McGowan Institute?
April 2008 | VOL. 7, NO. 4 | www.McGowan.pitt.edu
Science Takes Aim at Battlefield Injury in Massive Project Grant
PITTSBURGH, April 17 – 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.
A new federally funded institution – the Armed Forces Institute of Regenerative Medicine (AFIRM) – will be made up of the U.S. Army Institute of Surgical Research and consortia involving the McGowan-Wake Forest team and another led by Rutgers and the Cleveland Clinic. Each group was awarded $42.5 million. The Wake Forest-McGowan team includes collaborators from 15 other institutions.
“Researchers from the University’s McGowan Institute for Regenerative Medicine are known throughout the world for their cutting-edge research that is providing real hope for dramatic advances in human health,” said Pitt Chancellor Mark A. Nordenberg. “The Institute has fast become one of the nation’s leaders in developing organ and tissue technologies as viable clinical therapies, and through its involvement in AFIRM, the Institute will continue to progress in this vitally important area.”
AFIRM will be co-directed by Alan J. Russell, Ph.D., director of the McGowan Institute for Regenerative Medicine, and Anthony Atala, M.D., director of the Wake Forest Institute for Regenerative Medicine. The massive project will be dedicated to repairing battlefield injuries through the use of regenerative medicine, science that takes advantage of the body’s natural healing powers to restore or replace damaged tissue and organs. Therapies developed by AFIRM also will benefit people in the civilian population with burns or severe trauma due to illness or injury.
“Our goal is to use our position as the international leader in developing restorative therapies for battlefield trauma to improve the outcomes for our wounded,” said Dr. Russell, who is a founding president of the Tissue Engineering and Regenerative Medicine International Society (TERMIS). “Our ability to provide these treatments is in part due to our team’s long experience in this field and our broad pipeline of technologies.”
The McGowan and Wake Forest team has committed to develop clinical therapies over the next five years that will focus on:
▪ Burn repair
▪ Wound healing without scarring
▪ Craniofacial reconstruction
▪ Limb reconstruction, regeneration or transplantation
▪ Compartment syndrome
Collaborators and subcontractors for the McGowan-Wake Forest team include Allegheny Singer Research Institute; the California Institute of Technology; Carnegie Mellon University; the Georgia Institute of Technology; the U.S. Army Institute for Collaborative Biotechnology; Intercytex Group, Plc; Organogenesis Inc.; Oregon Biomedical Engineering Institute; the Pittsburgh Tissue Engineering Initiative Inc.; Providence Health System; Rice University; Stanford University; Tufts University; the University of California, Santa Barbara; and Vanderbilt University.
Government sponsors of AFIRM are the U.S. Army Medical Research and Materiel Command, the Office of Naval Research, the U.S. Air Force and the National Institutes of Health.
Amit Patel, MD, MS, Director of Cardiac Cell Therapy at the McGowan Institute, and collaborators in seeking new and more abundant sources of stem cells for use in regenerative medicine have identified a potentially unlimited, noncontroversial, easily collectable, and inexpensive source -- menstrual blood. "Studies have demonstrated that menstrual blood stromal cells are easily expandable to clinical relevance and express multipotent markers at both the molecular and cellular level," said Dr. Patel.
Stromal stem cells - cells that are present in connective tissues - have recently been identified in endometrial tissues of the uterus. When the fresh growth of tissue and blood vessels is shed during each menstrual cycle, some cells with regenerative capabilities are present and collectable. While collecting menstrual blood stromal cells (MenSCs) directly from tissue would be invasive, retrieving them during the menstrual cycle would not be.
Tests showed that MenSCs could differentiate into adipogenic, chondrogenic, osteogenic, ectodermal, mesodermal, cardiogenic, and neural cell lineages. According to Patel, the sample MenSCs expanded rapidly and maintained greater than 50 percent of their telomerase activity when compared to human embryonic stem cells and better than bone marrow-derived stem cells.
Researchers emphasized the importance of the abundance and plasticity of MenSCs. Based on the results of their studies, they noted the potential for MenSCs in regenerative transplantation therapies for many different organs and tissues. "The need for regenerative therapies using cells with the ability to engraft and differentiate is vast," said Patel.
