July 2007 | VOL. 6, NO. 7 | www.McGowan.pitt.edu

July marks the sixth anniversary of the McGowan Institute. This is an important opportunity to express thanks and appreciation for the commitment of our team of 220 faculty members who have led the sustained growth and maturation of the Institute.  Faculty alone can accomplish little.  We are fortunate to be joined by a committed and visionary staff as well as outstanding students and fellows.

The visibility of regenerative medicine is rapidly growing, as is the role that the McGowan Institute is playing to advance the science and clinical translation of new regenerative technologies. Pittsburgh continues to have increased visibility as a destination for regenerative medicine research, and we are also working to make Pittsburgh the destination of choice for regenerative therapies.

McGowan faculty, through grant money and philanthropy, spend more than $50 million a year on regenerative medicine research and clinical practice. Six years ago, the McGowan Institute was the first institute for regenerative medicine in the country. Today, including tissue engineering centers, there are 64.  Leading institutions are demonstrating real commitments to catapulting themselves to the head of the pack. The single-year budget for the Chinese National Tissue Engineering Center in Shanghai - a single entity - was $250 million last year. The California Institute for Regenerative Medicine’s budget this year is $1 billion.  The lieutenant governor of Rhode Island has called this unprecedented investment in infrastructure and research “the technology arms race between the states in the U.S.”  Our programs will continue to prosper through the excellence of our scientists and clinicians and the continued support of our sponsors, partners and benefactors.

At the McGowan Institute, our collective commitment remains to advance the sciences related to regenerative therapies, to educate scientists and engineers to pursue technologies related to regenerative medicine, and to lead a generation of clinicians in the implementation of regenerative therapies.  We have established a broad-based Center for Preclinical Studies that serves the needs of our faculty and numerous companies each year.

We can all look forward to another exciting year of advances in science and progress in the movement of our emerging technologies to clinical/commercial use. As noted above, our progress is directly attributable to all of the McGowan Team, and next year we will collectively be able to look back and say that we have made more progress along this road that we are traveling together.

Sincerely,
Alan J. Russell, Ph.D.

Dr. Savio L-Y. Woo has been named the University Professor of Bioengineering.  Woo founded and directs Pitt’s Musculoskeletal Research Center (MSRC), a multidisciplinary research and educational center.  It has hosted more than 450 orthopaedic surgeons, bioengineering students and staff.  In 1990, Woo joined the Department of Orthopaedic Surgery in Pitt’s School of Medicine as the inaugural A.B. Ferguson Professor after 20 years at the University of California at San Diego. In 2004, Woo moved to Pitt’s School of Engineering as a senior faculty member in the bioengineering department.

Throughout his career, Woo’s research has focused on knee ligament healing and repair, particularly medial collateral (MCL) and anterior cruciate (ACL) ligaments, two of the knee’s four major ligaments. He has published 295 refereed journal papers, 130 book chapters, and more than 741 abstracts.  Woo has also edited 11 books and 15 conference proceedings. In addition, he has given over 770 lectures. More recently his work has centered on functional tissue engineering of ligament healing and regeneration by examining the processes from molecular and cellular to tissue and organ levels, as well as the use of robotic technology to examine the function of the ACL replacement grafts.

Among his honors, Woo has been elected to the Institute of Medicine, The National Academy of Engineering and Academia Sinica. In 1998, Woo was the winner of the IOC Olympic Prize for Sports Medicine and was awarded the first Olympic Gold Medal at the Winter games in Nagano, Japan.  Read More

Anthony Delitto, Ph.D., PT, has been awarded a 2007 Lucy Blair Service Award from the American Physical Therapy Association.  In addition to being a McGowan Institute faculty member, Dr. Delitto is also a professor in the physical therapy department at Pitt’s School of Health and Rehabilitation Sciences.  Earlier this year, Dr. Delitto was given the honor of acting as a keynote speaker at the World Confederation for Physical Therapy held in Vancouver in June.

