July 2011 | VOL. 10, NO. 7 | www.McGowan.pitt.edu
Regenerative Medicine and the Body Future
July marks the 10th anniversary of the formation of the McGowan Institute for Regenerative Medicine. The starting organizational entities were the McGowan Center for Artificial Organ Development and about 75 faculty, who conducted independent research programs in their respective departments. As the title suggests, the original McGowan Center's focus was on the development of artificial organs and supporting technologies such as drag reducing agents, drugs that reduce damage from angioplasty, and scaffolding used to support cells for tissue-engineered applications, such as a myocardial patch.
Through faculty led strategic planning the vision, mission and programmatic focus evolved for a multidisciplinary team of what is now 230 McGowan affiliated faculty who are advancing the science and the clinical implementation of a multitude of regenerative medicine-based therapies.
The attached (PDF) provides an overview of the formation and growth of the Institute and a synopsis of the achievements of the McGowan Institute affiliated faculty.
McGowan Institute for Regenerative Medicine faculty member J. Peter Rubin, MD, a noted expert on adult stem cells derived from fat tissue and body contouring surgery, was recently named chief of the division of plastic and reconstructive surgery by the University of Pittsburgh School of Medicine.
"Peter Rubin has distinguished himself as one of the leading plastic surgeons and surgical scientists in the United States. He is well-funded as a scientific investigator, receiving support from the National Institutes of Health and the Department of Defense. He leads a program that is devising innovative strategies for the use of adipose (fat)-derived stem cells to not only address problems of tissue regeneration but also other diseases that benefit from stem cell-based therapies," said McGowan Institute for Regenerative Medicine affiliated faculty member Timothy Billiar, MD, George Vance Foster Professor and Chair, Department of Surgery at the University of Pittsburgh School of Medicine. "I am confident that under Dr. Rubin's leadership, plastic surgery will continue to thrive at the University of Pittsburgh as one of the leading programs in the United States."
In addition to his role as division chief, Dr. Rubin is director of the UPMC Life After Weight Loss Program, a leading center for plastic surgery after weight loss. He is co-director of the Adipose Stem Cell Center and co-director of the UPMC Aesthetic Plastic Surgery Center. His laboratory research focuses on applications of adult adipose-derived stem cells for restoring damaged tissues after trauma and cancer therapy. He currently is the lead investigator for clinical trials using technologies designed to improve the lives of wounded military personnel.
In his research, Dr. Rubin has found that fat tissue is a rich source of adult stem cells, which can be induced to turn into other types of tissue, or introduced into a site of injury and serve in a healing capacity. Dr. Rubin hopes the fat cells can eventually be used in the treatment of human diseases, and is especially interested in using them to repair breasts after breast cancer surgery.
The National Cancer Institute in collaboration with the National Institute of Biomedical Imaging and BioEngineering funded a 3-year study under the leadership of Dr. Rubin to examine the feasibility of using human preadipocytes, seeded on microcarrier scaffolds that can be injected into an animal model to produce a durable engineered soft tissue replacement. Human preadipocytes are derived from human adipose tissue. Co-investigators on the study included McGowan Institute for Regenerative Medicine faculty members Kacey Marra, PhD, Albert Donnenberg, PhD, and Vera Donnenberg, PhD. McGowan Institute for Regenerative Medicine deputy director Stephen Badylak, DVM, PhD, MD, served as an advisor to the research team. According to the team, fat-derived stem cells can be safely used to aid reconstruction of breast tissue after mastectomy as long as there is no evidence of active cancer.
Dr. Rubin's work is also funded by the U.S. Department of Defense Office of Technology Transition, an effort that was designed to jumpstart human trials of innovative research programs that aim to replace scars and defects with healthy, functional tissues.
Dr. Rubin has published extensively in the medical literature and has received numerous awards for his research work, most notably for the Presidential Early Career Award for Science and Engineering and for his National Institutes of Health-funded work with fat-derived stem cells in 2007.
