September 2004 | VOL. 9 | www.McGowan.pitt.edu

Tissue engineering technology used in life saving surgery

In 1986 Dr. Stephen Badylak and his research team began investigating naturally occurring “scaffolds” for organ and tissue reconstruction, and field that was later called “tissue engineering”. At that time, Dr. Badylak’s laboratories were at Purdue University; in January 2002 he brought his research program to the McGowan Institute where he has expanded his pioneering research in tissue engineering / regenerative medicine.

In his early studies, Dr. Badylak discovered that a strong, pliable tissue harvested from porcine small intestine provides an inductive scaffold for host cells to replace and repair damaged tissue. This biomaterial is called small intestinal submucosa, or SIS, and it is a naturally-occurring, complex matrix that is easy to handle, yet strong enough to hold sutures and provide support for weakened tissue (Illustration is provided courtesy of Cook Group)

As a naturally-derived, extracellular matrix (ECM) material, SIS is not chemically cross-linked. Since SIS is taken from a biological source and is processed to remove all cells, it is biocompatible and safe for human use. It is sterilized to eliminate pathogens and provide a long shelf life.

The initial SIS science developed by Dr. Badylak and his colleagues was subsequently licensed to DePuy, Inc. and Cook Biotech, Inc. These companies today market a variety of products whose origin is the Badylak SIS technology. See current Cook Biotech, and the DePuy product lines.

Success is measured in the significance and the frequency of outcomes. In the case of SIS-based clinical procedures, success has clearly arrived. SIS-clinical tissue engineering procedures have now assisted over 250,000 patients. The recent use of SIS-based products to facilitate the separation of 27 month-old twins who were co-joined at the head is noteworthy; this procedure was made possible, in part, by the availability of SIS technology.

Surgeons at the Children's Hospital at Montefiore Medical Center, New York City separated Carl and Clarence Aguirre, Filipino twins who were joined at the head. The doctors used Durasis Dural Substitute, a SIS-based biomaterial from Cook Biotech Inc., to replace the dura mater on the heads of the boys. Dura mater is the tough, fibrous sheath that surrounds the brain and spinal cord. The photo shows the Twins leaving Children’s Hospital [Photo Credit- The Children's Hospital at Montefiore].

Surgical team leader, Dr. James Goodrich, director of pediatric neurosurgery at Children's Hospital said that “Carl had nothing covering his brain. Clarence was lacking about a third of the covering,” Goodrich told the New York Daily News. “It probably didn't take us more than half an hour to reconstruct the top (with) a pseudo-membrane made of the inner lining of pig intestine. It allows natural fibers from each side to grow into it.”

“In time, the dura regenerates with this acting as a framework, like a mesh. For whatever reason, the pig intestine seems to be a nice source, because it's very hypoallergenic, there's no immune response to it, the body doesn't try to reject it.”

The SIS and ECM scaffold story does not end here…Dr. Badylak and his McGowan Institute colleagues and students are making significant progress on new tissue engineering technologies that may soon provide scaffolds for the replacement of damaged esophagus and trachea. He is recognized world-wide for his scientific achievements, but he is equally respected for his intensity and success in moving new technologies FROM THE LAB, TO COMMERCE, TO THE CLINIC…

Sources for Story
- Children's Hospital at Montefiore Medical Center
- New York Daily News
- Lafayette-West Lafayette Journal and Courier
- The Children's Hospital at Montefiore

 

Implications Include Developing Materials that Both Detect and Kill Biological Agents

McGowan Institute researchers have synthesized a simple molecule that not only produces perfectly uniform, self-assembled nanotubes but creates what they report as the first “nanocarpet,” whereby these nanotubes organize themselves into an expanse of upright clusters that when magnified a million times resemble the fibers of a shag rug. Moreover, unlike other nanotube structures, these tubes display sensitivity to different agents by changing color and can be trained to kill bacteria, such as E. coli, with just a jab to its cell membrane.