The Lucy Blair Service Award was established to recognize those members of the APTA whose contributions have been of exceptional value.  The award is named after Ms. Blair who had personal contact with several hundred physical therapists in 40 states and 3 Canadian provinces during the poliomyelitis epidemic of the early 1950s.  In addition to strengthening the quality of physical therapy services nationwide, Ms. Blair helped to evaluate the efficacy of gamma globulin and later, the poliomyelitis vaccine.

Although Dr. Delitto is primarily interested in conducting evidence-based studies in rehabilitation settings, particularly in populations who have musculoskeletal dysfunction, he continues to maintain a clinical practice, seeing patients who have low back pain.  His teaching interests are focused in clinical decision making and diagnostic process strategies.  Dr. Delitto believes that if the methods of successful rehabilitation professionals and strategists can be taught to students (especially the details of the decision making process), the field will be strengthened and improved as a whole.  

Rory Cooper, PhD, left this year’s 27th National Veterans Wheelchair Games a 4-time gold medal winner in the swimming events and a silver medal winner in the slalom. The Games were held in Milwaukee.

In addition to being a participating athlete, while in Milwaukee Dr. Cooper solicited volunteers to collect necessary data for the upcoming updates to the guidelines for the Americans With Disabilities Act (ADA)--updates that he believes are past due for redefinition.

Speaking to fellow wheelchair athletes, veterans, and others, Dr. Cooper said, “This is your chance to help define what the new guidelines will be.” Anyone interested in participating in this study should contact Dr. Cooper at rcooper@pitt.edu.  Alicia Koontz, Ph.D., co-investigator of the ADA study, reported that 50 people had participated in research studies during the Games.

Dr. Cooper’s team is also studying (1) a special joy stick developed for power wheelchairs; (2) rotator cuff injury and carpal tunnel syndrome in wheelchair users by means of ultrasound and physical examination; and (3) special performance equipment in power and manual wheelchairs that gathers data on distance, speed, and time of day. These devices were placed in manual chairs for basketball and quad rugby competitions at the Games.  Read More

McGowan Institute is hosting a variety of high school students this summer, some for short visits and tours, and one group consisting of internship students who will be here for four weeks.

The series of visits began July 12th when 10 young women participating in the Carlow College Summer Science Nation program visited and toured with Priya Ramaswami of the Wagner Lab, Dr. Ann Stewart-Akers of the Badylak Lab, and Donna Haworth of the Vorp Lab.  These high school students were presented with information and personal experiences pertaining to women and careers in science.  As Haworth said, “I think these types of things are very important and helpful to young women in science.”

On July 19th, 25 high school juniors and seniors from 7 different foreign countries participating in Duquesne University’s International Student Health Professions Institute toured and received a Power Point presentation by Dr. Tom Gilbert.  According to a Media Advisory bulletin released by Duquesne, these students specifically wanted to research educational opportunities and health careers in the Pittsburgh area because of its reputation as a leading health care center.  Besides touring McGowan, these students were also scheduled to shadow health care professionals at Mercy Hospital and receive a behind-the-scenes look at veterinary activity at the Pittsburgh Zoo.

The high school interns are made up of 3 PTEI interns: Usman Chatta, Nisha Maharaja, and Marvin Porter. Completing the group is an intern from McGowan, Kimberly Autore, the Wiegand Endowment recipient.  These outstanding students were selected from a group of almost 40 applicants and will be here participating in lab work and doing independent study until the first week of August.  The Wiegand Internship is funded by the Wiegand family and was set up to honor the life-changing experience that the daughter of Barbara and Bruce Wiegand had while interning here one summer.  It turned out to be a unique opportunity for that student and resulted in a career selection in the field of science that otherwise might not have happened. The goal of both the PTEI and Wiegand internships is to provide high school students with a first-hand opportunity to experience the excitement and vast employment and educational opportunities of careers in science and engineering.  It also offers an introduction to the field of tissue engineering.