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A team of researchers led by Dr. Sanjeev G. Shroff, bioengineering professor and Gerald E. McGinnis Chair in the Department of Bioengineering, has found a new pathway that regulates the strength of cardiac muscle contractions. These results could lead to the development of new drugs for treating weakened cardiac muscle and conditions such as congestive heart failure. The project and its results are so noteworthy that the story is featured on the cover of the April 11 issue of the Journal of Biological Chemistry.
The pathway discovered by Dr. Shroff and his colleagues regulates cardiac muscle contraction using the acetylation of cardiac proteins. “Acetylation is widely known to regulate such events inside the cell nucleus as gene regulation,” said Dr. Shroff, “but it’s never before been associated with heart muscle contraction.” Acetylation of certain heart muscle proteins is a process wherein a radical cluster of atoms called an acetyl group attach to a protein and change its function.
“We did not create this process,” Shroff explained, “we are just manipulating what is already there.” The next step in the research will involve studying cardiac contraction in the whole animal rather than just muscle samples.
Dr. Shroff’s paper was featured in the March Newsletter as the Publication of the Month. To view the paper in its entirety, go to: www.jbc.org/cgi/content/full/283/15/10135
McGowan Institute faculty member, Michael Sacks, PhD, William Kepler Whiteford Professor in the University of Pittsburgh Department of Bioengineering, is working with researchers at Children's Hospital of Boston to grow tissue-engineered heart valves in the lab. The team is using blood cells from sheep to grow the heart valves around polymer scaffolding and then implant them. After the implantation, the heart valves have worked successfully for up to 20 weeks.
“The ultimate goal is to create heart valves for children using their own tissue, a technique that is designed to allow the valves to grow along with the children's bodies,” said Dr. Sacks.
That would overcome a major problem children with heart valve problems now face. Many of them get valves from human donors, but those transplanted valves don't grow with the children, who then have to undergo anywhere from two to five valve replacement surgeries before they are adults. The other advantage of lab-grown valves would be to cut down on the calcium buildup that causes current prosthetic tissue valves to wear out. Calcium accumulation is a bigger problem in children than adults, because their bodies are still actively metabolizing it for growing bones. In addition, the implanted tissue valves children now get, whether from humans or animals, are cleansed in a substance called glutaraldehyde to prevent them from causing an immune reaction. But glutaraldehyde also becomes a magnet for calcium molecules, researchers say.
Right now, Dr. Sacks and his team are using the sheep's blood to grow a cellular matrix along polymer scaffolding. After the engineered valve is put into the sheep, their own tissues start to replace the polymer. “Tests so far have shown that this polymer replacement process is occurring in sheep after five months, when they are almost adults,” Dr. Sacks explained. “It has not yet proven whether the valves are growing at the same pace as the sheep's hearts.”
Recently McGowan Institute for Regenerative Medicine faculty member Derek Angus, MD, MPH, FRCP, FCCM, FCCP, weighed in on two new studies that try to answer one of the most pressing questions in critical care medicine: How much pressure should be applied to keep open the partially collapsed lungs of people being treated for the deadly condition called acute respiratory distress syndrome?
Unfortunately, that question has not yet been definitively answered. The results of two recent studies were published in the February 13 issue of the Journal of the American Medical Association along with an accompanying editorial by Dr. Angus and one of his colleagues. One study suggests that higher positive end-expiratory pressure (PEEP) is better, but the exact amount of pressure must be adapted to each person. Yet another contended there was no proof of the value of higher PEEP.
A marked feature of both studies was a continuation of the trend to change the pattern of forced breathing, with the number of breaths per minute doubled, and the tidal volume, the amount of air forced into the lung with each breath, halved. According to Dr. Angus, the results should have some impact on medical practice, pushing intensive care units toward use of higher PEEP levels based on a patient's needs.
Neither study showed significant changes in the death rate. In the French study of 767 people treated for acute respiratory distress syndrome (ARDS), the hospital mortality was 39 percent among those who got conventional treatment using relatively low PEEP, and 35.4 percent among those who got higher PEEP based on individual calculations. The comparable figures for the 983 people treated for ARDS in the Canadian study was 40.4 percent for those getting conventional treatment, and 36.4 percent for receiving higher PEEP based on individual characteristics.
