March 2010 | VOL. 9, NO. 3 | www.McGowan.pitt.edu
Annual McGowan Institute Retreat Successfully Concludes
The McGowan Institute for Regenerative Medicine held its 2010 Retreat March 7-10, 2010. The focus was on peer-to-peer networking, and the forum provided many chances to explore collaborative opportunities with other researchers and participating industrial partners who are working to bring regenerative medicine technologies to clinical use.
The participation and contributions of the commercial leaders - along with McGowan Institute faculty and trainees - provided for insightful discussions and identification of opportunities for collaboration. In addition to the welcome address, “The McGowan Institute: Past, Present, and Future,” from Alan Russell, PhD, Director, McGowan Institute, the retreat program included special presentations by the following guests:
- McGowan Institute Distinguished Lecture by Buddy D. Ratner, PhD, Professor of Chemical Engineering and Bioengineering, and Director-Engineered Biomaterials NSF Engineering Research Center, University of Washington
- Congressman Jason Altmire, Pennsylvania 4th Congressional District
- Peter D. Wearden, MD, PhD, Assistant Professor-Cardiothoracic Surgery, Children’s Hospital of Pittsburgh of UPMC
- Marc S. Malandro, PhD, CLP, Associate Vice Chancellor for Technology, Management and Commercialization, University of Pittsburgh
- Mel Pirchesky, President-Eagle Ventures, Inc.
- Eric J. Beckman, PhD, George M. Bevier Professor of Engineering, Co-Director, Mascaro Sustainability Initiative
The Retreat program, organized under the leadership of William R. Wagner, PhD, included over 80 scientific presentations including those given by invited researchers from other institutions.
Click Here for the full schedule of sessions, session organizers, and presenters.
The poster session was effective in introducing the focus of the Retreat and interests of the faculty and the guests. Kacey Marra, PhD, and her committee organized the session and judged the posters. The winners of the poster session were:
Category: Biomaterials and Tissue Engineering
- First Place: Andrew Glowacki, Siddharth Jhunjhunwala, Gustavo P. Garlet, Charles Sfeir, Steven Little: “Treating periodontitis through recruitment of regulatory lymphocytes”
- Second Place: Zuwei Ma, Devin M. Nelson, Cory Leeson, Yi Hong, Sang-Ho Ye, William Wagner: “Bioabsorbable and thermoresponsive hydrogels as injectable biomaterials”
Category: Cellular Therapies
- First Place: Julie Chandler, Eric Lagasse: “From stem cells to independent organoids: a differentiation assay for normal and cancerous intestinal stem cells”
- Second Place: Alex Chen, Masaho Okada, Kimimasa Tobita, Bruno Péault, Johnny Huard: “Regenerative medicine for myocardial infarction using perivascular stem cells”
Category: Medical Devices and Modeling
- First Place: Anthony Finoli, Eva Schmelzer, Greggory Housler, Daniel McKeel, Ian Nettleship, Jörg Gerlach: “Design and construction of a human bone marrow bioreactor”
- Second Place: Maxim Mikeev, Jinling Yin, Derek Barclay, Ruben Zamora, Yoram Vodovotz: “A self-regulating inflammation control and monitoring device: invitro proof of concept”
New at this year’s McGowan Institute Retreat, the University of Pittsburgh Office of Enterprise Development (OED) hosted the "Innovator Elevator Pitch." This event consisted of a series of scheduled brief presentations from participating faculty on the value of their technology to an audience which included industry participants and venture capitalists. This year’s winner of $10K in project funds was Major General (Ret.) Gale S. Pollock, whose pitch addressed emerging technologies to aid the visually impaired. The event facilitators were Marc S. Malandro, PhD, CLP, Associate Vice Chancellor for Technology Management & Commercialization, University of Pittsburgh and Mel Pirchesky, President, Eagle Ventures, Inc., and each audience member served as the selection panel.