Check back next month for more on the interns and the completion of this summer’s programs.

As recently reported in the Pittsburgh Business Times, Dr. Harvey Borovetz, a McGowan faculty member and chair of the department of bioengineering at Pitt, is part of a local team vying to develop a pediatric artificial heart before March 2009, when a $4.3 million contract from the National Heart, Lung and Blood Institute runs out.  Also on Borovetz’s team are Dr. James Antaki of CMU and Dr. Peter Wearden, a Children’s Hospital heart surgeon. Competing against the Pittsburgh team are The Cleveland Clinic Foundation, Jarvik Heart, Inc., Penn State University and Ension, Inc.

The main thrust behind Borovetz’s quest to develop this heart?  The current treatment for kids with failing hearts is woefully inadequate.  Children are currently treated with a machine the size of a home freezer on wheels.  This device, the ECMO, has a mortality rate of 1 out of 3 children.  Borovetz helped surgeons pioneer the ECMO for children in the 1970s.  The team is now trying to replace the ECMO (something of a miracle in its time) with a device the size of a quarter and with the works of a Swiss watch.  “Look at your thumb,” Borovetz says.  “That’s too big.”

While the technology shows promise, the search for commercial investors has been unsuccessful to date.  Only about 1,000 children per year nationwide will benefit from the pediatric artificial heart.  Few companies are willing to invest in such a small market.  Although artificial hearts for adults were developed over decades, this NIH contract gave researchers 5 years to come up with a workable design.  Read More

A collaborative international research team from the University of Pittsburgh School of Medicine and the University Medical College in Taiwan led by Michael Chancellor, M.D., found injections of botulinum toxin A, or Botox, into the prostate gland of men with enlarged prostate, eased symptoms and improved quality of life up to a year after the procedure.

"Many men have enlarged prostate," noted Dr. Chancellor.  "They take pills, but sometimes they don't work, or sometimes they have side effects, and they're afraid of surgery. So now, Botox has been shown to be safe and effective, and a single office injection, which takes about 5 minutes, can achieve success for one entire year. So, it's a new and very exciting alternative that is something between standard drugs and surgery."

During this year’s annual meeting of the American Urological Association, the results of this effort were presented.  The small study revealed that about 75 percent of men suffering from benign prostatic hyperplasia (BPH) experienced partial symptom relief following the treatment.  

According to the National Kidney and Urologic Diseases Information Clearinghouse, BPH usually occurs among men over the age of 50. More than half of all men over the age of 60 develop BPH.  This figure rises to 80 percent by the age of 80.

Between 40 percent and 50 percent of BPH patients acquire a loss of bladder control as the growing prostate squeezes against the urethra, the passage through which urine flows. Accompanying symptoms include a frequent need to urinate (often at night), trouble urinating (even when feeling the urge), blood in the urine, and urinary tract infections. In severe cases, bladder and kidney damage can result.

Once identified, patients with mild BPH may choose to do without treatment. However, those with more serious symptoms are often prescribed medications to shrink or relax the gland to relieve bladder blockage.  When that fails, the prostate can be reduced or removed via laser or microwave techniques, or invasive surgery.

Chancellor’s team found that nearly three-quarters of the patients experienced a 30 percent improvement in their symptoms for up to a year following the injection. None of the patients experienced significant side effects, such as erectile dysfunction or urinary incontinence.
A new worldwide study is under way to explore Botox's potential against BPH.

Read More

“We are very excited, because this is the first targeted therapy for liver cancer,” said Dr. Satdarshan P. Singh Monga of McGowan Institute and Pitt’s medical school in speaking about the significant new advance in the search for an effective treatment for human liver cancer.  Using a newly available monoclonal antibody, the researchers have demonstrated significant reductions in tumor cell proliferation and survival in human and mouse hepatocellular cancer (HCC) lines.  The research was published in the July issue of Molecular Cancer Therapeutics and has significant implications, not only for the treatment of liver cancer, but also for a number of different types of cancer.