How a single-step synthesis of a hydrocarbon and a simple salt compound produced these unique nanotube structures with antimicrobial capability is described in a paper posted on the Web site for the Journal of the American Chemical Society . “In these nanotube structures, we have created a material that has the ability to sense their environment. The work is an outgrowth of our interest in developing materials that both sense and decontaminate chemical or biological weapons,” said senior author Alan Russell, Ph.D.

Figure: SEM images of the formation of nanotubes and nanocarpets: (A) nanotubes and lamellar structures formed from the intermediates of quaternization; (B) lamellar structures of the bromine salt of 2; (C) linear nanotubes and one branched nanotube from compound 3 showing the monodispersity of the diameters; (D) nanocarpet; (E) front view of the nanocarpet; (F) side view of the nanocarpet.

“To our knowledge, the remarkable self-assembly of this inexpensive and simple lipid is unprecedented and represents an important step toward rational design of bioactive nanostructures. In addition, because they form within hours under room-temperature conditions, the significant costs of synthesizing carbon nanotubes can be reduced,” explained first author Sang Beom Lee, Ph.D., research assistant professor of bioengineering in the School of Engineering.

The most critical performance tests, say the researchers, were those involving E. coli, which were conducted to assess the material’s interactions with living cells. In the presence of E. coli, some strains of which are food-borne pathogens, the nanotubes turned shades of red and pink. Moreover, with the aid of an electron microscope, the researchers observed the tubes piercing the membranes of the bacteria like a needle being inserted into the cell. Both the polymerized (those that can change color) and the unpolymerized nanotube structures were effective antimicrobials, completely killing all the E. coli within an hour’s time.

“We are very encouraged by these results and we will be continuing our investigations of this novel material in collaboration with our colleagues at the University of Pittsburgh and the U.S. Army Research Office,” added Dr. Russell.

In addition to Drs. Russell and Lee, other authors, all from the University of Pittsburgh, are Richard Koepsel, Ph.D., department of chemical and petroleum engineering, School of Engineering; Donna B. Stolz, Ph.D., Center for Biologic Imaging, School of Medicine; and Heidi E. Warriner, Ph.D., department of chemistry, School of Arts and Sciences. MORE

 

The Commonwealth of Pennsylvania 2005 appropriations bill included $1.2 million to support a grant to the McGowan Institute from the PA Department of Health. This support is especially important in the development of preliminary data that can be used in new proposals to the National Institutes of Health and other Federal agencies. These “seed funds” permit McGowan faculty to identify new opportunities through early-stage studies where sufficient data is developed to make the National grant applications more competitive. Based on prior funding from the Commonwealth, every dollar of support from the State yields 10 to 15 times that level of research support from the Federal agencies. Specific studies in new grant will include the continued development of artificial and biohybrid organs, and studies to enhance research on the therapeutic applications of regenerative medicine and tissue engineering.

 

The potential therapeutic use of stem cells derived from fat will be discussed at the Second Annual Meeting of the International Fat Applied Technology Society (IFATS) Oct. 4 - 5 at the Sheraton Station Square in Pittsburgh. Scientists, academic surgeons and physicians and representatives of the biotechnology industry will present new research findings and consider future directions for this emerging field.

The scientific program, “Targeting Fat for Therapy: New Opportunities for Translational Research and Clinical Treatment,” will explore how adipose tissue – more commonly known as fat – discarded in liposuction procedures can offer a unique, simple and abundant source of stem cells that could be used for tissue engineering and regenerative medicine. Among the topics to be covered are:

- Techniques for harvesting and isolation of adipose-derived stem cells
- Characterization and maintenance of adipose-derived stem cells
- Applications for bone regeneration, peripheral nerve repair and heart repair
- Effects of bariatric surgery on fat cell physiology

Research has indicated adipose-derived stem cells can be coaxed into bone, nerve, cartilage and endothelial cells. J. Peter Rubin, M.D., assistant professor of plastic and reconstructive surgery, co-director of the Aesthetic Surgery Center, director of the Life After Weight Loss Program at the University of Pittsburgh Medical Center (UPMC), and a McGowan Institute faculty member, is the society’s current president. MORE

 

Dr. Harvey Borovetz feels that therapies currently involving metals, plastics, and fabrics will someday be replaced by therapies involving cells, tissues, and organs. “It makes the ultimate sense that tissues be replaced with tissues,” he said. “The future is clearly in regenerative medicine.”

