May 2011 | VOL. 10, NO. 5 | www.McGowan.pitt.edu
Regenerative Medicine and the Body Future
Ten research programs along with their corresponding McGowan Institute for Regenerative Medicine faculty were highlighted in the May issue of Pittsburgh magazine. Writer Melissa Rayworth notes that, "Teams of McGowan-affiliated engineers and scientists are tackling medical challenges and designing replacement organs that sometimes seem straight out of a sci-fi novel."
Featured regenerative medicine projects in Ms. Rayworth's story include:
- Battling Esophageal Cancer: Stephen Badylak, DVM, PhD, MD; Blair Jobe, MD
- Conquering Type 1 Diabetes: Massimo Trucco, MD
- Pediatric Liver Cell Therapy: Ira Fox, MD
- Growing "Ectopic" Organs: Eric Lagasse, PharmD, PhD
- Whole Organ Engineering: Alex Soto-Gutierrez, MD, PhD
- Corneal Tissue Repair and Regeneration: James Funderburgh, PhD
- Pediatric Ventricular-Assist Device (PediaFlow): Peter Wearden, MD, PhD; Harvey Borovetz, PhD
- Muscle Healing: Stephen Badylak, DVM, PhD, MD; J. Peter Rubin, MD
- Blood Vessel Tissue Engineering: David Vorp, PhD; William Wagner, PhD
Craniofacial Bone Tissue Engineering: Charles Sfeir, DDS, PhD; Prashant Kumta, PhD; Bernard Costello, MD, DMD
The McGowan Institute for Regenerative Medicine operates under three main pillars of research – Medical Devices and Artificial Organs, Tissue Engineering and Biomaterials, and Cellular Therapies – with a commitment to rapid Clinical Translation. Ms. Rayworth's article highlighted projects focused on all of these program elements:
- The goal of the Medical Devices and Artificial Organs program is to develop and refine technologies that will maintain, improve, or even restore the function of diseased organs. Research in this area focuses on efforts to replace tissue function with entirely synthetic constructs (fully artificial organs) or with constructs made of both synthetic and cellular components (biohybrid organs).
- Within the Tissue Engineering and Biomaterials program, Institute researchers are working to create biodegradable polymeric materials with appropriate mechanical properties that can be modified to incorporate biological activity. Using these biodegradable materials, tissue engineers are combining temporary scaffolds with cellular components to regenerate tissue.
- The field of cellular therapeutics is vast, affording an exciting array of potential applications. Within the Cellular Therapies program, researchers are working with a variety of cells, including stem cells and genetically manipulated cells, to repair or replace cellular function.
- In the area of clinical translation, through its affiliation with the University of Pittsburgh Medical Center, the McGowan Institute for Regenerative Medicine has access to one of the nation's finest health systems. In fact, the University of Pittsburgh Medical Center is consistently ranked by U.S. News and World Report as one of the best health systems in the country, with a well-established and well-organized clinical trial infrastructure, and a large, diverse population from which to draw study subjects. In addition, the Institute collaborates with the US Department of Defense in the clinical assessment of regenerative medicine-based therapies.
McGowan Institute for Regenerative Medicine faculty member Savio Woo, PhD, distinguished university professor of bioengineering in the Swanson School of Engineering, recently delivered the Inaugural Lecture for the Professors Albert Kobayashi and Jim Morrison Endowed Lectureship in the Department of Mechanical Engineering at the University of Washington (UW). Both Professors Kobayashi and Morrison had very long and distinguished careers and served as leaders in the ME department. Between 1965 and 1970, Dr. Woo was a graduate student at UW and was mentored by Professor Kobayashi.
Professor Kobayashi retired from UW in 1997 but is continuing his research in fracture mechanics. Professor Kobayashi is a member of the National Academy of Engineering, an Honorary Member of the Society for Experimental Mechanics (SEM), a Fellow of the American Society of Mechanical Engineers (ASME), and a member of the American Academy of Mechanics. He held numerous offices in SEM and ASME and was the president of SEM, 1989-90. In addition to his many awards from SEM, Japan Society of Mechanical Engineering, ASME, and American Society for Engineering Education, he was awarded the Order of Rising Sun, Gold Rays with Neck Ribbon from the Emperor of Japan on April 29, 1997. He was elected to the ME Hall of Fame in 2006. Three international symposiums honoring his 60th and 70th birthdays and his retirement were held in San Antonio, Tokyo, and Seattle, respectively. A mini-symposium in his honor was held in Austin 2007.