HCC remains a disease of grim prognosis mainly because of the poorly understood mechanism of how the disease originates and spreads. Statistically, most patients live only a short time after a liver cancer diagnosis.  The new therapy revolves around an RTK protein known as platelet-derived growth factor receptor-alpha or PDGFRa.  When human and mouse liver cancer cell lines were treated with the monoclonal antibody targeted against PDGFRa, it resulted in a significant decrease in tumor cell proliferation and a marked increase in tumor cell death.  In fact, all tumor cell lines experienced significant decreases in proliferation in response to the monoclonal antibody.

“We now have identified a pathway,” said Dr. Monga, “that appears to be overly active in more than 70 % of the cancers we examined and, when targeted, leads to significant reduction in tumor cell proliferation and survival .”  The Pitt research was funded by grants from the American Cancer Society, the NIH, the Cleveland Foundation and the Rangos Fund for Enhancement of Pathology Research. Read More

Alan Wells, M.D., a professor of pathology and graduate student Christopher Shepard presented results of a recent metastatic breast cancer study in Washington, DC at Experimental Biology 2007.  The results of this research are quite significant in the continued search for answers to better understand cancer and its treatment.  The study helps to explain the complex series of steps making up metastasis: how cancer cells leave the original tumor site, how they migrate to other parts of the body via the bloodstream or the lymphatic system, and how they are able to multiply and spread at the metastasis site.

When malignant cells break away from the primary tumor, they degrade proteins that make up the surrounding extracellular matrix (ECM) and that separate the tumor from adjoining tissue. The cancer cells are able to breach the ECM and escape to travel throughout the body. The researchers found evidence that once migrating tumor cells reach the site of a possible metastasis, they awaken a critical gene that had been dormant when the cells first became cancerous. While the gene was dormant, the cells escaped their tissue of origin and traveled throughout the body.  Arriving at the site of a new metastasis, the gene awakens and allows the cells to multiply and spread. 

Also on Dr. Wells’ recent schedule was a visit to Oregon State University (OSU) where he appeared as a Tsoo E. King Memorial Lectureship guest speaker.  The biennial student-run lecture was organized by OSU third year biochemistry graduate students. 

Dr. Wells’ lecture described how cell migration and tumor metastasis has been observed and manipulated by his lab and others in the country.  Dr. Wells explained the next step in his research is to identify the specific chemical compounds involved in the processes observed by his lab.  “With a better understanding of the chemical mechanisms involved, we will someday be able to turn aggressive cancer cells into less aggressive tumors or even a benign presence,” he said. Read More

A gene therapy used by University of Pittsburgh researchers offers new hope for treatment of peripheral neuropathy. The team, led by Joseph Glorioso, III, PhD, used a herpes virus to deliver a receptor that can be activated to shut down the pain signal associated with this type of pain.

Neuropathic pain is the result of damage to nerve fibers caused by injuries or diseases, such as diabetes and cancer.  Neuropathic pain is usually perceived as steady burning, "pins and needles," or "electric shock" sensations that occur either spontaneously or in reaction to external stimuli.  Unfortunately, neuropathic pain often responds poorly to standard pain treatments and occasionally may get worse instead of better over time. For some people, it leads to serious, long-term disability and dependence on pain medications that have a variety of unwanted side effects, including addiction.

