McGowan Institute?
October 2009 | VOL.8, NO. 10 | www.McGowan.pitt.edu
Grant Will Help Wounded Soldiers Recover from Facial Injuries
McGowan Institute for Regenerative Medicine faculty member J. Peter Rubin, MD, Associate Professor of Plastic Surgery at the University of Pittsburgh and co-director of the Adipose Stem Cell Center, has received a major funding award from the Department of Defense (DOD) to help wounded soldiers recover from devastating facial injuries using innovative surgical technologies based on the biology of fat tissue.
The research program involves the treatment of 20 injured soldiers with facial injuries. “As many as 26% of wounded soldiers suffer facial injuries and these can have a great impact on quality of life. While we can reconstruct the bony structure fairly well, it is the surrounding soft tissues that give people the recognizable human form. This project investigates how soft tissue grafting can more precisely restore facial form and improve the lives of our wounded soldiers,” Dr. Rubin says.
The 1.6 million dollar funding award, known as The Biomedical Translational Initiative, is a program under the Office of the Assistant Secretary of Defense for Health Affairs. The program objective of The Biomedical Translational Initiative is to fund the demonstration and validation of innovative technologies to improve the clinical outcomes of wounded military personnel.
“Fat grafting, or moving fat tissue from one part of the body to another, has been used as a cosmetic procedure for decades,” comments Dr. Rubin, “but we are now applying this technology for reconstructive surgery to accurately restore facial form after battlefield injuries.” The use of fat grafting for serious facial injuries, such as those resulting from roadside bombs, is facilitated in this project by specially designed devices and instruments for harvesting the fat tissue and implanting it into regions of scarred tissue.
Dr. Rubin assembled a team of specialists for this study with diverse and complimentary expertise. Researchers within the University of Pittsburgh include McGowan Institute faculty member Dr. Kacey Marra, co-director of the Adipose Stem Cell Center; Dr. Gretchen Haas, an expert on measuring the psychological effects of battlefield injuries and how they improve with treatment; and Dr. Barton Branstetter, a radiologist who specializes in high resolution imaging of the face. Other specialists working on this project include Dr. Sydney Coleman, a New York City plastic surgeon who pioneered fat grafting surgery; and Colonel Robert Hale, a military surgeon and expert in facial trauma.
SCIENTIFIC ADVANCES
The $800 billion American Recovery and Reinvestment Act (ARRA) was signed into law on February 17, 2009, by President Obama in order to combat current economic challenges. A significant portion of this funding is being dedicated to expanding support for basic and applied research at research institutions across the country. For example, the research programs of two McGowan Institute faculty members Stephen Strom, PhD, professor in the division of cellular and molecular pathology at the University of Pittsburgh, and Peter Wearden, MD, PhD, cardiothoracic surgeon and director of pediatric mechanical cardiopulmonary support at Children’s Hospital of Pittsburgh of UPMC and assistant professor of cardiothoracic surgery at the University of Pittsburgh School of Medicine, are receiving economic stimulus funding for their work in liver generation by using human cells and the development of a pediatric heart assist device, respectively.
Dr. Strom’s project, “Mice Humanized with Hepatocytes and iPS Cells from Patients with Metabolic Disease,” will receive almost $1 million in funding through July 2011. “This is huge for us,” said Dr. Strom, who has found a way to generate livers in mice by using human cells. Dr. Strom is excited about this opportunity resulting from the federal economic stimulus money, especially as it is often difficult to get funding for such futuristic projects.
Dr. Wearden’s project, “Development of the PediaFlow Pediatric Ventricular Assist Device (PVAD),” will receive more than $1 million in funding through August 2011. This funding will keep together a core team of researchers who have been working for several years on a mechanical heart for infants. Their research has allowed the device to be shrunk to about the size of a double A battery through their improved understanding of blood dynamics has increased.
In addition to Dr. Wearden’s research program being in receipt of additional funding, another program he leads--the Extracorporeal Membrane Oxygenation (ECMO) program at Children’s--recently received accolades from the Extracorporeal Life Support Organization (ELSO). The Children’s ECMO program receives patients from throughout the world to be treated through their cardiothoracic transplantation expertise. Children’s Hospital is one of a select group of centers in the world to be honored with an “Excellence in Life Support Award” from the ELSO, an international consortium of centers offering ECMO for support of failing organ systems in infants, children, and adults. Since the ECMO program at Children’s Hospital supported its first patient with ECMO in 1979, it has progressed to one of the nation’s leading ECMO centers, supporting nearly 45 patients a year.