Thanks are extended to all who made this year’s Retreat a success!Read More…
A liver transplant is currently the only effective treatment for end-stage liver disease. It remains a costly option fraught with risks, not only from the surgical procedure, but also because of lifelong drug therapy to suppress the immune system. McGowan Institute for Regenerative Medicine faculty member Eric Lagasse, PharmD, PhD, associate professor in the Department of Pathology at the University of Pittsburgh and the director of the McGowan Institute’s Cancer Stem Cell Center, foresees an alternative to liver transplantation. As recently reported by Michele Baum in PittMed, in Dr. Lagasse’s lab, research efforts focus on the use the body’s lymphatic system to serve as a bioreactor for regenerating a new liver.
“This is the first step of a complex idea that could lead to organogenesis,” says Dr. Lagasse.
In his lab, Dr. Lagasse and his team have found that when you inject liver cells into the peritoneum [the abdominal lining] of a mouse, they migrate to the lymph nodes. “Large nodules then form in the stomach and gut region, and we found out that they were essentially mini-livers,” explains Dr. Lagasse.
Injecting mice with liver cells appears to result in localized migration of hepatocytes to lymph nodes without affecting the function of other, neighboring nodes. In his experiments, in mice with tyrosinemia (a liver defect), transplanted liver cells functioned robustly—enough to rescue the animals from liver failure. The National Institutes of Health thought this approach was so ground-breaking Dr. Lagasse was awarded a 5-year, $2.9 million NIH Director’s Transformative R01 grant in 2009.
“For decades, people have been injecting cells of one kind or another. But it’s an extraordinary leap to think that you can take cells from one organ, inject them into another, and have [those cells] take on the characteristics of the first. Not only that—it works,” says Alan Russell, PhD, director of the McGowan Institute as well as a Pitt University Professor of Surgery with appointments in chemical engineering, bioengineering, and rehabilitation sciences and technology.
A healthy liver removes toxins and waste from the bloodstream and also works to aid digestion and regulate metabolism. There are many kinds of liver disease, yet the most common diagnosis leading to a transplant is cirrhosis, a scarring of the liver often related to long-term alcohol use. Cirrhosis may lead to liver cancer. Liver failure also can be tied to drug interactions, viral infections such as hepatitis C, or chemical poisoning.
McGowan Institute for Regenerative Medicine faculty member Rocky Tuan, PhD, is the director of the Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, and the executive vice chairman for orthopaedic research at the University of Pittsburgh. Dr. Tuan’s research focuses on the development, growth, function, and health of the musculoskeletal system, the biology of adult stem cells, and the utilization of this knowledge to develop technologies that will regenerate and/or restore function to diseased and damaged musculoskeletal tissues. In 2009, he came to Pitt from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), with a research portfolio with one major thrust: use the body’s own regenerative power—augmented with biomaterials, nanomaterials, and/or stem cells—to make musculoskeletal tissue exactly as the body would.
“The ultimate goal is cell-based therapy or cell-based tissue regeneration,” Dr. Tuan said, as reported by PittMed’s Joe Miksch. “But in order to regenerate tissue, you need to understand the building blocks, the cells—they’re the real tissue engineers.”
Dr. Tuan’s focus is how to create cartilage, tendon, and ligament tissues to replace those ravaged by injury or age. When these tissues are injured or worn by overuse, the result is often osteoarthritis—a painful, chronic, and difficult-to-treat condition that affects some 27 million Americans, according to the NIAMS.Replacement joints, as sophisticated as they have become, don’t hold up well over time. Dr. Tuan says we can do better, and we can do so by mimicking nature. Making man-made, or rather, “man-assisted” tissue in vitro from adult stem cells, particularly mesenchymal stem cells that are drawn from bone marrow, muscle, or fat, is the easy part—not that it’s particularly easy. The real difficulty arises, Dr. Tuan says, in making something that looks like muscle, cartilage, or a spinal disc function like muscle, cartilage, or a spinal disc. A cell’s best friend, to Dr. Tuan, is a scaffold matrix. Without a space-filling guide the mesenchymal stem cells can glom onto, there’s a high risk that they’ll be swept away before they can become tissue. “When you’re dealing with tissues whose main function is to bear weight, I think it’s good to have a scaffold that can take care of that aspect of it,” he says. With a goal of improving quality of life using modern technology, Dr. Tuan hopes his current tests make human clinical trials possible in 2 years. He also says he’s glad to be at Pitt to pursue this stage of his work. “For the kind of work I am interested in, Pittsburgh is a powerhouse,” Dr. Tuan says. “I don’t have to come in here and build anything, which is actually nice. Here, science is truly multidisciplinary, and I think it’s a lot more fun when you have different kinds of people thinking about these problems. It’s great to be in a place with that kind of interaction.”
