January 2008 | VOL. 7, NO. 1 | www.McGowan.pitt.edu

The University of Pittsburgh’s Bioengineering Department and McGowan Institute’s multidisciplinary faculty received praiseworthy coverage in a recent issue of the Pitt Chronicle. The bioengineering program, ranked in the national top 10 by U.S. News & World Report, has been instrumental in everything from UPMC’s groundbreaking artificial heart program to stem cell research.

Dr. Tim Maul, who earned his PhD in 2007, and Rebecca Long, a 5th year PhD student, were recognized for their recent achievements along with Bioengineering Department chair Harvey S. Borovetz, PhD.  Bioengineering’s integration with the School of Medicine gives recent students such as these “limitless opportunities,” according to Dr. Borovetz.  Because of integration with the medical school, bioengineering students have access to clinical settings, lab space, and faculty talent that enhances its success.  The department celebrated its 10th anniversary this past fall. 

The Chronicle story traced the history of new graduate programs that are based upon collaborations among schools within the University.  The collaborative trend has caused the old distinctions between disciplines to become increasingly obsolete, creating new departments like computational biology, molecular biophysics/structural biology, and integrative molecular biology.  The reason that these developments stir so much excitement in the field is that when scientific thinking crosses traditional boundaries, the ability to solve the big questions moves closer to reality.

Dr. Maul, a 2007 PhD graduate, used the bioengineering program to launch his current research into the design of injectable polymer- and lipid-based microbubbles that will seek out inflamed blood vessels.  He has studied in the McGowan Institute labs of Dr. David Vorp and Dr. William Wagner and has also researched the mechanics of the behavior of stem cells in blood vessels.  That work combined his knowledge of mechanical engineering, cellular and molecular biology, and statistics; it formed the basis of his doctoral thesis.

Rebecca Long was a Carnegie Mellon student who was drawn to Pitt by the opportunity to work with Dr. Michael S. Sacks, William Kepler Whiteford Professor of Bioengineering.  Long uses the science of mechanical engineering and physiology to further her research into tissue engineering.  Right now she is concentrating on the biomechanics of bladder cells in the hope of finding a solution to the atrophy that occurs in the bladder following a spinal cord injury.

It is certain that the multidisciplinary trend and its collaborational benefits will continue.  Dr. Borovetz feels certain that Pitt is training the next generation of leaders in the fields of tissue engineering, imaging technology, and prosthetics.

“I don’t know how or when,” he stated, “but I know that this is going to be the place where you’re going to see these kinds of discoveries being made.” Since Pitt’s faculty now ranks sixth in the nation in grants from the National Institutes of Health (NIH), Dr. Borovetz’s prediction seems closer to reality than ever.

Read more: Pitt Chronicle

TDon’t wait until it’s too late to register for the McGowan Institute Retreat scheduled for March 10, 11, and 12 at Nemacolin Woodlands.  Registration is required prior to February 15, 2008 if you plan to attend.

You won’t want to miss the Keynote Session on Monday, March 10 featuring Elizabeth Roberts, Lieutenant Governor of Rhode Island.   Lieutenant Governor Roberts was instrumental in Rhode Island’s push towards stem cell and regenerative medicine research. 

You will also want to be present for the Poster Session and Reception on Monday evening, a favorite of retreat attendees.  In addition, this year’s program features an Indoor Picnic on Tuesday evening that will promote a casual and fun atmosphere.  The Indoor Picnic follows Corporate Speed Dating, an opportunity for collaboration with industry representatives, on Tuesday afternoon. 

If you still need to register, visit: McGown Retreat

See you there!

Dr. Savio Woo is the first recipient of the College of Engineering, University of Washington’s prestigious Diamond Award for Distinguished Achievement in Academia. Beginning in 2006, the UW College of Engineering has bestowed the Diamond Award on outstanding alumni in industry. Dean Matt O’Donnell announced that Dr. Woo is the first to receive this award for his accomplishments in academia.

The Diamond Award acknowledges Dr. Woo’s pioneering work in bioengineering research. His landmark research on the biomechanics of the knee and healing of ligament injuries prompted orthopedic surgeons to abandon weeks or months of cast immobilization. Dr. Woo showed that rehabilitation with controlled movement and exercise actually speeds healing from devastating injuries.

Dr. Woo continues groundbreaking work in orthopaedics. Currently, he and his research team at Pitt’s Musculoskeletal Research Center, Department of Bioengineering, are using robotics to develop better surgical procedures. In collaboration with investigators at the McGowan Institute for Regenerative Medicine, his research team is also tackling ligament healing on the molecular and cellular levels through functional tissue engineering.