During his 36-year academic career Jim Morrison was an inspirational and beloved teacher to multiple generations of UW Mechanical Engineering students. In 2004 one of his former students, Henry Schatz (BSME '64), endowed the Morrison Undergraduate Scholarship Fund and the Morrison Chair in Mechanical Engineering, both of which were named in Jim's honor.
McGowan Institute for Regenerative Medicine director Alan Russell, PhD, distinguished university professor of surgery and professor in the University of Pittsburgh departments of Bioengineering, Chemical Engineering, and Rehabilitation Science and Technology, received a monetary gift award of $70,000 from ALung Technologies Inc. in support of research efforts in the area of respiratory assist devices. The award was presented to Dr. Russell by ALung's Peter DeComo, Chairman and Chief Executive Officer, and Nicholas Kuhn, Chief Operating Officer. ALung believes that the gift augments ongoing studies with the McGowan Institute for Regenerative Medicine and its Medical Devices Laboratory headed by William Federspiel, PhD, the William Kepler Whiteford professor of bioengineering, chemical engineering, and surgery, University of Pittsburgh. ALung's supportive effort is a good example of how university spin-out companies can provide support back to the University.
From technology originated at the McGowan Institute for Regenerative Medicine, ALung is developing the device—the Hemolung Respiratory Assist System—designed to replace or supplement ventilators in hospitals. ALung recently reported that the third German Hemolung patient – the fifth world-wide – recovered well from acute lung exacerbation within 6 days on the Hemolung Respiratory Assist System and received a double-lung transplant 4 weeks later.
The Hemolung Respiratory Assist System removes carbon dioxide and delivers 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 provides 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.
Minimally invasive esophagectomy has advanced to the point where it offers significant advantages over open esophagectomy in terms of operative morbidity and mortality, judging by the results of a single-center review of 980 cases headed by McGowan Institute for Regenerative Medicine affiliated faculty member James D. Luketich, MD, FACS, the Henry T. Bahnson Professor of cardiothoracic surgery, chief of the division of thoracic and foregut surgery at the University of Pittsburgh School of Medicine, and director of the Heart, Lung and Esophageal Surgery Institute at the University of Pittsburgh Medical Center (UPMC). The published series indicate that the operative mortality of open esophagectomy is 8%-21%, although a very few high-volume medical centers have reported rates as low as 3%. McGowan Institute for Regenerative Medicine affiliated faculty member Blair Jobe, MD, associate professor of surgery at the University of Pittsburgh and in the Heart, Lung and Esophageal Surgery Institute at the UPMC, is a co-author on the study.
"There is a perception among patients and physicians that open esophagectomy is to be avoided at all costs because of its substantial morbidity," Dr. Luketich said at the annual meeting of the American Surgical Association.
In his review of 980 consecutive, elective, non-urgent, minimally invasive esophagectomies, the 30-day mortality was just 1.8%. Median operative time was 6.7 hours, which dropped to 4 hours in cases that were not done by residents. The median ICU stay was 2.0 days, with a median hospital length of stay of 8 days. A median 21 lymph nodes were dissected, and 98% of cases had negative surgical margins.
"A less invasive surgical approach for esophageal cancer would improve the standard of care by reducing morbidity and shortening hospital stays and time to return to daily activities. If successful, surgeons might see more early-stage referrals from Barrett’s patients now in surveillance," added Dr. Luketich.
A modified Ivor-Lewis approach involving laparoscopic conduit preparation, videothoracoscopic esophageal mobilization, and intrathoracic anastomosis is preferable to the McKeown approach when the minimally invasive route is chosen. It entails fewer conduit complications and lower mortality, according to Dr. Luketich.
In this series, 49% of patients underwent a modified McKeown approach involving videothoracoscopic esophageal mobilization, laparoscopic conduit preparation, and neck anastomosis, whereas 51% were treated via the modified Ivor-Lewis approach.
This was a nonrandomized study, but patients in the two study arms were essentially the same in terms of baseline characteristics. In all, 95% were operated on for malignant disease, 80% were men, and 31% received preoperative chemotherapy and/or radiotherapy. Patients who were operated on in the most recent years of the series underwent the Ivor-Lewis approach because Dr. Luketich has come to prefer it. He noted that most trainees are more comfortable with it; they have far more experience with operating in the chest than the neck.