Together, researchers at the University of Pittsburgh and the University of Pittsburgh Medical Center are working to quickly identify and treat shock, a problem that affects an estimated 1 million emergency room patients every year. Circulatory shock, which is caused by a variety of problems such as heart attacks, happens when not enough blood reaches organs and other tissues. Time is therefore critical: The focus of efforts is to try to find better ways to diagnose shock earlier and reverse it.
As reported in the Pittsburgh Business Times, shock-related studies at Pitt include a $9.4 million study that is enrolling 1,950 people suffering from septic shock, which is caused by a massive internal infection. The National Institutes of Health-funded study will determine whether the number of shock deaths can be reduced by following specific steps. Also, a $600,000 study completed last year and funded by the Air Force showed a correlation between a simple blood test and the earliest signs of shock.
To help speed up identification of circulatory shock, McGowan Institute for Regenerative Medicine faculty member Michael Pinsky, MD, Professor of Critical Care Medicine, Anesthesiology and Bioengineering at the University of Pittsburgh School of Medicine, is working on a unique diagnostic medical device currently in clinical trials. In early shock, blood vessels constrict, which shunts blood away from fingers, toes, and other extremities, and into the body core and vital organs such as kidneys and brain. Dr. Pinsky’s device will quickly measure the vascular tension that makes this shift of blood possible, which will eventually help guide treatment decisions.
The device—named CVInsight—could provide the earliest warning yet for circulatory shock, a problem that can be fatal in up to 20 percent of cases, Dr. Pinsky said. CVInsight is a non-invasive medical device that overcomes the limitations of the current protocol of using static vital signs as a basis for assessing cardiovascular sufficiency. By performing a rapid and safe bedside test, the CVInsight device provides a functional measure of a patient’s cardiovascular stability, or lack thereof. The assessment of cardiovascular stability is performed using a stress test created from a passive leg raise; a proven way to create a safe cardiovascular “stress” measurement.
Recent advances in the understanding of the dynamic nature of circulatory control have introduced novel hemodynamic monitoring approaches that are continuous, noninvasive, and metabolic in their orientation. When these monitoring strategies are used as physiology-based feedback to guide caregiver-directed protocolized therapy, they can lead to a new and robust approach to the resuscitation of trauma patients. CVInsight meets the need for a device that can be used by a lesser competent care provider, such as emergency response personnel, so that critically ill patients can receive effective shock treatment quickly.
Symptoms of circulatory shock can be as vague as feelings of anxiety. Standard diagnostic tools, such as heart rate and blood pressure, don’t always reflect trouble that’s brewing inside. The result can be delayed diagnosis, which complicates treatment.Read more…
McGowan Institute for Regenerative Medicine faculty members Mark Roberts, MD, chair of health policy and management at University of Pittsburgh’s Graduate School of Public Health, and Derek Angus, MD, professor in critical care medicine as well as health policy and management at the University of Pittsburgh and vice chair for research in the Department of Critical Care, are co-authors on a study, funded by the National Institutes of Health’s National Institute on Aging, which showed that patients admitted to hospitals with higher-intensity end-of-life care live longer than those admitted to hospitals with low-intensity approaches. Higher-intensity care refers to greater use of life-sustaining measures such as ICU admission, intubation or mechanical ventilation, kidney dialysis, and feeding tubes. The study examined admission records of more than one million patients 65 and older in Pennsylvania hospitals between 2001 and 2005.