According to a University of Pittsburgh study led by McGowan Institute for Regenerative Medicine affiliated faculty member Blair Jobe, MD, professor and director of esophageal research and esophageal diagnostics and therapeutic endoscopy, Department of Cardiothoracic Surgery, Pitt School of Medicine, medically treated patients with mild or no symptoms of gastroesophageal reflux disease (GERD) are at higher risk for developing esophageal cancer than those with severe GERD symptoms. McGowan Institute for Regenerative Medicine affiliated faculty member James Luketich, MD, 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, was a member of the research team.
Many patients who develop adenocarcinoma, a common form of esophageal cancer, are unaware that they have Barrett's esophagus – a change in the cells lining the esophagus often due to repeated stomach acid exposure. In some cases, Barrett's esophagus develops into esophageal cancer.
"Typically, patients with severe GERD symptoms are screened for Barrett's esophagus, but those with mild or absent symptoms are not. Unfortunately, many patients who develop adenocarcinoma don't know that they have Barrett's esophagus until it has transformed into cancer and become advanced, leading to obstruction," said principal investigator Dr. Jobe.
The study included 769 GERD patients who presented for their first upper endoscopy, in which a flexible endoscopic camera is guided through the esophagus and stomach to look for tissue changes.
"Our research indicates that even patients without severe symptoms may benefit from Barrett's esophagus screening," Dr. Jobe noted. "If GERD patients are screened early enough, there is a better chance that Barrett's esophagus can be identified before it becomes cancerous," he stated. "We are learning that the chronic and long-term use of PPIs may not be entirely without consequences and may lead to more insidious problems such as calcium malabsorption or cause one to be asymptomatic in the face of continued esophageal injury from GERD."
Dr. Jobe and his Pitt colleagues have established the Barrett's Esophagus Risk Consortium (BERC), in which primary care patients are being screened with in-office, small-caliber, unsedated endoscopy in an attempt to better understand risk factors for the condition as well as lower the threshold for screening. The multicenter effort is funded by the National Institutes of Health.
McGowan Institute for Regenerative Medicine affiliated faculty member Joon Sup Lee, MD, clinical director of the UPMC Cardiovascular Institute, associate chief in the Division of Cardiology at the University of Pittsburgh School of Medicine, and associate professor in the Department of Medicine at the University of Pittsburgh, served as the principal investigator of the Pittsburgh clinical trial site for the Autologous Cellular Therapy CD34-Chronic Myocardial Ischemia (ACT34-CMI) Trial (March 2006-2009 and October 2007-June 2010, sponsored by Baxter Healthcare Corporation). The ACTC34-CMI trial was the first human Phase II adult stem cell therapy study in the United States designed to investigate the efficacy, tolerability, and safety of blood-derived selected CD34+ stem cells to improve symptoms and clinical outcomes in patients with chronic myocardial ischemia (CMI), a severe form of coronary artery disease.
The results of this Phase II adult stem cell therapy study indicated that an injection of stem cells into the heart could offer hope to many of the 850,000 Americans whose chest pain doesn't subside even with medicine, angioplasty, or surgery. Patients who received the new treatment reported half as many chest pain episodes and improved exercise capability compared to those who received a placebo.
The study was the first randomized, controlled trial of stem-cell therapy to show significant improvements in both chest pain and exercise tolerance – the two debilitating features of "refractory" angina, or chest pain that persists in spite of medication, surgery, or angioplasty.
Researchers used the patients' CD34+ stem cells, which circulate through the blood and are important in forming new blood vessels. The stem cell injection is meant to create new vessels in the diseased heart muscle, improving blood flow to the area and reducing episodes of chest pain.
In the study, 167 patients at 26 U.S. medical centers were randomized to one of three injection groups: low dose (100,000 CD34+ cells/kg body weight); high dose (500,000 CD34+ cells/kg body weight); or a placebo.
Normally, there are too few CD34+ cells to provide enough for therapy. So, researchers used a drug to increase the number of the cells in the body before collecting them. Using a catheter threaded into the heart, the researchers injected CD34+ cells into muscle identified as receiving insufficient blood.