As a bioengineer, Dr. Borovetz, professor and chairman, department of bioengineering; professor of chemical and petroleum engineering; and Robert L. Hardesty Professor of Surgery, also knows that bioengineers will be critical to regenerative medicine. “Ultimately, you’re trying to understand processes at microscopic and nano scales and translate that to an understanding of how the organ process evolves and works,” he explains. “This type of investigative work clearly involves bioengineering.”

Much of the future of bioengineering lies in what has been accomplished in the past, and for Dr. Borovetz, the past has been a blessing. When asked about his career, he said, “I don’t consider it a career, I consider it an odyssey.” A physicist by education, Dr. Borovetz began his work in the aerospace industry. It left him unsatisfied and looking for more interaction with people, but wanting to maintain his technical background. Bioengineering filled that void and he earned his master’s degree and PhD in bioengineering from Carnegie Mellon. In 1976, he was hired by Dr. Robert Hardesty in the Department of Surgery and Dr. Bartley Griffith joined the department one year later. When Dr. Thomas Starzl arrived in 1980 and liver transplants began, Drs. Hardesty and Giffith developed the heart transplant program. Dr. Borovetz supplied technical support for the transplant program, and once the now world-class heart transplant program was developed, the team started the working with artifical hearts. “It was the third weekend of October 1985 when we implanted the first patient with an artificial heart,” Dr. Borovetz remembers easily. Having only trained on animals, Dr. Borovetz said he was petrified, “but quietly so” he added.

He was the first bioengineer in the clinical artificial heart program, which today has grown into a company, Vital Engineering, which has supported the implantation of hundreds of patients, and provides consulting and training to industry and clinical centers nationally and internationally. In the early days, it was an extraordinary pioneering effort in saving lives. From that point on, his career seems to have been a whirlwind. “I would’ve never believed that I would be working in an operating room or have such direct contact with patients as I did in those early years,” he said.

Not only did he work in the operating room, but he would sleep in the hospital and in on-call rooms with doctors, monitoring patients overnight. “When you work with folks in the middle of the night, in good times and bad, it’s really something special,” he said.

Dr. Borovetz has worked tirelessly for University of Pittsburgh students, providing special opportunities through the Artificial Heart Program and the Department of Bioengineering. Today he is the chairman of the Department of Bioengineering. “We had an infrastructure of bioengineering in the School of Medicine, so we thought, ‘Why not develop the opportunity for bioengineering to grow in the School of Engineering?’ ” Once they had accumulated a critical mass of researchers, the department was officially established in 1998. Today there are nearly 300 undergraduate and graduate students in the Bioengineering program at the University of Pittsburgh.

After spending most of his life around heart surgeons, Dr. Borovetz admits they are a driven breed and he is still trying to keep up. “It’s hard to impress heart surgeons,” he said laughing. When a group of colleagues decided to run marathons, Dr. Borovetz said he had to hold up his end of the bargain. In the last five years, he’s run eight marathons. “My daughters say that my mind is young, but my body is not.”

While he may not physically run any more marathons, his marathon lifestyle seems to continue. In April 2004, Dr. Borovetz and consortium were awarded a $4.5 Million grant from the NIH to develop an implantable, left Ventricular Assist Device (VAD) to support the failing heart of newborns for periods up to 6 months. A long continuance of his PhD research in artificial organs for babies, his investigative team envisions the pediatric VAD to be about the size of a quarter, with features designed to meet the special needs of patients with congenital and acquired heart defects who are as young or small as a newborn baby. “The desire to bring these technologies to pediatric care has always been there,” he said. “Fortuitously, the NIH has made funding available.” The $4.5 million contract is in conjunction with Children’s Hospital of Pittsburgh and Carnegie Mellon University.