"While neither study changed overall mortality much, both made moves in the right direction," Angus said. "There was a trend toward lower mortality in both studies [with higher PEEP]. In both studies, there was clearly improved oxygenation. And both reduced the need to use rescue therapies, last-ditch attempts to use experimental, sometimes crazy things to keep patients alive."
Dr. Angus is a professor of medicine, a professor in the Department of Health Policy and Management, a professor with tenure in Critical Care Medicine, and vice chair for research in the Department of Critical Care Medicine at the University of Pittsburgh.
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McGowan Institute for Regenerative Medicine faculty member Steven DeKosky, MD, professor of neurology, psychiatry, neurobiology, human genetics, and director of the Alzheimer’s Disease Research Center at the University of Pittsburgh, confirms through a groundbreaking study that Pittsburgh Compound-B (PiB) binds to the telltale beta-amyloid deposits found in the brains of patients with Alzheimer’s disease. The finding is a significant step toward enabling clinicians to provide a definitive diagnosis of Alzheimer’s disease in living patients.
Until now, the beta-amyloid deposits to which PiB binds have been confirmed, without question, only in the autopsied brains of patients afflicted with Alzheimer’s. The new findings, which correlate PiB-identified beta-amyloid deposits from living patients to their post-mortem autopsy results, will ultimately aid in the early diagnosis of Alzheimer’s, help clinicians monitor the progression of the disease, and further the development of potential treatments.
“This is final confirmation of what we have believed all along— that Pittsburgh Compound-B allows us to accurately assess the amount of beta-amyloid plaques in brains of people afflicted with Alzheimer’s,” said Dr. DeKosky.
Invented and developed by Pitt researchers Chester Mathis, PhD., professor of radiology and pharmaceutical sciences, and William Klunk, MD, PhD, professor of psychiatry and neurology, PiB is a radioactive compound that, when coupled with positron emission tomography (PET) imaging, can be injected into the bloodstream to enable researchers to visualize the brains of people with the memory-stealing illness and see the location and distribution of the beta-amyloid plaque deposits associated with Alzheimer’s. The distinguishing factor between Alzheimer’s disease and other dementias is the presence of these amyloid plaques, which are thought to kill brain cells.
“This work is an important step forward in the development of new tools for both research and clinical care,” noted Neil Buckholtz, PhD., chief of the Dementias of Aging Branch of the National Institute on Aging, National Institutes of Health, which supported the study. “It provides additional evidence validating the use of PiB to identify beta-amyloid deposits in living individuals and advancing the potential use of PiB as an outcome measure in clinical trials of anti-beta-amyloid therapeutics.”
The recent study findings were reported in the neurology journal Brain, in a collaborative article with Dr. DeKosky as the corresponding author. It is estimated that up to 4.5 million people in the United States have Alzheimer’s, including 50 percent of those older than age 85 and 10 percent of those over age 65. The number of those affected is expected to triple over the next 50 years.
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Ronald Herberman, MD recently accepted for the University of Pittsburgh Medical Center (UPMC) Cancer Centers the National Chairman’s Citation for Excellence in Community Service from the Leukemia and Lymphoma Society. The UPMC organization was nominated by the Pittsburgh Chapter of the Society and was selected from a field of 50 nominees. Dr. Herberman is the director of the University of Pittsburgh Cancer Institute (UPCI) and UPMC Cancer Centers as well as being on the faculty of the McGowan Institute for Regenerative Medicine.
“We have a strong commitment at the UPMC Cancer Centers to community service, as well as to innovative clinical and translational research, and we are proud that the Pittsburgh chapter of the Leukemia and Lymphoma Society nominated us for the award in recognition of our efforts to support our patients, who come to us from all over western Pennsylvania and beyond,” said Dr. Herberman.