The team of researchers found a survival benefit in hospitals with more intensive treatment styles, but this benefit lessened with time. After 30 days, patients treated at high-intensity hospitals had a 7 percent risk of dying compared to 9 percent at low-intensity hospitals. By 6 months post-admission, the risk of dying increased to 18 percent compared to 19.5 percent respectively. Risk of dying was the same for higher-intensity hospitals as average-intensity hospitals 6 months after admission.
Unlike previous studies that assessed records of people who died having received life-sustaining measures, the team looked at all seniors admitted to hospitals to determine the impact of intensity style on survival.
“Looking solely at people who received life support and died will not give you a true indication of how these measures impact survival,” said team leader Amber E. Barnato, MD, MPH, associate professor of medicine, clinical and translational science and health policy, University of Pittsburgh. “That’s akin to being a Monday morning quarterback. Instead, we looked at a hospital’s approach to people who were sick enough to die.”
The study did not address questions about the cost effectiveness of greater end-of-life treatment intensity or the quality of life experienced by the patients who lived longer because they went to a more intensive hospital.
McGowan Institute for Regenerative Medicine faculty members John Kellum, MD, FACP, FCCM (pictured left), professor of Critical Care Medicine at the University of Pittsburgh School of Medicine, transplant physician in anesthesiology at the Thomas E. Starzl Transplantation Institute, and co-director at the Mechanisms and Novel Therapies for Resuscitation and Acute Illness (MANTRA) Lab, and Derek Angus, MD, MPH, FRCP, FCCM, FCCP (pictured right), professor in Critical Care Medicine as well as Health Policy and Management at the University of Pittsburgh and vice chair for research in the Department of Critical Care, are co-authors on a Pitt study that showed kidney injury was linked to greater risk of death among pneumonia patients. Patients hospitalized with even mild to moderate community-acquired pneumonia who developed acute kidney injury (AKI) were more likely to die after discharge than pneumonia patients whose kidneys remain healthy. The study also found a strong relationship between AKI and levels of inflammatory biomarkers.
Doctors have long known that sepsis, a systemic response to severe infection, can trigger abnormalities in kidney function that contribute to higher mortality rates, but the impact of AKI in people with milder infections has not been well characterized, said lead author Raghavan Murugan, M.D., assistant professor in the Department of Critical Care. “Our study found that kidney injury was quite common among pneumonia patients whose illness course was otherwise uncomplicated,” he said. “They also had a higher risk of dying that persisted even 50 to 100 days after admission, which is surprising because most appeared stable and ready for discharge after 8 days in the hospital.”
The data were gathered from more than 1,800 participants with community-acquired pneumonia in the multicenter Genetic and Inflammatory Markers of Sepsis (GenIMS) study. A third of all patients were diagnosed with AKI, identified by abnormal creatinine levels or urine output, either on the first day of admission or sometime during their hospital stays, as were a quarter of those with mild or moderate pneumonia. Also, a third of all the pneumonia patients progressed to severe sepsis, and of that group more than half developed AKI. Compared to those without kidney injury, AKI patients had longer hospital stays and a higher risk of dying at hospital discharge (11 vs. 1.3 percent), 90 days later (24 vs. 9.8 percent), and 1 year (36.3 vs. 20.1 percent) later.
Another key study finding is that pneumonia patients who also developed AKI had higher concentrations of biomarkers of inflammatory and blood coagulation pathways than those who did not have a kidney injury.
“This suggests that the immune response in pneumonia is different in patients with AKI,” Dr. Murugan said. “It may be a bidirectional relationship. A stronger immune response might have caused AKI or the response was a consequence of AKI, or it worked both ways.”Read more. . .
AWARDS AND RECOGNITIONS
The McGowan Institute for Regenerative Medicine congratulates faculty member John Pacella, MD, MS, assistant professor of medicine, UPMC Cardiovascular Institute, on his receipt of the American Heart Association’s Claude R. Joyner, M.D., Research Award for his research on coronary collateral blood vessels, the body’s natural bypasses to blocked arteries. Dr. Pacella’s work will focus on determining the size of these collaterals in the microcirculation, as well as how they regulate blood flow between neighboring coronary arteries.
