fared better in another experiment involving more severe blood loss; five of 15 survived the two-hour observation period, compared to one of 14 treated with saline solution alone. Seven animals receiving no treatment all died within 35 minutes.

According to the Department of Health and Human Services, trauma is the leading cause of death for those under the age of 40. In the United States, traumatic injuries result in approximately 150,000 deaths per year; complications resulting from the loss of large amounts of blood account for almost half these deaths. The research was supported by the Defense Advanced Research Projects Agency. [More]

 

Jörg C. Gerlach, MD, PhD

The field of regenerative medicine is in the formative stages and has a vast and exciting future, according to Jörg C. Gerlach, MD, PhD, Director of the Bioreactor Group at the McGowan Institute for Regenerative Medicine.

Dr. Gerlach heads the McGowan Institute’s Bioreactor Group working on technologies for the clinical translation of tissue engineering and stem cell biology into cell-based therapies. His biomedical research projects focus on artificial organs-such as trachea replacement, hybrid organs-such as endothelial cell seeded vascular prostheses, on bio-artificial systems where the current focus is on liver support systems for extracorporeal organ support, and on cell production systems enabling cell transplantation. Dr. Gerlach is internationally recognized for his work in developing cell culture methods, and bioreactor technology.

He is educated in surgery, hepatology, intensive care and experimental transplantation medicine. In addition Dr. Gerlach has an engineering background with expertise in artificial organ development, hybrid system research and preclinical studies. His “science focus” coupled with his clinical experience, makes Dr. Gerlach uniquely qualified to pursue the innovative regenerative medicine projects that are under his leadership in Pittsburgh and in Berlin.

Dr. Gerlach began his professional career in 1987 when he received his MD/PhD from the Freie University in Berlin, Germany. His graduate research addressed the development of an artificial trachea. Subsequently he served his residency in Surgery at Humboldt University, Berlin, and earned a second PhD in Bioengineering (2002) from Strathclyde University, Glasgow, Scotland. After pursuing a third thesis project, Dr. Gerlach was appointed the Head of Experimental Surgery, Dept. of Surgery, Charité Medical Faculty, Humboldt University in Berlin. In 2002 he was appointed Professor of Experimental Surgery at Humboldt University.

It was during his research in Berlin that he began his pioneering work that led to the development of the Modular Extracorporeal Liver Support (MELS) system (see photograph). Even today, he continues collaboration with several research groups in Europe; in Berlin he successfully coordinated pilot studies on patients using bioreactor technology incorporating liver cells from organs deemed not fit for transplant. This technology enables patients with acute liver failure to receive interim support, until organ regeneration occurs.

To date, Dr. Gerlach and his colleagues have “saved” 23 patients who were suffering from acute liver failure. In order to bring this lifesaving technology to critically ill patients, Dr. Gerlach designed the extracorporeal liver support system so that it was suitable for use on small aircraft. This permitted him to take his life saving technology to distant locations and support a patient on the flight back to Berlin. For the 23 cases, about a third of the patient’s livers healed sufficiently to remove the extracorporeal support and the patient was discharged without the need for a transplant. For the remainder of the patients, the MELS provided support until they received a liver transplant.

In order to make the promising extracorporeal liver support available to hospitals beyond the clinical university, Dr. Gerlach founded the Hybrid Organ GmbH, Berlin, offering an extracorporeal liver support system. The current version of the Modular Extracorporeal Liver Support (MELS) concept integrates dialysis and detoxification into the hybrid liver devices.

It was in January 2003 that Dr. Gerlach joined the McGowan Institute for Regenerative Medicine and the faculty of the Departments of Surgery, and Bioengineering at the University of Pittsburgh. He was excited by the opportunities to collaborate with the many other scientists and clinicians whose interests were also in regenerative medicine. His primary research interests include the maintenance and differentiation of cells in vitro for extracorporeal, temporary clinical use as a hybrid organ; production of cells for transplantation in cell-based therapy; production of regenerative mediators by cells in bioreactors for drug therapy and regenerative medicine applications. His primary focus has been the use of liver cells, but he, and members of his research groups in both Berlin and Pittsburgh, are also using skin, bone marrow, and stem cells for these innovative therapeutic concepts.

Dr. Gerlach is the recipient of various awards including the 1989 Young Researcher Award of the International Society for Artificial Organs and the 1996 Young Researcher Award of the European Society for Artificial Organs (ESAO). He is currently chair of the ESAO Liver Support Working Group, and section editor for regenerative medicine of the International Journal of Artificial Organs. He is a member of the European Society for Artificial Organs, and a member of the Tissue Engineering Society Europe, a Fellow of the Berlin Society of Surgeons, and a Fellow of the German Society of Surgeons.

Dr. Gerlach is the first author of 79 peer reviewed publications, and holds 3 patents. His publications deal with organ replacement, tissue engineering, bio-medical technology engineering, as well as with transplantation medicine, transplantation immunology, and organ preservation.

He has been proactive in community service, being responsible for the establishment of a Medical Logistics Unit at Berlin Central Airport, served as the Chair Tissue Engineering Committee Berlin (1998–2000) and was the initiator of a GMP Center for Clinical Studies in Berlin. In his “spare” time in Pittsburgh, Dr. Gerlach enjoys touring the region on his motor cycle.