Furthermore, outcomes are better than results with the McKeown approach. Indeed, the 30-day mortality rate was just 1.2% with the Ivor-Lewis minimally invasive esophagectomy chest (MIE-chest) approach vs. 2.5% with the McKeown MIE-neck approach. The major morbidity rate was 31% in the MIE-chest group, significantly less than the 36% with the MIE-neck group. This difference was driven by the increased risk of laryngeal nerve injury with the McKeown approach. The incidence of vocal cord paresis or paralysis was 8% in the MIE-neck patients, compared with 1% in the MIE-chest group.
Rates of other complications were closely similar in the two groups: 6% for empyema, 5% for acute respiratory distress syndrome, 5% for pulmonary embolism, 2% for acute MI, 3% for heart failure, and 5% for anastomotic leak requiring surgery.
Quality of life assessments using the Short Form-36 indicate that by 90 days, post-MIE patients scored in the age-adjusted normal range.
McGowan Institute for Regenerative Medicine affiliated faculty member John Kellum, MD, FACP, FCCM, professor of critical care medicine at the University of Pittsburgh, is the co-chair of Kidney Disease Improving Global Outcomes (KDIGO), an international program of the National Kidney Foundation (NKF). As reported by Kate Johnson, Medscape Medical News, nephrologists got a sneak peak at the first-ever clinical practice guidelines on acute kidney injury, announced at the NKF's 2011 Spring Clinical Meetings.
The guidelines were developed by KDIGO and should be published this summer. They are a push toward increasing awareness about the prevention, recognition, and management of acute kidney injury (AKI), said Dr. Kellum.
"AKI is a prevalent problem. Upwards of two thirds of ICU [intensive care unit] patients and as many as 20% of all hospitalized patients develop acute kidney injury, so it’s a massive issue," he told Medscape Medical News. "It’s really not been well appreciated that even mild injury, resulting in small changes in renal function acutely, can have significant short-term and long-term consequences," he explained.
According to KDIGO, research in the past 10 years has identified preventable risk factors and improvements in AKI management, "which are not widely known and invariably practiced worldwide, resulting in lost opportunities to improve the care and outcomes of patients with AKI."
The guidelines, which should be published this summer, are aimed at "frontline physicians" and cover everything from defining and diagnosing AKI, the recognition and modification of risk factors, and treatment and follow-up, said Dr. Kellum.
"These guidelines recognize that frontline physicians — not just nephrologists, or intensivists — but emergency room physicians, family practitioners, general internists, radiologists, cardiologists — all the sorts of people that are likely to see these patients early on — really need to be aware of the kinds of things that lead to acute kidney injury and what kinds of things can be done about it."
McGowan Institute for Regenerative Medicine affiliated faculty member James Luketich, MD, FACS, the Henry T. Bahnson Professor of cardiothoracic surgery, chief of the division of thoracic and foregut surgery at the University of Pittsburgh School of Medicine, and director of the Heart, Lung and Esophageal Surgery Institute at the University of Pittsburgh Medical Center, along with researchers at the University of Pittsburgh Cancer Institute (UPCI) recently reported that patients with advanced non-small cell lung cancer can safely take an experimental oral drug intended to protect healthy tissue from the effects of radiation.
The team’s findings support further clinical testing of the agent, called manganese superoxide dismutase (MnSOD) plasmid liposome, to determine if giving it alongside chemotherapy and radiation will prevent damage to normal cells that is the typical cause of side effects in cancer treatment, said senior investigator Joel S. Greenberger, MD, professor and chair, Department of Radiation Oncology, Pitt School of Medicine, and co-director of the lung and esophageal cancer program at UPCI.
“If we can sufficiently protect tissues that are normal, we should be able to deliver our cancer treatments more effectively and perhaps even at higher doses,” he explained. “Our aim is to improve the quality of life of patients by minimizing side effects while providing the best treatment for their cancers.”
Preclinical testing has shown that generating higher levels of MnSOD in healthy cells can suppress the production of inflammatory molecules and reduce cell death, micro-ulceration, and esophagitis. Because the agent is delivered to healthy tissue, it does not protect tumor cells from radiation treatment. In fact, Dr. Greenberger noted, experiments hint that when it is given to cancer cells, it actually encourages cell death because of abnormalities in their cellular metabolism.
He and his team plan to investigate the use of MnSOD plasmid liposome for other cancers, such as protecting the rectum from radiotherapy for prostate cancer and protecting the bladder during ovarian or endometrial cancer treatment.