Dr. Pacella received his M.S. in Mechanical Engineering from Lehigh University and then went on to receive his M.D. from the University of Pittsburgh School of Medicine. Over the years, Dr. Pacella has held several positions which include having an Internal Medicine Residency in the Department of General Internal Medicine at the University of Pittsburgh. He also was a Biomechanics Researcher for the Musculoskeletal Research Center at the University of Pittsburgh and a Project Manager and Project Engineer at Allegheny General Hospital.
Dr. Pacella’s graduate research focused on the design and fabrication of a biventricular assist device to perform automatic cardiac massage. He performed in vivo and in vitro testing on the device and analyzed the biomechanics and geometry of systolic myocardial deformation. His undergraduate research focused on controls engineering, biomechanics, and robotics.
Congratulations, Dr. Pacella!Read more…
McGowan Institute for Regenerative Medicine faculty member Joon Sup Lee, MD, has been named president-elect of the American Heart Association, Allegheny Division. Dr. Lee will serve as president from July 1, 2010 to July 1, 2012.
Dr. Lee currently holds the positions of Assistant Professor of Medicine at the University of Pittsburgh, Clinical Director of the Cardiovascular Institute at the University of Pittsburgh Medical Center (UPMC), and Associate Chief in the Division of Cardiology at the University of Pittsburgh School of Medicine. Dr. Joon Lee received his M.D. from Duke University, School of Medicine in Durham, North Carolina.
As part of his work in the Cardiovascular Institute, Dr. Lee is involved in several clinical research trials conducted at UPMC. Two trials of note include:
- UPMC and Baxter Healthcare Corp. are currently partnered in a regenerative medicine clinical trial to study whether a patient's own stem cells can be used to treat severe coronary artery disease. Dr. Lee heads the CD34+ stem cell trial being conducted at UPMC-Presbyterian Hospital. Stem cell therapy injections into the heart were explained on the CBS Evening News by Dr. Lee; the program highlighted a patient who recently received injections of her own stem cells in hopes of growing new heart arteries.
- Dr. Lee is a co-investigator of the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) Clinical Trial. C-PORT is a group of cardiovascular specialists including physicians and nurses, clinical trial specialists, healthcare economists, quality-of-life researchers, hospital administrators, and government healthcare regulators who have designed and implemented a clinical trial comparing primary percutaneous coronary intervention (PCI) with thrombolytic therapy for patients with acute myocardial infarction (AMI) who present to community hospitals. UPMC McKeesport has been designated a site for this clinical trial to determine if there are differences in the outcome of PCI, also known as angioplasty, when performed in hospitals that do not offer cardiac surgery versus hospitals with heart surgery capabilities.
The American Heart Association and American Stroke Association are committed to fighting heart disease and stroke throughout Southwestern Pennsylvania. The Allegheny Division office serves Pittsburgh in the Allegheny, Armstrong, Beaver, Blair, Butler, and Cambria Counties.
It was the heart transplant patients of McGowan Institute for Regenerative Medicine faculty members Robert Kormos, MD, Director Artificial Heart Program, Co-Director Heart Transplantation at UPMC and Medical Director of Vital Engineering, Dennis McNamara, MD, cardiologist and Associate Professor of Medicine at the University of Pittsburgh, and Michael Mathier, MD, Director of the Pulmonary Hypertension Program and Director of the Cardiovascular Fellowship Program at the University of Pittsburgh, who were the inspiration for a professional ballet performance held at Pittsburgh’s Byham Theater. The choreographed performance was entitled “Heart (Function vs. Emotion)” and was held in celebration of American Heart Month.
Last spring, and after noticing medical themes in some of her past work, Dr. McNamara suggested to Bodiography artistic director and choreographer Maria Caruso that the experiences of some of his heart patients may be the foundation for a new ballet. After meeting his patients, Ms. Caruso agreed. Also, to more accurately reflect the line between a heart’s function and its emotion, the production’s choreographer visited the operating room during a heart transplant procedure.