The Leukemia and Lymphoma Society is the world’s largest voluntary health organization dedicated to funding blood cancer research, education, and patient services. The Society’s mission is to cure leukemia, lymphoma, Hodgkin’s disease, myeloma, and to improve the quality of life of patients and their families. Since its founding in 1949, the Society has invested more than $550 million in research specifically targeting blood cancers.
UPMC Cancer Centers offer cancer patients exceptional care and innovative treatments close to home. Working in tandem with the UPCI, the region’s only National Cancer Institute-designated Comprehensive Cancer Center, UPMC Cancer Centers provide the latest advances in cancer prevention, detection, diagnosis, and treatment at more than 40 community-based locations throughout the region. UPCI integrates the academic and research activities for cancer at the University of Pittsburgh and UPMC.
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McGowan Institute faculty member Robert Kormos, MD, is director of the UPMC Artificial Heart Program. Since its founding in 1985, this program has become one of the most active mechanical circulatory assist centers in the United States, supporting patients on various devices. Among many other milestones, in 1990, UPMC became the first medical center in the world to discharge a patient from the hospital while still supported by a ventricular assist device.
These and other regenerative medicine projects being researched in the Pittsburgh area show that current business investment depends on growing the knowledge base instead of the physical resource base.
In a recent interview concerning the growth of research and investments in the area published in the Pittsburgh Tribune-Review Dr. Kormos stated, “This supply chain of brain power in Pittsburgh has helped to revolutionize artificial heart research. Collaboration between medical researchers at UPMC, the University of Pittsburgh, and the McGowan Institute led to the creation of the HeartMate II, an artificial heart that has been placed in 880 patients. It could get Food and Drug Administration approval as a bridge before heart transplantation this year. Through that collaboration, we've been able to introduce into the heart failure community a very viable solution to end-stage heart failure.”
Weighing 12 ounces and approximately 1.5 inches in diameter and 2.5 inches long—about the size of a D-cell battery—HeartMate II is significantly smaller than currently approved devices which weigh closer to three pounds. As such, it may be suitable for a wider range of patients, including small adults and children. The design also makes the device quieter and simpler to use. The long-term vision for mechanical heart devices is to use them to give the heart a rest while it repairs itself with the help of cell therapy, perhaps by injecting a patient's own stem cells into damaged areas of their heart.
McGowan Institute for Regenerative Medicine faculty member Freddie Fu, MD, is the David Silver Professor of Orthopaedic Surgery and chairman of the Department of Orthopaedic Surgery at the University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center. Nowadays, patients seeing Dr. Fu are getting younger and younger—a surprising change.
As reported in the New York Times, a torn anterior cruciate ligament (ACL), an injury that doctors used to classify as rare in children, is occurring more and more frequently. Although there are no complete or official numbers, orthopaedists at leading medical centers estimate that several thousand children and young adolescents are getting ACL tears each year, with the number being diagnosed soaring recently. Some centers that used to see only a few such cases a year are now seeing several each week. And contrary to the old belief that boys are more prone to the injury than girls, as many as eight times more girls than boys are suffering the tears, doctors report.
Doctors say the injury occurs simply from twisting the knee, and diagnoses are on the rise partly because it can now be easily detected and partly because the very nature of youth sports has changed. Now that almost every child with a hurt knee gets a magnetic resonance imaging, doctors are finding the ligament tears on a regular basis. The other reason for the reported surge in ACL tears, doctors speculate, is that the best athletes are more or less constantly at risk. They play year-round and on multiple teams with frequent games, in which the risk of injury is higher than in practice because of the intensity of play.
The standard and effective treatment for such an injury in adults is surgery. But the operation poses a greater risk for children and adolescents who have not finished growing because it involves drilling into a growth plate, an area of still-developing tissue at the end of the leg bone.
Drilling into the growth plate may cause permanent damage to the still-growing bones of young children. After drilling, surgeons replace the torn ligament with a tendon taken from elsewhere in the body, like the hamstring, or from a cadaver. But if the drilling damages a child’s growth plate, the leg bone will not develop normally.
Some surgeons are developing new and technically demanding methods to repair ACL tears in children, drilling holes to create little tunnels in bone that is already finished growing and threading tendons around the growth plate. But the tendons are not anchored where they would normally be and the long-term effects of the operation are not known.