AWARDS AND RECOGNITIONS
McGowan Institute for Regenerative Medicine affiliated faculty member Joon Sup Lee, MD, clinical director, University of Pittsburgh Medical Center (UPMC) Cardiovascular Institute, has been named co-director of UPMC’s newly created Heart and Vascular Institute (HVI). UPMC has combined the operations of its departments of cardiac surgery, vascular surgery, and cardiology to create the HVI, which will deliver world-class and compassionate care to patients while furthering the hospital system’s commitment to cardiovascular innovations. Along with Dr. Lee, Victor Morell, M.D., chief, pediatric cardiothoracic surgery, Children's Hospital of Pittsburgh (CHP) of UPMC, and Michel Makaroun, M.D., chief, UPMC division of vascular surgery, will serve as co-directors.
The HVI will consist of University of Pittsburgh Physicians (UPP) from the Cardiovascular Institute (CVI) and from the Division of CT surgery. The areas will merge on July 1, after which the CVI will no longer exist.
Dr. Lee, who will head cardiology at the HVI, had been with the UPP CVI since 1996. Dr. Lee has been the CVI’s clinical director since 2003.
Dr. Morell, who will head cardiac surgery in the HVI, also will serve as vice-chair and director of cardiovascular services for the Department of Cardiothoracic Surgery. Dr. Morell was chosen after a national search to fill the position. Dr. Morell has been chief of cardiothoracic surgery at CHP since 2004 and the associate program director of the thoracic surgery residency at the University of Pittsburgh since 2005.
Dr. Makaroun will oversee vascular surgery at the HVI. He was appointed UPMC’s chief of vascular surgery in 1999. In addition to his new role at the HVI, Dr. Makaroun will continue to be the division chief of vascular surgery.
UPMC is ranked among America’s best hospitals by U.S. News & World Report for heart care and heart surgery, and has one of the largest cardiac catheterization programs in the country. Its physicians have been leaders in implanting ventricular-assist devices and in developing minimally invasive techniques for vascular procedures.
McGowan Institute for Regenerative Medicine faculty member Steven Little, PhD, Assistant Professor and Bicentennial Alumni Faculty Fellow, Departments of Chemical Engineering, Bioengineering, Immunology, has been elected as the chair of the Drug Delivery Special Interest Group of the Society for Biomaterials. Dr. Little will serve the 2011-2013 term of office. The Society's Special Interest Groups provide a forum for networking and new ideas within a focused environment.
The Drug Delivery Special Interest Group deals with the science and technology of controlled release of active agents from delivery systems. Controlled drug release is achieved by the use of diffusion, chemical reactions, dissolutions, or osmosis, used either singly or in combination. While the vast majority of such delivery devices are based on polymers, controlled release can also be achieved by the use of mechanical pumps. In a broader sense, controlled release also involves control over the site of action of the active agent, using the active agent using pro-drugs, targetable water soluble polymers or various microparticulate systems. Relevant aspects of toxicology, bioavailability, pharmacokinetics, and biocompatibility are also included.
The Society for Biomaterials is a professional society which promotes advances in biomedical materials research and development by encouragement of cooperative educational programs, clinical applications, and professional standards in the biomaterials field. Biomaterials scientists and engineers study cells, their components, complex tissues and organs, and their interactions with natural and synthetic materials and implanted prosthetic devices, as well as develop and characterize the materials used to measure, restore, and improve physiologic function, and enhance survival and quality of life.
McGowan Institute for Regenerative Medicine faculty member Freddie Fu, MD, 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, was a featured physician in the May issue of Pittsburgh magazine. Writer Melissa Rayworth described Dr. Fu “as an educator teaching medical professionals about a unique orthopaedic surgery technique and an ‘ambassador,’ spreading the good news about Pittsburgh and pushing for positive change, including greater diversity, in his profession.”
In her report Ms. Rayworth covers a day-in-the-life of Dr. Fu. When not on the road (almost 4 months of the year Dr. Fu is crisscrossing America), Dr. Fu’s days in Pittsburgh may begin as early as 4 am and end as late as 11:30 pm. In addition to performing surgery, Dr. Fu might also be participating in sports medicine conferences, Orthopaedic Grand Rounds, anatomic ACL reconstruction meetings, medical student meetings, patient clinic, visits to members of the Pittsburgh Ballet Theatre (Dr. Fu is their head physician), catching up on local and international news, phone calls, and emails.
Through his recognition, Dr. Fu promotes the medical opportunities now available in the Pittsburgh region as well as influencing the face of orthopaedic medicine to include men and women students and colleagues from diverse ethnic backgrounds.