Dr. Glorioso, known for his work surrounding the herpes simplex virus (HSV), stated that “the inability to effectively manage neuropathic pain associated with injuries and illnesses is a growing national and international problem. Gene therapy offers a more targeted, less toxic approach for effectively managing this condition.”  Read More

A collaborative project between the Federspiel and Russell labs has resulted in a method of making artificial lungs more efficient, using an enzyme that helps to remove CO2 from the blood. The result, they hope, will be a smaller device that can be used in a wider range of patients. The smaller units that Drs. Federspiel and Russell envision could be used to treat a much wider range of conditions, such as temporary lung infection caused by emphysema or lung damage resulting from smoke inhalation. Currently, people with these conditions are put on a ventilator, but the pressure this exerts on the lungs can cause further damage by stretching the tissue. "The more you can get the invasiveness down, the more applications for the device," Dr. Federspiel says. Read More

Several years ago, McGowan faculty Eric Beckman, PhD, and Michael Buckley, MD, invented a novel medical adhesive technology.  The new adhesive was designed to meet a market demand for a strong, safe tissue adhesive to improve the wound closure process.  The product positions tissues for optimal healing while minimizing fluid accumulation. To move the technology towards clinical use, Cohera Medical was formed, and the invention rights were licensed by the University of Pittsburgh to Cohera.

In a recent announcement by the NIH regarding its Small Business Innovation Research (SBIR) Program Awards, Cohera Medical won a Phase I SBIR Award for $180,000 that will help in the development of its lead product, TissuGlu™.  The project will focus on developing a sprayable formulation for TissueGlu™ use in plastic surgery.  The SBIR program encourages small business to explore their technological potential and provides the incentive to profit from commercialization. By including qualified small businesses in the nation's R&D arena, high-tech innovation is stimulated along with entrepreneurial spirit as the US works to meet specific research and development needs.

Studies in the lab have demonstrated that the bond created with TissuGlu™ is as strong after one hour as a normal wound is after a week of healing. Because the adhesive is created from sugars and amino acids, the components into which it breaks down are designed to be benign and lead to virtually no immune system response.  Cohera anticipates full FDA approval for TissuGlu™ as an internal surgical adhesive by 2009. 

The Cohera story is a great example of product research; it shows how an invention can transform from an idea into reality. Read More

The Regenerative Medicine Podcasts for July offer some intriguing topics:

#35- Milica Radisic, Ph.D.
Dr. Milica Radisic visits and discusses her studies related to functional tissue engineering. Dr. Radisic is an Assistant Professor, Institute of Biomaterials and Biomedical Engineering, Department of Chemical Engineering and Applied Chemistry, University of Toronto.

In the podcast, Dr. Radisic discusses the research in the Laboratory for Functional Tissue Engineering at the University of Toronto; focus areas include:

• Biomimetic approach to cardiac tissue engineering
• Development of functional, clinically sized (1-5 mm thick), compact cardiac constructs with physiologically relevant cell densities (108 cells/cm3)
• Advanced bioreactors for functional tissue engineering of myocardium
• Biophysical modulation of engineered myocardium
• Separation of heterogeneous cell populations (MEMS)

#36 – Alejandro Nieponice, M.D.
Alejandro Nieponice, M.D. visits Regenerative Medicine Today and discusses his studies related to tissue engineering and translational medicine. Dr. Alejandro Nieponice is currently a Research Assistant Professor of the department of surgery at the University of Pittsburgh and a faculty member of the McGowan Institute for Regenerative Medicine. He is also a surgical associate and director of the Clinical Translation Unit at the Austral University Hospital in Buenos Aires, Argentina.

Dr. Nieponice’s main goal is to foster clinical translation of novel tissue engineering approaches by bridging his surgical and research backgrounds. To accomplish that, he has promoted the creation of a Clinical Translation Unit within the operative room at the Austral University Hospital, providing full cell culture capabilities to facilitate clinical translation of cell-based technologies.