Dr. Woo is one of the rare scientists honored by membership in both the Institute of Medicine and the National Academy of Engineering.  He is also a member of  Academia Sinica (PRC) and has received the highest honors from many professional societies including the Bioengineering Division of the ASME, the American Society of Biomechanics, the International Society of Biomechanics, and the American Orthopaedic Society for Sports Medicine.  One of Dr. Woo’s other significant achievements is receiving an International Olympic Committee (IOC) gold medal at the 1998 games in Nagano, Japan for his contributions to sports medicine—one of only four scientists honored with such a medal by the IOC.

Read more: UW Engineering's Diamond Awards

MNearly 5 million people live with heart failure, and about 550,000 new cases are diagnosed each year in the United States. More significantly, approximately 50,000 US patients die annually waiting for a donor heart.  To help eliminate this problem, researchers from the McGowan Institute for Regenerative Medicine and other university locations throughout the nation are working towards advances in generating heart tissue in the lab.

Work in the lab often begins with organ decellularization—the process of removing all of the cells from an organ leaving only the extracellular matrix (ECM), the framework between the cells, intact.  McGowan faculty member Stephen Badylak, DVM, PhD and MD, has demonstrated through his work over the years that decellularized tissues and organs can be successfully used as bioscaffolds derived from xenogeneic ECM.  The decellularized tissues and organs have been used in numerous tissue engineering applications.

Photo caption: An empty heart: In this photo series, a heart containing cells (top) becomes a scaffold stripped of cells (bottom).  Photo credit: University of MN

The safety and efficacy of such scaffolds when used for the repair and reconstruction of numerous body tissues has been shown in both preclinical animal studies and in human clinical studies.

More than 1.5 million human patients have been implanted with xenogeneic ECM scaffolds. These ECM scaffolds are typically prepared from porcine organs such as the small intestine or urinary bladder, which are subjected to decellularization and terminal sterilization without significant loss of the biologic effects of the ECM. The composition of these bioscaffolds includes the structural and functional proteins that are part of native mammalian extracellular matrix. The three-dimensional organization of these molecules distinguishes ECM scaffolds from synthetic scaffold materials and is associated with constructive tissue remodeling instead of scar tissue formation.

Dr. Badylak’s lab has successfully evaluated the ability of ECM derived from porcine urinary bladder to serve as an inductive scaffold for myocardial repair. Building on the foundation of Dr. Badylak’s work, scientists from the University of Minnesota Center for Cardiovascular Repair grew functioning heart tissue by taking rat and pig hearts and reseeding them with a mixture of live cells.

After successfully removing all of the cells from both rat and pig hearts, University of Minnesota researchers, led by Doris Taylor, PhD, injected them with a mixture of progenitor cells that came from neonatal or newborn rat hearts and placed the structure in a sterile setting in the lab to grow. The results were very promising, Taylor said. Four days after seeding the decellularized heart scaffolds with the heart cells, contractions were observed. Eight days later, the hearts were pumping.

Researchers are optimistic this discovery could help increase the donor organ pool. However, it is clear that more work is required to get a fully functional heart.

Researchers hope that the decellularization process could be used to make new donor organs. Because a new heart could be filled with the recipient’s cells, researchers hypothesize it’s much less likely to be rejected by the body. And once placed in the recipient, in theory the heart would be nourished, regulated, and regenerated in a similar manner to the heart that was replaced.

Although heart repair was the first goal during research, decellularization shows promising potential to change how scientists think about engineering organs. “Going forward, our goal is to use a patient’s stem cells to build a new heart,” said Taylor. “It opens a door to this notion that you can make any organ: kidney, liver, lung, pancreas – you name it…” she said.

Commenting on the Minnesota work, Dr. Badylak stated it "fits right in with other work in regenerative medicine."

"Stem cells will respond depending on what they see around them," Badylak said. "What they are doing is to provide a lot of favorable signals for stem cells to become heart cells. They take stem cells that want to become heart cells and encourage them to act appropriately. It sounds great."

The newly reported work "provides great proof of principle that you can get heart tissue to form," according to Badylak. "The next step is to determine how you can use this information therapeutically. The eventual goal is to put it into a patient that needs it."

Other tissue engineering scientists around the country said there are enormous obstacles to using the technique for people, but they described the work as exciting and a landmark.

Read More: HealthDay

Six months ago, a parvovirus destroyed his heart and put him in cardiac arrest.  Today, after resuscitation, a heart-lung machine, respirators, an experimental heart, and a heart transplant, 2-year-old Harold “TJ” Wilson has returned home to Adams, Butler County, where he again plays with Thomas the Tank Engine and watches "Elmo" DVDs.  McGowan Institute for Regenerative Medicine faculty member Peter Wearden, MD, PhD, Assistant Professor of Cardiothoracic Surgery, and Director of Pediatric Mechanical Cardiopulmonary Support at Children’s Hospital of Pittsburgh of UPMC, and one of the transplant team’s surgeons, was one of the physician’s on TJ’s care-giving and treatment team.