The ELSO award recognizes centers that demonstrate exceptional commitment to evidence-based processes and quality measures, staff training and continuing education, patient satisfaction, and ongoing clinical research. Children’s Hospital is one of only 55 centers in the world to receive this award since ELSO’s inception in 2006.
McGowan Institute for Regenerative Medicine congratulates faculty member Eric Lagasse, PharmD, PhD, associate professor in the Department of Pathology, University of Pittsburgh, and the Director of the Cancer Stem Cell Center, on his receipt of a 2009 NIH Director's Transformative R01 Award, 1 of 42 inaugural awards granted. This $3 million award will fund Dr. Lagasse’s project, “Organogenesis of Ectopic Tissue in Lymph Node,” which proposes to address some of the solutions to the development of complex 3-dimensional tissue models and a new paradigm by using lymph nodes as in vivo bioreactors to grow tissue or organ substitutes. His initial study and proof of concept will be centered around the generation of ectopic liver in lymph nodes for patients suffering end-stage liver diseases.
Today, a life-saving organ transplant is many patients only option when disease strikes. However, organs available for transplant cannot meet the current demand. Through his efforts and this project, Dr. Lagasse thinks he's found a way to get the body to grow replacement tissue for failing organs.
"There are patients out there dying because there is no solution to their problem," said Dr. Lagasse. "I'm really pushing toward eventually doing this in a patient, and I'm going to try to get there in 5 years. Every time I talk to a surgeon about this, they get very excited."
Accelerating the current pace of discovery through the support of highly innovative research is an ongoing effort at the NIH, but the NIH Director's T-R01 Program is new this year. Named for the standard investigator-initiated research project that the NIH supports, the R01, the T-R01s provide a new opportunity for scientists that is unmatched by any other NIH program. Since no budget cap is imposed and preliminary results are not required, scientists are free to propose new, bold ideas that may require significant resources to pursue. They are also given the flexibility to work in large, complex teams if the complexity of the research problem demands it.
In 2009, the NIH is awarding $348 million to encourage investigators to explore bold ideas that have the potential to catapult fields forward and speed the translation of research into improved health. The full complement of awards is granted under three innovative research programs supported by the NIH Common Fund’s Roadmap for Medical Research: the NIH Director’s Transformative R01 (T-R01) Awards, Pioneer Awards, and New Innovator Awards. The Common Fund, enacted into law by Congress through the 2006 NIH Reform Act, supports cross-cutting, trans-NIH programs with a particular emphasis on innovation and risk taking. A portion of these New Innovator Awards is also supported by funding from the American Recovery and Reinvestment Act.
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McGowan Institute faculty members Adriana Zeevi, PhD, professor of pathology and surgery at the University of Pittsburgh Medical Center (UPMC), Abhinav Humar, MD, chief of transplantation, staff physician, and professor in the department of surgery at UPMC, and George Mazariegos, MD, pediatric liver and intestine transplant surgeon at Children’s Hospital of Pittsburgh of UPMC and the Thomas E. Starzl Transplantation Institute, are co-authors on a study recently published which assessed the evolution of intestinal and multivisceral transplantation. The data, from the largest single-center experience of adult and pediatric intestinal and multivisceral transplantation, show that survival rates have improved with the advent of innovative surgical techniques, novel immunosuppressive protocols, and better post-operative management. The researcher team reported on the first 500 intestinal and multivisceral transplants conducted at the UPMC from 1990 to 2008, which represent more than 25 percent of the worldwide experience.
Over nearly 2 decades divided into 3 eras, 453 patients received 215 intestine, 151 liver-intestine, and 134 multivisceral transplants. Some of these patients are the longest surviving intestinal and multivisceral transplant recipients in the world, surviving more than 19 years post-transplant with excellent quality of life.
During what the researchers dubbed Era I (1990 to 1994), transplant recipients were treated with the immunosuppressive drug tacrolimus and steroids. In 1994, this protocol was discontinued due to high mortality and morbidity rates. The 5-year survival rate for these patients was 40 percent.
Era II (1995 to 2001) introduced the use of donor bone marrow to encourage organ acceptance. The 5-year survival rate for these patients was 56 percent.
During Era III (2001 to 2008), patients were given a pre-conditioning protocol with agents that deplete recipients’ own immune calls. Their post-transplant drug regimen was minimal and was initiated with tacrolimus, followed by steroids when necessary. Tacrolimus doses were subsequently spaced to a single dose twice to three times per week with a careful weaning process that started 3 to 6 months after transplant. Through the use of new immunosuppressive and management strategies, the 5-year survival rate for these patients increased to 68 percent, which is similar to any other abdominal and thoracic organ transplant procedure.