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

Authors:	Péault B, Rudnicki M, Torrente Y, Cossu G, Tremblay JP, Partridge T, Gussoni E, Kunkel LM, Huard J.
Title:	Stem and progenitor cells in skeletal muscle development, maintenance, and therapy
Summary:	Satellite cells are dormant progenitors located at the periphery of skeletal myofibers that can be triggered to proliferate for both self-renewal and differentiation into myogenic cells. In addition to anatomic location, satellite cells are typified by markers such as M-cadherin, Pax7, Myf5, and neural cell adhesion molecule-1. The Pax3 and Pax7 transcription factors play essential roles in the early specification, migration, and myogenic differentiation of satellite cells. In addition to muscle-committed satellite cells, multi-lineage stem cells encountered in embryonic, as well as adult, tissues exhibit myogenic potential in experimental conditions. These multi-lineage stem cells include side-population cells, muscle-derived stem cells (MDSCs), and mesoangioblasts. Although the ontogenic derivation, identity, and localization of these non-conventional myogenic cells remain elusive, recent results suggest their ultimate origin in blood vessel walls. Indeed, purified pericytes and endothelium-related cells demonstrate high myogenic potential in culture and in vivo. Allogeneic myoblasts transplanted into Duchenne muscular dystrophy (DMD) patients have been, in early trials, largely inefficient owing to immune rejection, rapid death, and limited intramuscular migration--all obstacles that are now being alleviated, at least in part, by more efficient immunosuppression and escalated cell doses. As an alternative to myoblast transplantation, stem cells such as mesoangioblasts and CD133+ progenitors administered through blood circulation have recently shown great potential to regenerate dystrophic muscle.
Source:	Mol Ther. 2007 May;15(5):867-77

 

PIs:	Stephen Badylak, DVM, PhD, MD
Co-PIs:	Susan Braunhut, Ph.D., professor of biological sciences at the University of Massachusetts at Lowell Lorraine Gudas, Ph.D., chairman of the pharmacology department and Revlon Pharmaceutical Professor of Pharmacology and Toxicology, Weill Medical College of Cornell University, New York City Ellen Heber-Katz, Ph.D., professor, molecular and cellular oncogenesis program, The Wistar Institute in Philadelphia Shannon Odelberg, Ph.D., assistant professor, departments of internal medicine and neurobiology and anatomy, University of Utah, Salt Lake City Hans-Georg Simon, Ph.D., a developmental biologist and assistant professor of pediatrics, Children’s Memorial Research Center and Northwestern University in Chicago
Title:	“Mammalian Limb Restoration”
Description:	The regenerative ability of adult human tissues, organs, and appendages is typically very limited.  The default mechanism of wound repair in humans and most other mammals is characterized by scar tissue formation.  However, there is evidence for some site-specific regeneration-like processes during mammalian embryologic development and during the early postnatal period.  In addition, there is lifelong self-renewal capability for selected cell populations such as hematopoietic cells, intestinal epithelium, and hepatocytes. In contrast, urodele amphibians possess extraordinary abilities to regenerate lost structures, such as the limbs and tail, throughout their lifetime.   These regenerative processes are dependent upon the formation of a blastema at the site of injury.  This regeneration blastema is comprised of a self-organizing pool of proliferating progenitor cells genetically programmed to develop into a phenocopy of the lost structure.  The blastema carries its own extracellular matrix and its own gene expression signature.  The work described in this project will attempt to unlock the regenerative potential in humans by determining the genetic signature of the developing blastema and attempting to recreate portions of the fetal development process in humans. The research will involve several milestones including identification of cells that participate in the formation of a blastema-like structure in mammals, the spatiotemporal location of such cells during the remodeling process and the identification of bioactive molecules that induce, maintain, and complete such a process.  The culmination of this work would eventually be the application of these identified mechanisms and events to the injured mammal in a mouse model.  A highly interdisciplinary research team has been developed with expertise in developmental biology, molecular biology, matrix biology, pharmacology, immunology, and with training in medicine, veterinary medicine, physics, and computational methods of data mining.  Significant preliminary data has been generated to support the fundamental approach.  Well defined milestones have been identified and a management scheme has been established that assures close collaboration among the principal investigators and their respective laboratories at six different institutions.
Source:	DARPA (W911NF-06-1-0067); Year 2 funding ($3,605,738).
Term:	6/15/07 – 6/14/08

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