"I have a special fondness for TJ.  He has incredible spirit," Dr. Wearden said. "There's something about him, and maybe that's because he went through so much with us."

Children's, one of the busiest transplant centers in the nation, does 20 pediatric lung, heart, and heart-lung transplants a year. It's also a leading center for heart-assist devices.  TJ was fortunate to be in the ideal place during his recovery’s most critical junctures.

Critical heart/lung medical devices—the Extra Corporeal Membrane Oxygenation (ECMO) machine and the Berlin Heart—were both utilized in TJ’s care.  Each of these devices supported TJ when his body could not.  They served as two significant bridges to a successful heart transplant. 

TJ’s case marked the first time ECMO was used in Children's emergency room; placing tubes in his neck while he was undergoing chest compressions added to the challenge.  Because the Food and Drug Administration has yet to approve its use in the United States, Children's Hospital had to seek a "compassionate use" permit before implanting the Berlin Heart. The FDA gave its approval—the fifth one Children's has received—and a Berlin Heart was shipped in from Germany.

In addition to the superior medical team and devices, doctors said it helped that TJ was strong-willed, intelligent, and cooperative. He also benefited from having parents who are good caregivers.

Read more: Pittsburgh Post-Gazette

Andrew Schwartz, PhD, McGowan Institute for Regenerative Medicine faculty member and Professor of Neurobiology at the University of Pittsburgh leads a team of neuroscientists who have significantly advanced brain-machine interface (BMI) technology to the point where severely handicapped people who cannot contract even one leg or arm muscle now can independently compose and send e-mails and operate a TV in their homes. They are using only their thoughts to execute these actions.

Thanks to the rapid pace of research on the BMI, one day these and other individuals may be able to feed themselves with a robotic arm and hand that moves according to their mental commands.

“Our work has shown how important the learning process is when using brain-controlled devices,” says Dr. Schwartz.  “By permitting the subject to adaptively recode the generated neural activity, the overall performance of the device is dramatically increased.”

“Furthermore, as we have progressed in this work, it has become apparent that the basic idea of 'intention' during learning is very important and can be addressed by the direct observation of the neuronal transformations taking place during this fundamental processing,” Dr. Schwartz says.

At the University of Pittsburgh, scientists recently succeeded in developing the technology that allows a rhesus macaque monkey to mentally control a robotic arm to feed itself pieces of fruit. The robotic arm's fast and smooth movements were triggered by electrical signals that were generated in the monkey's brain when the animal thought about an action.

In previous studies, this lab developed the technology to tap a macaque monkey's motor cortical neural activity making it possible for the animal to use its thoughts to control a robotic arm to reach for food targets presented in 3D space.

In Dr. Schwartz’s latest studies, macaque monkeys not only mentally guided a robotic arm to pieces of food but also opened and closed the robotic arm's hand, or gripper, to retrieve them. Just by thinking about picking up and bringing the fruit to its mouth, the animal fed itself.

The monkey's own arm and hand did not move while it manipulated the two-finger gripper at the end of the robotic arm. The animal used its own sight for feedback about the accuracy of the robotic arm's actions as it mentally moved the gripper to within one-half centimeter of a piece of fruit.

"The monkey developed a great deal of skill using this physical device," says Meel Velliste, PhD. "We are in the process of extending this type of control to a more sophisticated wrist and hand for the performance of dexterous tasks."

Velliste and the other members of the Pittsburgh research team point out that imparting skill and dexterity to these devices will help amputees and paralyzed patients to perform everyday tasks.

The animal's thoughts emitted electrical signals that were recorded by tiny electrodes that the scientists had implanted in the monkey's motor cortex. A computer-decoding algorithm translated the signals into the robotic arm and gripper's movements.

BMI is already being tested in humans--with promising results, said Schwartz.

Read more:  Society for Neuroscience

McGowan Institute for Regenerative Medicine faculty member David J. Hackam, MD, PhD, co-director of the Fetal Diagnostic and Treatment Center at Children’s Hospital of Pittsburgh of UPMC and Magee-Womens Hospital reports that his lab has discovered that neonatal mice with mutations in critical areas of the immune system are protected from necrotizing enterocolitis (NEC), a leading cause of death in premature newborns.  NEC is  a case of defenders becoming unwitting attackers, says Hackam, who reported these findings at the American Society for Cell Biology’s 47th Annual Meeting.
By way of background, it is known that the toll-like receptors TLR4 are key players in the innate immune system. Protruding from enterocytes that form the innermost barrier-like layer of the small and large intestines, TLR4 receptors are primed to recognize pathogenic bacteria and sound the alarm.