“The findings support the minimization of immunosuppressive therapy for intestinal and multivisceral transplant patients,” said lead researcher Kareem Abu-Elmagd, M.D., Ph.D., director, Intestinal Rehabilitation and Transplantation Center, Thomas E. Starzl Transplantation Institute, and professor of surgery, University of Pittsburgh School of Medicine. “Our research found that survival rates for such transplant recipients greatly increased as treatment strategies evolved; this included the reduction in the use of immunosuppressive therapy.”
McGowan Institute for Regenerative Medicine faculty member William J. Federspiel, PhD, the University of Pittsburgh's William Kepler Whiteford Professor of Chemical Engineering, Surgery and Bioengineering, and Director of the McGowan Institute’s Medical Devices Laboratory, oversees current laboratory research that is tackling fundamental problems associated with making artificial lungs more efficient and biocompatible, and is developing next generation artificial lungs or blood oxygenators. Dr. Federspiel is also a co-founder of ALung Technologies, Inc., a Pittsburgh-based medical start-up company, for which he currently serves as Chief Scientific Officer. ALung is the leading developer of a device—the Hemolung System—designed to replace or supplement ventilators in hospitals.
ALung recently announced that it will soon begin its Indian and German clinical trials on the company's Hemolung System which is expected to positively impact clinical outcomes and reduce the length of hospital stays by several days, resulting in a significant reduction of total medical costs for providers and insurers. The trials expected to begin in the fourth quarter of 2009 involve 5 patients in India and 20 patients in Germany.
The Hemolung System is designed to remove carbon dioxide and deliver oxygen directly to the patient's blood via a small catheter, inserted into the jugular or femoral vein, similar to acute kidney dialysis. This treatment is expected to provide a significant benefit over intubation and mechanical ventilation, in that it will allow the patient to talk and eat, and avoid sedation, while giving the lungs the opportunity to heal.
The Hemolung consists of a small cylindrical oxygenator that is approximately 4 inches in diameter. A cylindrical bundle of micro-porous hollow fiber membranes woven into a mat is wrapped in multiple layers around a central core. Oxygen flows through the hollow fiber membranes, while blood is circulated though the hollow fiber bundle. The core is spun at approximately 1000 RPM, dramatically enhancing gas exchange, as well as serving as a pump to move the blood through the external circuit.
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The Personal Mobility and Manipulation Appliance (PerMMA) is an electric-powered wheelchair with robotic arms attached. The arms can be manipulated by the wheelchair user or a remote user via the internet. The device is being developed to help wheelchair users that have limited hand function (people with high levels of spinal cord injury, Cerebral Palsy, etc.). McGowan Institute for Regenerative Medicine faculty member Rory Cooper, PhD, FISA/PVA Endowed Chair and a Distinguished Professor of the Department of Rehabilitation Science and Technology, School of Health and Rehabilitation Sciences, University of Pittsburgh, leads the PerMMA project which is a part of the Quality of Life Technology Engineering Research Center supported by the National Science Foundation and the Human Engineering Research Laboratories (HERL), which is a Veteran’s Administration Rehabilitation Research and Development Service Center of Excellence.
PerMMA's robotic arms can be manipulated either by the wheelchair user themselves or via remote control on the internet by a user at another location. Because the wheelchair has webcams attached that are positioned to see what the wheelchair user sees, a remote user is able to evaluate the wheelchair user's environment and control the robotic arms to assist them. So, if the wheelchair user needed assistance completing a task, they would call for help. An assistant, via the internet, would see the wheelchair user's environment and control PerMMa's robotic arms to help the wheelchair user complete the task. Some of the tasks PerMMa has done remotely include picking up objects and bringing them within the wheelchair user's reach, heating up food in a microwave, getting a drink of water, etc.
Recently HERL students demonstrated PerMMA to some prominent visitors that were in Pittsburgh for the G-20 Summit. The Prime Minister of Australia Kevin Rudd (pictured standing far center) and first lady Ms. Therese Rein (pictured seated) were both interested in the functionality of PerMMA. Also, the Chinese Minister of Commerce Mr. Chen Deming (pictured above right) and his colleagues received a demonstration of the technology.
The PerMMA project also receives support from the U.S. Department of Veterans Affairs, the National Institutes of Health, and the Paralyzed Veterans of America.
