McGowan Institute?
September 2006 | VOL. 5, No.9 | www.McGowan.pitt.edu
New Contrast Agents Track Organ Rejection
Under the leadership of Dr. Chien Ho, McGowan Institute faculty member and alumni professor of biological sciences at Carnegie Mellon University, an emerging imaging technology may significantly change the post-transplant testing for possible organ rejection. While organ transplants give patients a new lease on life, preventing their immune systems from rejecting the organ sometimes presents a challenge. Physicians must strike a balance between suppressing the immune system so that it does not reject the organ and maintaining enough activity to ward off infections. Tracking how well the body accepts the new organ is critical to this process.
The current "gold standard" for monitoring organ rejection is tissue biopsy, an invasive procedure in which a physician removes a small sample from the transplanted organ for testing. Biopsy has two drawbacks: patient discomfort, as the physician must perform the procedure multiple times, and poor selectivity since the biopsy removes tissue from only a limited number of sites, missing rejection starting elsewhere in the organ.
To overcome these limitations, Dr. Ho and his colleagues are developing a new method to monitor organ rejection using magnetic resonance imaging (MRI). They inject polymer-coated nanometer- and micrometer-sized iron oxide particles into the blood where macrophages – immune cells that scavenge the body for foreign substances – ingest the particles and carry them to rejection sites in the transplanted organ. Because the highly magnetic iron particles can be clearly identified by MRI, researchers then use MRI to track the macrophages.
In a recent experiment, Dr. Ho's research group transplanted a living heart from one rat into the abdomen of another rat. Researchers injected the iron oxide particles into the host rat, and then performed MRI scans at regular intervals over the next several days as the rat's body rejected the transplanted heart.
Dr. Ho notes that the research has wider implications for tracking individual cells. "Tracking cell migration is not only very important in cell and developmental biology, but also in clinical medicine. This method is potentially useful for studying developing stem cells, the migration of cancer cells, inflammatory processes, and gene expression."
Monitoring rejection in other organs, such as kidneys, livers, and lungs may also be possible. But using the contrast agents in the liver and lungs will be an imaging challenge. Iron found in the liver, the body's largest iron storage site, can drown out the contrast agent's signal. To use the agents in transplanted lungs, researchers must overcome imaging artifacts created by the organ's many air sacs.
This research is supported by the National Institute of Biomedical Imaging and Bioengineering.
Dr. William Wagner, Deputy Director, McGowan Institute, Dr. Anthony Atala, Director, Institute for Regenerative Medicine, Wake Forest University Baptist Medical Center, and McGowan Institute faculty member, and Dr. Roderic Pettigrew, Director, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health were the guests on the Diane Rehm Show (WAMU-88.5 FM, American University Radio) on August 31, 2006. These scientists joined guest host Laura Knoy to provide an update on the recent research and success in the effort to repair or build human organs and tissues.
The discussions addressed the status of tissue engineering and regenerative medicine, and the important role that these emerging technologies can play in health care. As an example, while there are 25,000 organ transplants annually, there is a demand for 95,000 organs…a shortfall of 70,000 organs a year! There has been progress in using tissue engineering to repair/reconstruct damaged and diseased organs and tissues.
While much needs to be accomplished, the achievements to date offer substantial enthusiasm that in the future these emerging technologies will address many medical needs and issues.
A recording of the broadcast is available here; approximately 60 minutes.
Molecular Art Networking Sessions
Based on the requests of faculty and graduate students for more and different types of networking sessions, the Moleculart project will continue in the Fall term. Our goal is to have a scientific gathering that fosters networking in a different environment. Please save the dates and join us on October 3rd and December 6th;
- October 3, 2006
Artist: Center for Biological Imaging
Time: 5:00 – 7:00 PM
Place: S-100 BST - December 6, 2006
Artist: Laura Backman
Time: 4:30 – 6:30 PM
Place: S-100 BST
20th Anniversary of the Artificial Heart Program
To commemorate the contributions and the success of the UPMC Artificial Heart Program over the past 20 years, and to help raise funds for new scientific and clinical initiatives, a Gala Celebration will be held on October 14, 2006.
Approximately 5 million individuals in the United States suffer from congestive heart failure (CHF) and an additional 500,000 are diagnosed each year.