Dr. Fu says he is “helping people of different cultures and genders enter my field.” If a multitude of unique voices and perspectives can be brought into his program, he says, “it becomes a better specialty” because each brings slightly different skills and ideas.
Dr. Fu joined the University of Pittsburgh School of Medicine faculty in 1982 as an assistant professor of orthopaedic surgery and director of sports medicine. He became clinical vice chairman of the department of orthopaedic surgery in 1990 and executive vice chairman in 1994. Dr. Fu was also instrumental in the establishment of the Sports and Preventive Medicine Institute in 1985. Under Dr. Fu's medical directorship over 12 years, the facility - now called the University of Pittsburgh Medical Center for Sports Medicine - has grown into and remains one of the world's largest, most comprehensive and highly regarded sports medicine centers. He also was instrumental in the establishment of the University of Pittsburgh's Sports Medicine Fellowship Program, which has attracted more than 600 surgeons who travel from all over the world to learn surgical techniques and conduct research with Dr. Fu and his colleagues in the department of orthopaedic surgery and UPMC's Musculoskeletal Research Center.
McGowan Institute for Regenerative Medicine affiliated faculty member George Michalopoulos, MD, PhD, is the recipient of the American Liver Foundation’s Distinguished Scientific Achievement Award for 2010. The award honors scientists who undertake novel work, mentor other researchers, and attract substantial funding over the course of their careers.
Professor Michalopoulos is the chair of University of Pittsburgh’s Department of Pathology. Dr. Michalopoulos specializes in liver regeneration and was the first to identify hepatocyte growth factor and its receptor, c-Met. Dr. Michalopoulos, says it’s an “acrobatic balance” to do his own work while mentoring others and managing the department.
A professor in and chair of University of Pittsburgh’s Department of Pathology, Dr. Michalopoulos specializes in liver regeneration and was the first to identify hepatocyte growth factor and its receptor, c-Met. Dr. Michalopoulos, says it’s an “acrobatic balance” to do his own work while mentoring others and managing the department.
Dr. Michalopoulos received his medical doctoral degree at Athens University School of Medicine in 1969. A residency in Anatomic Pathology and a Ph.D. study in Oncology were completed at the Wisconsin Medical Center, in Madison, in 1977. Dr. Michalopoulos moved to Duke University as an Assistant Professor in 1977, and stayed at Duke University until 1991. He then moved to Pittsburgh and joined the university faculty in April of 1991. In addition to his current appointment, Dr. Michalopoulos also served as Associate Vice Chancellor for Health Sciences and Interim Dean of the School of Medicine from November of 1995-1998.
The Regenerative Medicine Podcasts remain a popular web destination. Informative and entertaining, these are the most recent interviews:
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Hoppo T, Komori J, Manohar R, Stolz DB, Lagasse E.
Rescue of lethal hepatic failure by hepatized lymph nodes in mice.
BACKGROUND & AIMS: Hepatocyte transplantation is a potential therapeutic approach for liver disease. However, most patients with chronic hepatic damage have cirrhosis and fibrosis, which limit the potential for cell-based therapy of the liver. The development of an ectopic liver as an additional site of hepatic function represents a new approach for patients with end-stage liver disease. We investigated the development and function of liver tissue in lymph nodes in mice with liver failure.
METHODS: Hepatocytes were isolated from 8- to 12-week-old mice and transplanted by intraperitoneal injection into 8- to 12-week-old fumarylacetoacetate hydrolase mice (Fah(-/-)), a model of the human liver disease tyrosinemia type I. Survival was monitored and the locations and functions of the engrafted liver cells were determined.
RESULTS: Lymph nodes of Fah(-/-) mice were colonized by transplanted hepatocytes; Fah(+) hepatocytes were detected adjacent to the CD45(+) lymphoid cells of the lymphatic system. Ten weeks after transplantation, these mice had substantial improvements in serum levels of transaminases, bilirubin, and amino acids. Homeostatic expansion of donor hepatocytes in lymph nodes rescued the mice from lethal hepatic failure.CONCLUSIONS: Functional ectopic liver tissue in lymph nodes rescues mice from lethal hepatic disease; lymph nodes therefore might be used as sites for hepatocyte transplantation.
Gastroenterology. 2011 Feb;140(2):656-666.e2. Epub 2010 Nov 9.
The Role of mTOR (mammalian Target Of Rapamycin) Complex 1 and 2 in liver regeneration and ectopic liver organogenesis
03/09/11 – 1/9/12
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