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AWARDS AND RECOGNITIONS
McGowan Institute for Regenerative Medicine, along with the University of Pittsburgh School of Engineering, congratulates the recipient of the 2009 Board of Visitor’s (BOV’s) Faculty Award: Steven Little, PhD, McGowan Institute faculty member and Assistant Professor and Bicentennial Alumni Faculty Fellow, University of Pittsburgh Departments of Chemical Engineering, Bioengineering, and Immunology. Researchers in Dr. Little’s lab focus upon therapies that are biomimetic in that they replicate the biological function and interactions of living entities using synthetic systems.
The purpose of the BOV’s Faculty Award is to recognize the single-most outstanding member of the School of Engineering faculty who has had the most productive previous academic year in areas such as program development, leadership in the development of graduate research programs, meritorious recognition by peers at the national level, and special recognition as a teacher.
Congratulations, Dr. Little!
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McGowan Institute for Regenerative Medicine faculty member David Hackam, MD, PhD, a pediatric surgeon at Children’s Hospital of Pittsburgh of UPMC, and researcher at the University of Pittsburgh School of Medicine, has been named 1 of 12 winners of the prestigious Hartwell Individual Biomedical Research Awards for his research into necrotizing enterocolitis (NEC), a leading killer of premature infants. The Hartwell Individual Biomedical Research Awards provide each investigator $100,000 per year for 3 years. The 12 award-winning research proposals represent innovative and cutting-edge technology from disciplines that include molecular biology, diagnostics, imaging, infectious diseases, tissue engineering, and neurobiology.
NEC is a severe inflammatory disease of the intestine that affects thousands of premature infants in the United States each year. In extreme cases, NEC leads to perforation of the intestine, a condition that can be fatal if not treated with emergency surgery.
Dr. Hackam and his team have identified a genetic “switch” that is turned on in infants who develop NEC. This grant, funded by The Hartwell Foundation, will enable continued work in the laboratory toward developing new medications to turn this switch off.
In the premature infant intestine, a “switch” called toll-like receptor 4 (or TLR4), is “turned on” in premature babies by bacteria and other stressors, leading to NEC. Dr. Hackam and team discovered that turning off the TLR4 switch in mice can reverse the intestinal damage and restore intestinal health.
To identify new medications that can turn off the TLR4 switch, and thus both prevent and cure NEC, Dr. Hackam and colleagues, including Paul Johnston, Ph.D., from the University of Pittsburgh Drug Discovery Institute, will use high-content screening to assess over 200,000 chemicals to determine which can keep the TLR4 switch in the “off” position.
Congratulations, Dr. Hackam!
Photograph: The Hartwell Foundation. Read more…
The McGowan Institute for Regenerative Medicine congratulates faculty member Michael Boninger, MD, a renowned researcher in spinal cord injury and assistive technology, on his recent appointment as the University of Pittsburgh School of Medicine chair of the Department of Physical Medicine and Rehabilitation (PM&R). Pitt’s Department of PM&R is ranked No. 1 in research funding from the National Institutes of Health. The department currently comprises 33 full-time, multidisciplinary faculty members who train and educate the next generation of rehabilitation physicians and researchers.
Since November 2007, Dr. Boninger has directed the UPMC Institute for Rehabilitation and Research (IRR), which combines medical care and research to help patients regain independence and enhance their quality of life. The IRR recently opened new clinical and research quarters, offering an expansion of specialized services for stroke, pain management, and brain and spinal cord injuries, among others. Dr. Boninger will continue serving this role along with his position as associate dean for medical student research at the Pitt School of Medicine and his secondary Pitt appointments in the School of Engineering and School of Health and Rehabilitation Sciences.
Dr. Boninger is recognized for his extensive research on spinal cord injury, assistive technology, and overuse injuries, particularly those associated with manual wheelchair propulsion. He currently receives research funding from the National Institutes of Health, the National Institute on Disability and Rehabilitation Research, the U.S. Department of Defense, the U.S. Army’s Telemedicine and Advanced Technology Research Center, and the U.S. Department of Veteran Affairs. Also interested in medical student research and education, he has authored more than 150 peer-reviewed journal publications, 20 book chapters, and nearly 200 refereed conference proceedings.
Dr. Boninger is director of Pitt’s Model Center on Spinal Cord Injury and medical director of the Human Engineering Research Laboratories (HERL), a joint venture among UPMC, the University of Pittsburgh, and the VA Pittsburgh Healthcare System, and designated a “Center of Excellence for Wheelchairs and Related Technology” by the U.S. Department of Veterans Affairs.
Congratulations, Dr. Boninger!