As a pioneer in heart research, UPMC continually strives to stay on the cutting edge of research through the Artificial Heart Program. The Artificial Heart Program, within the Heart, Lung and Esophageal Surgery Institute (HLESI) provides the kind of treatment options that give patients hope.
In an effort to move the ground-breaking programs on to the next level, there is a need for additional funding. The goal of these fundraising efforts is the establishment of a new interdisciplinary team that brings together experts in Bioengineering, Cardiology, Cardiovascular Surgery, Cell Biology and Regenerative Medicine.
With the help of many generous supporters, the plan is to establish in the very near future treatment options for congestive heart failure that would end its reign as the number one killer of both men and women.
The Black Tie Gala will feature special guest Regis Philbin. For additional information, please contact Cheryl Matevish at 412-647-0523 or mcheryl@pmhsf.org
Regenerative Medicine Today Podcasts
The Regenerative Medicine Podcasts continue to be well received. There have been over 4,100 downloads to date. The most recent podcasts are:
Until its planned closing in summer 2006, the Whitaker Foundation contributed more than $700 million to various universities and medical schools, primarily to support biomedical engineering education and research. The foundation helped to create 30 biomedical engineering programs and helped finance the construction of 13 university buildings, many of them subsequently bearing the name Whitaker in some form. In podcast #17, Dr. Peter Katona, who served the Whitaker foundation as President and Chief Executive Officer from 2000 to 2006, will tell us about the full breadth of the Whitaker Foundation’s influence on the field of bioengineering, why its leaders chose to end the foundation’s run, and share his sage advice to young people considering bioengineering careers. (Dr. Katona ought to know: nearly 1,500 young researchers began their careers with Whitaker Foundation funding.) For more on the Whitaker Foundation, visit their web site [http://www.whitaker.org/] #18- Dr. Harvey Borovetz – Bioengineering, University of Pittsburgh Twenty years ago, a pioneering team of clinicians and engineers had a vision to use a mechanical heart-assist device as an aid to a patient with a failing heart, and to ascertain if such a heart assist device could serve as a “bridge” for an ailing heart until a transplantable organ became available. While the team consisted of many diverse disciplines, the lead biomedical engineer was Dr. Harvey Borovetz. In this interview, Dr. Borovetz provides a retrospective look at the initial days of what has become a relatively routine clinical procedure to support a weakened heart with a ventricular assist device until a heart transplant can be implemented. Dr. Borovetz shares the progress that has been made in the engineering as well as the clinical procedures. In podcast #18, Dr. Borovetz also provides a glimpse at the future, sharing his vision on the emerging technology development that he is leading to provide equivalent cardiac care for infants and children. For more information, the following web sites may be of interest: |
#17- Dr. Peter Katona - Whitaker FoundationVisit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
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Freddie H. Fu, professor and chairman of the Department of Orthopaedic Surgery at the School of Medicine, has been elected president of the American Orthopaedic Society for Sports Medicine (AOSSM). Dr. Fu will serve as vice president this year, president-elect in 2007, and will be installed as president in July 2008.
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Raman Venkataramanan, professor of pharmaceutical sciences, has been elected as vice chair for the pharmacokinetics, pharmacodynamics and drug metabolism section of the American Association of Pharmaceutical Scientists. Dr. Venkataramanan’s one-year term begins November 1.