About a third of participants had minor elevations of troponin, an enzyme that signals a heart attack when accompanied by changes in an electrocardiogram (EKG), researchers said. However, patients felt no chest pain and experienced no EKG changes.
Later this year, the researchers will begin a phase III trial of the therapy, the level usually required before the Food and Drug Administration considers approving a drug.
Through outstanding research at Carnegie Mellon University (CMU), McGowan Institute for Regenerative Medicine affiliated faculty member Philip LeDuc, PhD, CMU associate professor of mechanical engineering with courtesy appointments in Biomedical Engineering, Biological Sciences, and Computational Biology departments, and a team of scientists developed renewable energy using bacteria and microtechnology. The world's smallest microbial fuel cell could be used to power underwater remote sensors or even medical implants.
As reported, the new device, the size of a single strand of human hair (total volume of just 0.3 microliters), generates energy from the metabolism of bacteria on thin gold plates in micro-manufactured channels. The fuel cell recruits necessary bacteria to create a biofilm that utilizes natural organic compounds as fuel to generate power.
Future versions of this tiny bacteria-powered fuel cell could replace batteries in microelectronic devices. While batteries are used to do that today, fuel cells are able to store more energy in the same space.
"Our biology-powered fuel cell could be less costly to make and more easily deployed in remote areas than conventional batteries that require invasive maintenance," said Dr. LeDuc, a co-author of the study.
For now, however, the microbial fuel cells produce only very tiny amounts of electricity — up to 127 amps per cubic meter, about 7,000 times less than a AA battery, said Kelvin Gregory, co-author and an assistant professor of civil and environmental engineering at CMU. At this level, a single microfluidic microbial cell could potentially power itself as a remote sensor, but for larger applications, many cells would need to be stacked together to increase the power output. Luckily, multiplexing is a common feature of microfluidics, said Dr. LeDuc. "It's like computer chips — you can put a ton of these things in parallel."
Sophisticated simulation techniques typically used for medical training could provide a powerful way of examining interactions between physicians and patients to reveal, for example, how race and other factors influence decision-making, said University of Pittsburgh School of Medicine researchers and McGowan Institute for Regenerative Medicine affiliated faculty member Derek Angus, MD, MPH, FRCP, FCCM, FCCP, professor and chair of the Department of Critical Care Medicine and director of CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illnesses) Center at the University of Pittsburgh. In a study, they found that hospital-based physicians did not treat black and white mock patients differently in an intensive care scenario, but they overestimated the preference for life-sustaining intervention in both groups and among blacks in particular.
Previous research has shown that compared to white patients, black patients with late-stage cancer are more likely to be admitted to an intensive care unit (ICU) and to receive life-sustaining interventions such as dialysis or breathing support by a ventilator, said lead investigator Amber E. Barnato, M.D., associate professor of medicine.
Also, research suggests that black patients are more likely to prefer aggressive life-sustaining treatment.
Conducted at the Peter M. Winter Institute for Simulation Education and Research (WISER) at Pitt, the scenario mimicked the triage environment and time pressure in which decisions about ICU admission and intubation are typically made. The researchers simulated a scenario in which a black or white patient with either end-stage gastric or pancreatic cancer experienced dangerously low blood pressure or oxygen levels. Then they assessed how doctors dealt with it medically and surveyed them about their perceptions of patient preferences.
The researchers found no treatment decision differences regarding administration of opiate pain killers, a trial of noninvasive mechanical ventilation, elicitation of intubation preferences, chart documentation of preferences, ICU admission, intubation, comfort measures only, and palliative care consultation. Surveys showed that the physician participants believed that a black patient with late-stage pancreatic cancer was more likely than a similar white patient to prefer potentially life-prolonging chemotherapy over palliative care, to want breathing support via a ventilator to extend life by 1 week, and less likely to want a "do not resuscitate" order if hospitalized.