Read more…
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#74 – Robert Bowser, PhD |
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| Authors: | BP Witteman, TJ Foxwell, S Monsheimer, A Gelrud, GM Eid, A Nieponice, RW O'Rourke, T Hoppo, ND Bouvy, SF Badylak, BA Jobe. |
| Title: | Transoral Endoscopic Inner Layer Esophagectomy: Management of High-Grade Dysplasia and Superficial Cancer with Organ Preservation. |
| Summary: | Limitations of endoscopic therapies for Barrett's esophagus and superficial cancer include a compromised histological assessment, the need for surveillance, subsequent procedures, and stricture formation. Circumferential en bloc resection of the mucosa-submucosa complex followed by deployment of a biologic scaffold onto the remaining muscularis propria may address these concerns. The objective of this study was to determine technical feasibility of transoral resection of the esophageal lining. MATERIALS AND METHODS: Transoral endoscopic inner layer esophagectomy was performed in ten swine. Endpoints included procedure duration, hemorrhage, number of perforations, and adequacy of resection length and depth. RESULTS: Procedures were successfully completed in all animals without perioperative mortality. Procedure times averaged 179 min (range 125-320). No perforations were found, and a mean of 1.7 (0-4) interventions for hemorrhage was required. Complete longitudinal resection was achieved in nine of ten animals. Resection depth included all mucosal layers in 100% of tissue sections, the submucosal layers, SM1 in 100%, and SM2 in 96%. A portion of SM3 was adherent to the muscularis propria in 70%. CONCLUSION: Transoral endoscopic resection of the inner esophageal layers was feasible and reproducible. This technique may facilitate a single-step definitive treatment and staging tool for early neoplastic lesions, obviating the need for esophagectomy. |
| Source: | Journal of Gastrointestinal Surgery. 2009 Oct 14. |
| PI | J. Peter Rubin |
| Title | Biomedical Translational Initiative: Structural Fat Grafting for Craniofacial Trauma |
| Description | Facial trauma injuries, especially those sustained in military combat, are characterized by destruction of bone and soft tissue anatomy. While the bony skeleton can often be reconstructed, the overlying soft tissue is difficult to restore. Importantly, it is the structure of the soft tissue that imparts the normal human form, and adequate reconstruction of soft tissue defects allows trauma victims to reintegrate into society. Current procedures for soft tissue reconstruction of the face primarily involve tissue flap reconstruction procedures. Synthetic (e.g silicone) implants for soft tissue trauma of the face have no practical role and are fraught with complications and poor results. Tissue flap operations are extensive, often including microvascular surgery, and do not precisely correct the deformities. Autologous fat grafting, performed through a minimally invasive means, has the potential to correct deformities with much greater precision and lower morbidity. While autologous adipose tissue grafting may provide a minimally invasive means of accurately restoring facial soft tissue structure after trauma, graft resorption is a significant limitation. In this study, we capitalize upon two enabling technologies to make fat grafting effective for the wounded soldier and validate outcomes: 1) Specialized instrumentation for fat tissue harvest (Lipokit, Medi-Khan USA, Inc , California) that concentrates adipose stem cells, and 2) Specialized instrumentation for fat tissue injection (Coleman Cannula System, Mentor Medical, California) that allow for precise placement of appropriately sized aliquots of fat within the injured tissues and adjust to irregularly shaped and scarred tissue beds. Both of these devices are approved by the FDA. We hypothesize that results from fat grafting for facial trauma, made possible by these two enabling technologies, will show good restoration of tissue volume and craniofacial form. Additionally, we hypothesize that the results will be durable and patient quality of life improved. Validation will be accompanied by a plan to make this technology broadly available to physicians treating combat injuries. The specific aims of the study are: 1) Treat disfiguring craniofacial injuries in 20 soldiers with fat grafting to improve form with a high level of precision. Facial appearance and persistence of treatment effect will be assessed using aesthetic grading scales, state of the art 3D photography, and high resolution CT scanning with 3D reconstruction. Patients will be followed for 9 months after treatment to define long term outcomes. 2) Assess biologic properties of the cells within the fat graft and correlate with clinical outcomes. This will include adipose stem cell yield per volume of fat tissue, cell proliferation, capacity for adipogenic differentiation, lipolysis, and cell sub-population analysis by multiparameter flow cytometry. Results of these assays will be correlated with graft volume retention to search for predictors of good clinical outcome that are related to variation on adipose biology between subjects. |
| Source | Department of Defense |
| Term | 10/01/09 to 3/31/2010 |
| Amount: | $1,618,653 ($1,141,964 direct / $ 476,689 indirect) |
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