Publication of the Month | September 2006 |
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| Author(s) | Yijen L. Wu, Qing Ye, Lesley M. Foley, T. Kevin Hitchens, Kazuya Sato, John B. Williams, and Chien Ho Pittsburgh NMR Center for Biomedical Research, Department of Biological Sciences, Carnegie Mellon University |
| Title | In situ labeling of immune cells with iron oxide particles: An approach to detect organ rejection by cellular MRI |
| Summary | In vivo cell tracking by MRI can provide means to observe biological processes and monitor cell therapy directly. Immune cells, e.g., macrophages, play crucial roles in many pathophysiological processes, including organ rejection, inflammation, autoimmune diseases, cancer, atherosclerotic plaque formation, numerous neurological disorders, etc. The current gold standard for diagnosing and staging rejection after organ transplantation is biopsy, which is not only invasive, but also prone to sampling errors. Here, we report a noninvasive approach using MRI to detect graft rejection after solid organ transplantation. In addition, we present the feasibility of imaging individual macrophages in vivo by MRI in a rodent heterotopic working-heart transplantation model using a more sensitive contrast agent, the micrometer-sized paramagnetic iron oxide particle, as a methodology to detect acute cardiac rejection. |
| Source | Proceedings of the National Academy of Sciences 103: 1852-1857, 2006 |
Grant of the Month
Grant of the Month | September 2006 |
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| PI | Mitchell P. Fink, MD |
| Co-PIs | Marina V. Kameneva, PhD and Alan J. Russell, PhD |
| Title | Next Steps in the Development of Drag Reducing Polymers for Treatment of Life-Threatening Hemmorrhagic Shock in Combat Casualties Using Small Volumes of Resuscitation Fluid |
| Description | Early deaths due to battlefield injuries are secondary to exsanguinations or overwhelming central nervous system trauma, whereas late deaths are secondary to sepsis and multiple organ system dysfunction syndrome. Currently, the primary strategy for treating hemorrhagic shock is to control ongoing bleeding and restore intravascular volume by infusing an asanguineous fluid (e.g., Ringer’s lactate solution) and packed red blood cells. However, conventional approaches toward resuscitation require administration of large volumes of fluids that are intrinsically heavy and bulky (e.g., normal saline solution or various colloidal solutions) and/or difficult to store (packed red blood cells). Interestingly, if intravascular volume expansion successfully restores cardiac output and arterial blood pressure before definitive hemostasis has been achieved, then, paradoxically, resuscitation can promote bleeding and shorten survival. Thus, logistical considerations limit the capacity of first responders to provide adequate conventional resuscitation on the battlefield and even in some cases of civilian trauma. In view of these considerations, an ideal initial resuscitation fluid for the initial management of hemorrhagic shock would require administration of just a small volume to improve tissue perfusion and oxygen utilization without increasing blood pressure to such an extent that endogenous hemostatic mechanisms (soft platelet-fibrin plugs) are disrupted. Polymers with a molecular mass >10 exp 6 Da and a relatively linear structure are drag-reducing polymers (DRPs) that have been shown to reduce resistance to turbulent flow in pipes, thereby increasing flow rate at constant pressure (Toms effect). The flow conditions associated with the Toms effect probably do not occur when blood flows through arteries, arterioles, capillaries, venules and veins. Nevertheless, a number of studies have shown that intravenous administration of DRPs to experimental animals increases blood flow rate and decreases blood pressure and calculated peripheral vascular resistance without affecting blood viscosity or vascular smooth muscle tone. Furthermore, in a preliminary series of experiments, Kameneva et al. reported that survival was markedly improved when rats were resuscitated from hemorrhagic shock with a DRP-containing fluid. Prompted by these observations, we used seed-grant funding from DARPA to carry out a study to test the hypothesis that intravenous administration of very small volumes of an aloe vera-based DRP might improve oxygen consumption and extend survival time in rats subjected to otherwise lethal hemorrhage. The aloe vera-derived DRP used for these studies was a mixture of polysaccharides with an average molecular mass of ~4x10 exp 6 Da. Treatment of the rats with 7 ml/kg of the aloe vera-derived DRP (i.e., ~20% of the shed blood volume) significantly prolonged survival relative to treatment with a similar volume of the normal saline vehicle. While these results are exciting and have created considerable “buzz” in both the scientific and lay press, there clearly is much to be done before the DRP concept can be tested clinically and developed commercially for the treatment of combat casualties or other indications. The aloe vera extract is a complex mixture of polysaccharides, and the natural product has not been optimized with respect to a number of chemical parameters (e.g., charge, molecular mass, hydrophobicity, and chain-branching) that might affect its ability to augment oxygen delivery and improve perfusion in vivo. Accordingly, the present proposal seeks to extend our preliminary DARPA-supported studies by using modern chemical methods to create a manageable library of biocompatible blood-soluble polymers. The polymers will be synthesized and modified using a statistically designed approach. These compounds will be evaluated both in vitro and in vivo for DRP-like properties, and the most promising compounds will be evaluated in a rat model of lethal hemorrhagic shock. A key aspect of the first phase of the research will be to determine to what degree the in vitro tests are effective predictors of in vitro utility. A “lead compound” will be identified, and this agent will be extensively evaluated in a clinically relevant rodent model of lethal hemorrhagic shock. |
| Source | DARPA |
| Term | Year 2: 03/01/06 – 02/28/07 |