Dr. Gerlach’s vision for the future of regenerative therapies moves from the current focus on extracorporeal support devices, like the MELS, to the repair of liver deficiencies by the direct injection of liver stem cells into the damaged organ. He notes that “the bioreactor technology will still play a critical role in this advanced therapy, as there will be a need to proliferate and differentiate...in the bioreactor sufficient cells for the therapeutic procedures.”

 

The National Institutes of Health (NIH) has awarded a grant of nearly $1.4 million to the University of Pittsburgh and Magee-Womens Research Institute (MWRI) to fund research aimed at basic understanding of ovarian follicles – one of the basic building blocks of life.

The five-year grant, through the NIH’s National Institute of Child Health and Human Development, marks the largest received thus far by project principal investigator Elizabeth McGee, M.D., assistant professor of obstetrics, gynecology and reproductive sciences at the School of Medicine.

“The follicle is the ‘essential ingredient’ of the ovary, providing both egg cells and the hormones necessary for female physical development and reproduction,” said Dr. McGee, who also is an assistant investigator at MWRI. “Depending on timing, follicular dysfunction can cause infertility and premature menopause or derail puberty and result in severe osteoporosis.”

As an example, she noted, abnormal follicle growth is typical in women who have polycystic ovarian syndrome, a disorder associated with infertility and long-term cardiovascular health risks.

In the United States, some 9 million women used infertility services in 1995, according to the Centers for Disease Control, and indications are that the problem is increasing. While infertility is age-related, there are other factors that are far less well known.

“Modern infertility treatment concentrates on the last two weeks of follicular development, but it actually takes six to 15 months for follicles to mature to ovulation,” said Dr. McGee. “That’s analogous to getting prenatal care only in the last two weeks of pregnancy.”

Very little is known about how ovarian follicles grow in their early stages. Research into the genetic interactions of this prolonged early period of development could have significant impact on future infertility treatment, she said.

“Knowledge of early follicular development could lead to infertility treatments earlier in the ovarian cycle that may have fewer side effects,” added Dr. McGee. “If we can find the defects early enough in follicular development, we may be able to correct them without the costly, inconvenient treatment options that are standard today.” [More]

 

NIH funded a five-year $4.6 million grant from the National Center for Research Resources to establish a Center for Neuroanatomy with Neurotropic Viruses. The center, the only one of its kind, will use viruses to trace the intricate circuitry and architecture of the nervous system in order to better understand its function and organization.

The center will be co-directed by Peter Strick, Ph.D., Professor of Neurobiology and J. Patrick Card, Ph.D., Associate Professor of Neuroscience at the School of Arts and Sciences.

As a national resource, it brings together leading experts in virology and neuroscience, including those from Princeton University and Thomas Jefferson University, to advance technology that uses viruses to define circuit architecture in the nervous system. “Tracing certain viruses through the nervous system provides a powerful means for functional dissection of neural circuitry. But the approach is a costly endeavor beyond the reach of most investigators. The center will provide the necessary resources and focus to energize this technology development and make it more widely available,” said Dr. Strick.

“In establishing the center here, the NIH recognizes the concentration of world-class expertise in this unique area of research. The University of Pittsburgh is home to a surprising number of investigators who have been influential in the development and application of this methodology,” added Dr. Card. According to Drs. Strick and Card, the center will enable the further development of the virus tracing technique to improve and expand its capabilities; provide training opportunities for scientists from other institutions; and foster collaborations and multidisciplinary studies that will help advance scientific understanding. [More]

 

Influence of Extracellular Matrix Proteins in the Mineralization Process of Bone and Dentin

In collaboration with Dr. Prashant Kumta of the Department of Materials Science and Engineering at Carnegie Mellon University, Dr. Charles Sfeir will lead a 4-year study to investigate the influence of extracellular matrix proteins in the mineralization process of bone and dentin. This R01 grant, funded for $1.3 million was awarded by the National Institute of Dental Craniofacial Research (NIDCR)

Biomineralization is a complex process and is one of the final stages involved in the formation of mineralized tissue such as bone and dentin. The research will be directed to the influence of extracellular matrix proteins in the mineralization process of bone and dentin in which apatite crystals are grown. Using proteomics and specific high-resolution mineral characterization techniques sensitive to amorphous and crystalline inorganic materials, the research will assess the effect of the post-translational modification and more precisely, the phosphorylation of specific bone/dentin extracellular matrix proteins and their role in the biomineralization process.

This is a multidisciplinary approach to understand the biology of mineralization using molecular biology techniques combined with state-of-the-art mineral characterization probes executed in collaboration with Dr. Kumta. These detailed fundamental studies of the molecular pathways involved in mineralization will lay the foundation for the development of novel approaches for synthesizing not only equilibrium and non-equilibrium mineral phases but also stabilizing unique morphologies under the control of specific extracellular matrix motifs, opening the doors for exciting applications in biology and tissue engineering.

 

Diana Spencer
412-235-5156
spencerdk3@upmc.edu