"These findings could mean that in this setting, physician beliefs about patient preferences did not change their treatment decisions," Dr. Barnato said. "It's also possible that there were no differences because this scenario isolated race from other social and cultural variables, such as socioeconomic status, religiosity, trust, and level of advanced care planning, that may influence physician behavior."
Future research will explore the interaction of race and those variables in end-of-life decision-making.
McGowan Institute for Regenerative Medicine faculty member Albert Donnenberg, PhD, professor of infectious disease and microbiology in the Graduate School of Public Health and a professor of medicine in the School of Medicine at the University of Pittsburgh, was part of a multi-university team of researchers who found that transfused blood may need to be stored in a different way to prevent the breakdown of red blood cells that can lead to complications including infection, organ failure, and death. The team recently reported the latest findings from its ongoing exploration of the interaction between red blood cell breakdown products and nitric oxide (NO), revealing new biological mechanisms that can reduce blood flow and possibly damage vital tissues after administration of blood that has been stored for longer than 39 days.
In recent years, doctors have noted that transfusion of either many units of blood or of blood stored a long time may be associated with a greater frequency of complications, such as increased infection risk, kidney, lung, or multi-organ failure, and death, particularly among medically vulnerable patients, explained senior investigator Mark T. Gladwin, M.D., chief, Division of Pulmonary, Allergy and Critical Care Medicine, Pitt School of Medicine, and director of Pitt's Vascular Medicine Institute.
"When blood sits for a while, some of the cells break down and release their contents, which include molecules of hemoglobin and red blood cell microparticles," he said. "These accumulate in the stored bag of blood and are transfused into the patient with the blood. In the bloodstream, the hemoglobin and microparticles bind to and destroy NO, a very important molecule that is used by the body to keep blood vessels dilated for normal blood flow."
The scavenging of NO causes blood vessel constriction that can prevent tissues and organs from getting adequate oxygen and activate the platelets and the coagulation system, as well as cause inflammation, Dr. Gladwin said.
From their experiments, the university collaborators found that human blood stored under standard conditions accumulated "free" hemoglobin that was no longer contained in a cell and microparticles of damaged cells. Those breakdown products reacted with NO about 1,000 times more quickly than did intact red blood cells. Also, transfusion of even very low concentrations of hemoglobin caused blood vessel constriction and hypertension in a rat model.
AWARDS AND RECOGNITIONS
McGowan Institute for Regenerative Medicine affiliated faculty member Michael Boninger, MD, professor and chair of the University of Pittsburgh School of Medicine's department of physical medicine and rehabilitation (PM&R) and director of the University of Pittsburgh Medical Center Rehabilitation Institute, was selected by the faculty of the Department of Physical Medicine and Rehabilitation at the University of Medicine & Dentistry of New Jersey (UMDNJ)-New Jersey Medical School to receive the 2011 New Jersey Medical School PM&R Teaching Award.
Dr. Boninger is a renowned researcher in spinal cord injury and assistive technology. The author of five U.S. patents, 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.Dr. Boninger also 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.
The mission of the Department of PM&R at UMDNJ-New Jersey Medical School and The University Hospital is to maximize the capacity of individuals with physical disability so as to resume their life roles through excellence in patient care, education, research, and community service.
The McGowan Institute for Regenerative Medicine congratulates its affiliated faculty members for their recent honors and appointments. Erin Sullivan, MD, director of the Division of Cardiothoracic Anesthesiology and associate chief anesthesiologist at UPMC Presbyterian Hospital, received a one-year reappointment to the educational track subcommittee on cardiac anesthesia, the committee on surgical anesthesia, and the committee on governmental affairs. Jonathan H. Waters, MD, chief of anesthesiology at Magee-Womens Hospital, has been appointed to the committee on blood management.
The McGowan Institute also congratulates faculty member Peter Wearden, MD, PhD, director of the pediatric mechanical cardiopulmonary support program at Children's Hospital. Dr. Wearden received the Smart Heart Award from the Children's Heart Foundation. The award is given to a physician who demonstrates innovative approaches to the care of pediatric cardiac patients. Dr. Wearden is being honored for his work with PediaFlow, a pediatric ventricular-assist device.