But Hackam’s group found that the stresses of oxygen deprivation and bombardment by bacterial toxins, conditions that can occur in premature infants with underdeveloped lungs, stimulate too much production of TLR4. Like an unstoppable alarm, the increased numbers of TLR4 blare out signals that eventually tip the cells into cellular suicide. They also stop enterocytes from migrating to close wounds in the intestines.

These events, which do not occur in the TLR4-deficient mice, allow NEC to spread as the fragile lining of the gut gives way, releasing a flood of pathogens into the bloodstream. Even with modern advances in neonatal care, NEC affects 20 percent of premature babies and is fatal in nearly half of all cases, according to Hackam.

Hackam’s group discovered another way to switch off the molecular alarm in mice with NEC by interfering with production of a focal adhesion kinase (FAK) that the researchers found associated with TLR4. By shutting down FAK with small interfering RNA, the TLR4 siren was silenced. Under these conditions, the researchers watched enterocytes regain the ability to migrate, a property important for healing the damaged tissue.

Says Hackam, “We hope to develop treatment strategies that allow us to block the TLR4 switch from working--perhaps by influencing its interaction with FAK--using novel treatments that could be administered as a component of oral feeds.”

Read more: EurekAlert!

Five seventh grade students from Chartiers-Houston Middle School toured the McGowan Institute for Regenerative Medicine on January 17, 2008 as part of the Carnegie Science Center’s “Connect to Excellence” program.  The visit included the Badylak, Wagner, Vorp, Sacks and Lagasse Labs and featured interactive experiments conducted by the students while in each of the labs.  For example, in the Wagner Lab, students participated in setting up a mock circulation loop with a heart pump. In the Vorp Lab, students made agarose blood vessels, which they got to keep.

After the tours, the students enjoyed a pizza lunch and talked about what they had learned. This is the second year that McGowan Institute has hosted students from Chartiers-Houston and their science teacher, Gary Popiolkowski. 

What do the students experience here that cannot be covered in the classroom?  According to Popiolkowski, these students were selected from over 100 candidates and represent some of the top students in their age group. They will report back to their classmates and their family about not only the exciting work being done at McGowan Institute, but also about the importance of Pittsburgh as a center for tissue engineering and regenerative medical research.  Hopefully, the time spent on these students today will pave the way for a new wave of scientists and innovations in the future. 

The Regenerative Medicine Podcasts continue to explore pertinent topics. The most recent podcasts are:

#44-Dr. Peter Wearden - Dr. Wearden visits Regenerative Medicine Today and discusses his pioneering clinical work in pediatric cardiac care as well as pediatric mechanical circulatory support systems.

#45-Dr. Eric Lagasse - Dr. Lagasse discusses research on the identification of cancer stem cells and possible alternative cancer therapies.

Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.

Authors:	Eric Lagasse, PhD, PharmD
Title:	Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer.
Summary:	Our understanding of the role of stem cells in cancer development is evolving quickly. In the course of tumor expansion, a subpopulation of tumor cells with stem cell-like features has been noted. These cancer stem cells give rise to transit amplifying tumor cells, which comprise the majority of the tumor mass prior to terminal differentiation. Combining this finding with genetic instability, a well-known engine for cancer development and metastases, a new model emerges for cancer where normal stem cells and their cellular pathway acquire stochastic malignant abilities. In this model, when cancer stem cells self-renew, many genetic variants are produced. Just as microbes 'learn' to defeat antibiotics, genetically heterogeneous cancer stem cells may possibly acquire resistance to various chemotherapeutic approaches. Drug-resistant microorganisms selected by spontaneous mutation of bacterial DNA may not be so different than the drug-resistant and genetically instable cancer stem cells recurring after chemotherapeutic treatment. In this gloomy view of cancer, cancer stem cells with genetic instability can be considered as 'the best vehicle with the best engine', a formidable challenge for the future development of new anticancer therapies.
Source:	Gene Therapy (2008) 15, 136–142; published online 8 November 2007. Available online: http://www.nature.com/gt/journal/v15/n2/full/3303068a.html

PIs:	Harvey Borovetz, PhD
Title:	Levitronix Phase II SBIR
Description:	Development of a magnetically levitated, bearingless pump for a pediatric ventricular assist device.
Source:	NIH
Term:	9/30/07-6/30/10
Amount:	Year 1 direct = $383,458 Year 1 indirect = $98,658 Year 1 total = $482,116 Total award for the entire project period: ~$1.68 million

Newsletter Comments or Questions: McGowan@pitt.edu

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A program of the University of Pittsburgh and the University of Pittsburgh Medical Center