The future in regenerative medicine therapies is promising, and just as Dr. Borovetz was in the early years of organ transplant, he is clearly a pioneer with a passion and the drive to advance the delivery of these cutting-edge technologies to patients. Editors note: our appreciation to Kate Ledger for her contributions to this story.

 

Freddie H. Fu, M.D., professor and chairman of the department of orthopaedic surgery, McGowan Institute faculty member and noted sports medicine physician at the University of Pittsburgh Medical Center, was appointed on September 16, 2004 by Pennsylvania Governor Edward G. Rendell to serve on the newly created Governor’s Advisory Commission on Asian American Affairs.

Dr. Fu is one of 15 prominent Pennsylvania residents officially appointed to begin serving a two-year term on the new commission. The group’s mission is to serve as Gov. Rendell’s liaison to the Asian American community and to advise the governor on policies, procedures, legislation and regulations that affect the Commonwealth’s Asian American community and that will enable responsiveness to the needs of Asian Americans. The commission will develop, review and recommend to the governor policies in the areas of health and human services, housing, education, employment, business formation and development, public accommodations and in contracting practices and procedures. MORE

 

Congratulations to the following students in Dr. Vorp’s laboratory for the recently awarded fellowships:

American Heart Association PA-DE Affiliate Pre-doctoral Fellowship (2 year fellowship with a 3rd year competitive renewal)

J. Scott VanEpps "Improving the Understanding of the Role of Biomechanical Forces in Atherogenesis: A Combined Computational and Experimental Approach"

Timothy Maul "Influence of Mechanical Forces on Adult Progenitor Cells: Implications for Vascular Tissue Engineering"

NIH F31 aka Ruth Kirschstein National Research Service Award (NRSA); (3 year fellowship)

Rachelle Prantil "Biomechanics and Function of the Pathologic Urethra"

Timothy Maul "Influence of Mechanical Forces on Adult Progenitor Cells"

 

In April 2004, Dr. Amit Patel, Director of Cardiac Stem Cell Therapy, McGowan Institute reported that injections of adult stem cells into damaged heart tissue significantly improved heart function in patients with severe congestive heart failure. This report was based on the studies that Dr. Patel and his colleagues had conducted in other countries. It was the first prospective randomized trial of this experimental cellular therapy. Dr. Patel presented these findings at the American Association for Thoracic Surgery on April 25, 2004. Photo credit – Business Week- May 24, 2004

To further understand the mechanisms that yield these promising initial results, the Pittsburgh Foundation has funded a study here under the leadership of Dr. Robert Kormos, Medical Director, McGowan Institute. Upon FDA approval, the pilot study involving five patients will assess the feasibility, as well as the efficacy of transplanting bone marrow derived progenitor cells into the myocardium of patients with cardiomyopathy. What is unique about the study is that all of the patients will be supported by a Left Ventricular Assist Device (LVAD) while they are waiting for a heart transplant. This unique model allows the study team to implant these cells into a heart which has its function supported by the LVAD, thereby reducing the risk due to the direct cellular injection. It also gives the team a unique opportunity to examine the heart and the effects of cellular transplantation on the myocardial tissue, as the heart will eventually be removed at the time the patient receives his/her heart transplant.

This study will document what potential changes occur in the myocardium following transplantation of these cells. Furthermore, detailed characterization of the injected cell population will be performed, in an effort to understand the biology of the transdifferentiation process. This study provides a unique opportunity to observe the effects of the progenitor cells in-vivo in the patients with congestive heart failure (CHF).

The ultimate goal of Regenerative Medicine is to maximize the body’s potential to heal itself in the face of organ damage or failure, before chronic irreversible changes occur that lead to the more costly and higher risk therapies such as conventional heart surgery, transplantation, or mechanical support. To that end, this study will investigate the injection of a subset of progenitor cells which promote regenerative healing of the myocardium in patients who are already undergoing left ventricular assist device implantation.

 

Diana Spencer
412-235-5156
spencerdk3@upmc.edu