The Children's Heart Foundation aims to bring health, hope and happiness to children impacted by congenital heart defects, which is the number one birth defect in the United States.
Further accolades go to Yoram Vodovotz, PhD, Director of the Center for Inflammation and Regenerative Modeling and Professor of Surgery, Immunology, Computational and Systems Biology, Clinical and Translational Science, and Communication Science and Disorders, and his team, who was recognized at IGI Global's Fourth Annual Excellence in Research Journal Awards. The article, titled "SPARK: A Framework for Multi-Scale Agent-Based Biomedical Modeling," appeared in the International Journal of Agent Technologies and Systems, 2(3). The paper was written by Alexey Solovyev, Maxim Mikheev, Leming Zhou, Joyeeta Dutta-Moscato, Cordelia Ziraldo, Gary An, Yoram Vodovotz, and Qi Mi.
IGI Global is an international publishing company specializing in scholarly research publications and databases covering all aspects of information science technology utilization and management. The award was given based on the following criteria: contribution to the field; originality of the research; practicality of research/results; quality of writing; rigor of the research; and substantive research and methodology.
Congratulations to all!
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Mi Q, Constantine G, Ziraldo C, Solovyev A, Torres A, Namas R, Bentley T, Billiar TR, Zamora R, Puyana JC, Vodovotz Y.
A dynamic view of trauma/hemorrhage-induced inflammation in mice: principal drivers and networks.
BACKGROUND: Complex biological processes such as acute inflammation induced by trauma/hemorrhagic shock/ (T/HS) are dynamic and multi-dimensional. We utilized multiplexing cytokine analysis coupled with data-driven modeling to gain a systems perspective into T/HS.
METHODOLOGY/PRINCIPAL FINDINGS: Mice were subjected to surgical cannulation trauma (ST) ± hemorrhagic shock (HS; 25 mmHg), and followed for 1, 2, 3, or 4 h in each case. Serum was assayed for 20 cytokines and NO(2) (-)/NO(3) (-). These data were analyzed using four data-driven methods (Hierarchical Clustering Analysis [HCA], multivariate analysis [MA], Principal Component Analysis [PCA], and Dynamic Network Analysis [DyNA]). Using HCA, animals subjected to ST vs. ST + HS could be partially segregated based on inflammatory mediator profiles, despite a large overlap. Based on MA, interleukin [IL]-12p40/p70 (IL-12.total), monokine induced by interferon-γ (CXCL-9) [MIG], and IP-10 were the best discriminators between ST and ST/HS. PCA suggested that the inflammatory mediators found in the three main principal components in animals subjected to ST were IL-6, IL-10, and IL-13, while the three principal components in ST + HS included a large number of cytokines including IL-6, IL-10, keratinocyte-derived cytokine (CXCL-1) [KC], and tumor necrosis factor-α [TNF-α]. DyNA suggested that the circulating mediators produced in response to ST were characterized by a high degree of interconnection/complexity at all time points; the response to ST + HS consisted of different central nodes, and exhibited zero network density over the first 2 h with lesser connectivity vs. ST at all time points. DyNA also helped link the conclusions from MA and PCA, in that central nodes consisting of IP-10 and IL-12 were seen in ST, while MIG and IL-6 were central nodes in ST + HS.CONCLUSIONS/SIGNIFICANCE: These studies help elucidate the dynamics of T/HS-induced inflammation, complementing other forms of dynamic mechanistic modeling. These methods should be applicable to the analysis of other complex biological processes.
PLoS One. 2011 May 10;6(5):e19424.
Rick Koepsel, Alan Russell, Tom Gilbert
Nanotechnology Based Infection Control for Ventricular Assist Devices
NanoDynamics Life Sciences, Inc. DBA LIG Sciences (via an NIH SBIR)
05/15/11 – 04/30/13
Year 1: $191,955 direct and $67,890 IDCTotal: $348,421 direct and $490,000 IDC
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