The first part of her ballet centered around the function of the heart and the art of dance. The dancers were dressed in red and represented the patients' hearts. The second half of the ballet focused on emotion, including a "frantic section," because patients never know when they're getting a heart. On stage, Dr. Kormos re-created the motions of a surgery.
“You know, a lot of the emphasis these days is on the technology,” Dr. Kormos begins. “People forget that a good portion of this is still an art. A lot of successful physicians and surgeons look at medicine as more than just a science, a job, or a profession. They're able to express their creativity -- we just work on a different canvas. And a lot of it is choreography, which Maria saw.”
UPMC’s Heart Transplantation Program is one of the few programs nationwide to have performed more than 1,000 cardiac transplants and 900 lung or heart-lung transplants. This experience helped UPMC lead the nation in lung and heart-lung transplants in 2005. More than 40 heart and heart-lung transplantations are done each year, with the greatest post-transplantation longevity among UPMC recipients now approaching 20 years.Read more…
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Nathaniel T. Remlinger, Caitlin A. Czajka, Mark E. Juhas, David A. Vorp, Donna B. Stolz, Stephen F. Badylak, Sebastien Gilbert, Thomas W. Gilbert
Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction
Tracheal injury is a rare but complex problem. Primary tracheal reconstructions are commonly performed, but complications such as tension and inadequate vascular supply limit the length of surgical resection. The objective of the present study was to determine whether a hydrated, decellularized porcine tracheal extracellular matrix showed the potential to serve as a functional tracheal replacement graft. Porcine tracheas were decellularized and evaluated to characterize their biochemical composition and biomechanical behavior. Hydrated decellularized tracheal matrix (HDTM) grafts (>5 cm) were implanted heterotopically beneath the strap muscle and wrapped in the omentum in a canine model for 2 and 8 weeks followed by histologic and mechanical analysis. HDTM patches (2 x 3 cm) were also used in a patch tracheoplasty model. The repair site was evaluated bronchoscopically and radiographically, and the grafts were analyzed by histologic methods to evaluate epithelialization and persistence of the cartilage rings. The present study showed that HDTM maintains mechanical characteristics necessary for function under physiologic loading conditions even after 8 weeks of heterotopic implantation. After orthotopic implantation, the grafts were shown to support development of a columnar, pseudostratified, ciliated epithelium, but the cartilage structures showed histologic evidence of degradation and limited new cartilage formation. The results of the study showed tracheal ECM scaffolds support the formation of site-specific epithelium and provide sufficient mechanical integrity withstand physiologic pressures in the short-term. However, for long-term success, it appears that pre-implantation to allow vascularization or preseeding of the graft with chondrocytes will be necessary. Copyright 2010 Elsevier Ltd. All rights reserved.
Biomaterials. 2010 May;31(13):3520-6. Epub 2010 Feb 7.
Multi-scale model of thrombosis in artificial circulation
|Co-Investigators||William Wagner, James Antaki|
The objective of the project is to advance the accuracy and utility of a predictive model for thrombosis in blood-wetted cardiovascular devices. The research is built upon a combination of a previous model developed by the PI and colleagues for shear-mediated thrombosis and recent progress in modeling cellular-scale hemodynamics. Further incorporation of a model for synergy of platelet agonists is intended to yield a comprehensive design tool that is practical for design optimization of cardiovascular devices.Computer simulations will predict the dynamic interaction of red blood cells (RBCs) with platelets (Plts) in blood flow, and will rely upon a sophisticated theory of interacting continua that can predict the distribution of cells in any arbitrary flow path. The model will be validated and calibrated by both micro-scale computer simulations and microscopic visualization of blood cells in micro-channels. The predictive capacity of model will be demonstrated in three benchmark applications: (1) parallel plate study incorporating various microscopic steps and crevices, (2) flow within blade tip of rotary blood pump, and (3) hydrodynamic bearing for rotary blood pump.
CMU via R01 from the NIH
02/01/09 – 01/31/14 (2nd year funding received)
Newsletter Comments or Questions: McGowan@pitt.edu