Read more… The New York Times
The Regenerative Medicine Podcasts continue to explore pertinent topics. The most recent podcasts are:
#48-Joan Schanck – Ms. Schanck, Director of Education and Workforce Development at the Pittsburgh Tissue Engineering Initiative (PTEI) discusses educational programs for students from K-12 and beyond.
#49-Steve Winowich – Mr. Winowich, Director of Clinical Bioengineering with the Artificial Heart Program at UPMC, reviews the unique partnership between clinical staff and bioengineers in regard to providing mechanical circulatory support to patients prior to a heart transplant.
#50-Kacey Marra, PhD – Dr. Marra is an assistant professor in the Department of Surgery at the University of Pittsburgh. She is also Lab Director of the Plastic Surgery Research Lab. Dr. Marra’s research focuses on the utilization of adipose-derived stem cells for neuronal tissue engineering applications.Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
| Authors: | Engelmayr GC Jr, Soletti L, Vigmostad SC, Budilarto SG, Federspiel WJ, Chandran KB, Vorp DA, Sacks MS. |
| Title: | A novel flex-stretch-flow bioreactor for the study of engineered heart valve tissue mechanobiology |
| Summary: | Tissue engineered heart valves (TEHV) have been observed to respond to mechanical conditioning in vitro by expression of activated myofibroblast phenotypes followed by improvements in tissue maturation. In separate studies, cyclic flexure, stretch, and flow (FSF) have been demonstrated to exhibit both independent and coupled stimulatory effects. Synthesis of these observations into a rational framework for TEHV mechanical conditioning has been limited, however, due to the functional complexity of tri-leaflet valves and the inherent differences of separate bioreactor systems. Toward quantifying the effects of individual mechanical stimuli similar to those that occur during normal valve function, a novel bioreactor was developed in which FSF mechanical stimuli can be applied to engineered heart valve tissues independently or in combination. The FSF bioreactor consists of two identically equipped chambers, each having the capacity to hold up to 12 rectangular tissue specimens (25 x 7.5 x 1 mm) via a novel "spiral-bound" technique. Specimens can be subjected to changes-in-curvature up to 50 mm(-1) and uniaxial tensile strains up to 75%. Steady laminar flow can be applied by a magnetically coupled paddlewheel system. Computational fluid dynamic (CFD) simulations were conducted and experimentally validated by particle image velocimetry (PIV). Tissue specimen wall shear stress profiles were predicted as a function of paddlewheel speed, culture medium viscosity, and the quasi-static state of specimen deformation (i.e., either undeformed or completely flexed). Velocity profiles predicted by 2D CFD simulations of the paddlewheel mechanism compared well with PIV measurements, and were used to determine boundary conditions in localized 3D simulations. For undeformed specimens, predicted inter-specimen variations in wall shear stress were on average +/-7%, with an average wall shear stress of 1.145 dyne/cm(2) predicted at a paddlewheel speed of 2000 rpm and standard culture conditions. In contrast, while the average wall shear stress predicted for specimens in the quasi-static flexed state was approximately 59% higher (1.821 dyne/cm(2)), flexed specimens exhibited a broad intra-specimen wall shear stress distribution between the convex and concave sides that correlated with specimen curvature, with peak wall shear stresses of approximately 10 dyne/cm(2). This result suggests that by utilizing simple flexed geometric configurations, the present system can also be used to study the effects of spatially varying shear stresses. We conclude that the present design provides a robust tool for the study of mechanical stimuli on in vitro engineered heart valve tissue formation. |
| Source: | Ann Biomed Eng. 2008 May;36(5):700-12. |
| PIs: | Alan J. Russell, PhD and Anthony Atala, MD |
| Title: | Armed Forces Institute for Regenerative Medicine |
| Description: | 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.
Compartment syndrome, a condition related to inflammation after surgery or injury that can lead to increased pressure, impaired blood flow, nerve damage and muscle death. |
| Source: | Department of Defense |
| Term: | 2008-2013 |
| Amount: | $42.5 million |
Newsletter Comments or Questions: McGowan@pitt.edu