Newsletter - Regenerative Medicine at the McGowan Institute

The 8th Annual McGowan Institute for Regenerative Medicine Scientific Retreat is set to take place on March 9-11, 2009 at Nemacolin Woodlands Resort. An informal mixer will occur on the evening of March 8, 2009.

Under the leadership of Dr. William Wagner, the program committee has planned an exciting group of speakers and topics. The program will include distinguished guest speakers, a poster session, and potential external partners and collaborators, so there will be multiple opportunities for networking and collaboration.

In addition to the McGowan Institute Distinguished Lecture, which will be given by Jeffrey A Hubbell, PhD of the Regenerative Medicine and Pharmacobiology Laboratory, Ecole Polytechnique Fédérale de Lausanne, Switzerland, the following sessions will be offered:

Clinical Translation of Biologic Scaffold Materials
Applications and Approaches for Optical Imaging: From Single Molecules to the Whole Animal
AFIRM-Selected Topics
Ocular Regeneration: Applied Fundamentals
Biomechanics in Regenerative Medicine Training Program
New Cardiovascular Technologies
Translational Systems Biology: Applications to Regenerative Medicine
Bioreactor Technologies and Applications
Translating Regenerative Technologies for Commercial Delivery
Damage Associated Molecular Pattern Molecules and Regenerative Medicine
Cardiovascular Bioengineering Training Program
Training Opportunities for Young Scientists and an Introduction to the Resources Provided by the Office of Academic Career Development
Induced pluripotent stem cells (iPS)
Neural Engineering
Assessment of 3-D Printing Technologies
NSF ERC for Revolutionizing Metallic Biomaterials

The registration deadline is February 15, 2009 (or sooner; no reservations will be accepted once the reservation quota is filled.)

Carnegie Science Center Award Winners Announced

Donna Haworth The Carnegie Science Center recently announced the winners of the Thirteenth Annual Carnegie Science Awards 2009. We are pleased to learn that Donna J. Haworth is the first winner in the newly created category of University/Post-Secondary Student Award, which recognizes scientific advances through research, effectiveness in increasing the public awareness of the role of science or engineering to society, and inspiring youth in the promotion of career opportunities.

Ms. Haworth is a member of the Vorp lab at the McGowan Institute, and her graduate training is in the area of tissue engineering, with a specific focus on the development of a tissue engineered urethral wrap (TEUW). She earned her Bachelor’s of Science from Youngstown State University, School of Engineering in Youngstown, Ohio. She studied Chemical Engineering and graduated Summa Cum Laude. Currently, she is working towards her PhD in Bioengineering at the University of Pittsburgh. She expects to graduate in August 2009.

McGowan faculty member Dr. Charleen Chu McGowan Institute faculty member Charleen T. Chu, MD, PhD received an Honorable Mention in the category of Emerging Female Scientist, which recognizes a female leader whose cutting-edge work is inspiring change in math, science, or technology. Dr. Chu is an associate professor of Neuropathology within the Pathology Department at the University of Pittsburgh. She is being recognized for her contributions in mitochondrial kinases and autophagic cell death, which impacts research across organ systems.

We are also pleased to recognize the Honorable Mentions of Marc S, Malandro, PhD, CLP for the Catalyst Award, which acknowledges excellence in promoting public awareness of scientific issues and advancing science in society, and of Patrick Daly for the Start-Up Entrepreneur Award, which recognizes entrepreneurs who have successfully commercialized research in science and technology. Dr. Malandro is the head of the University of Pittsburgh’s Office of Technology Management; Mr. Daly is the President and CEO of Cohera, Inc, which is a licensee of McGowan Institute developed technology.

The Carnegie Science Awards program was established in 1997 to recognize and promote outstanding science and technology achievements in western Pennsylvania. The awards will be presented on May 8, 2009.

Congratulations to all!

Biomimetics: A New Regenerative Medicine Approach

McGowan faculty member Dr. Steven Little Biomimetics is the word most frequently used in scientific and engineering literature that is meant to indicate the process of understanding and applying (to human designs) biological principles that underlie the function of biological entities at all levels of organization. Researchers use the inspirations found in nature to emulate "life's genius" for the purpose of improving manufacturing processes, creating new medicines, changing the way people grow food, or harnessing energy. McGowan Institute faculty member Steven Little, PhD, Assistant Professor in the Department of Chemical Engineering with joint appointments in Bioengineering, Immunology, and Medicine, is a biomimetician. As reported in PittMed, in his lab he has managed to manipulate what’s manmade so it behaves as though it’s part of nature.

Dr. Little and his colleagues are focused on a variety of biomimetic-type research projects. Examples of what is occurring in his lab include:

•    using synthetic vasculature to deliver growth factors to accelerate wound healing;
•    encouraging tissue growth by creating artificial and biodegradable, yet bioactive, scaffolding;
•    delivering genetic material to immune cells by using synthetic pathogens;
•    engineering a homogenous and essentially inexhaustible supply of antigen-presenting cells that can spur or limit an immune response more efficiently than their natural cousins;
•    engineering a drug-delivery particle that will present an immunosuppressant drug to dendritic cells only;
•    making drug delivery vehicles that can be custom-crafted to release a specific drug over a particular time course; and,
•    investigating a strategy for summoning cells through the controlled release of chemokines.

Dr. Little says he and his colleagues are at the beginning of what may become a new discipline. This excites him. “Biomimetics is tremendously new,” he says. “We are definitely pushing the limits of what chemical engineers do and what bioengineers do.”

“That’s what makes me so excited about it,” he says. “It just looks at this stage to be limitless in what we might be able to accomplish.”

Read more…

Regenerative Medicine and Trauma Care for Today’s Soldiers

Army Medics in Action In 2008, the U.S. government funded a multi-million dollar medical research effort in support of today’s soldiers. The collaborative, national program—the Armed Forces Institute of Regenerative Medicine (AFIRM)—employs the science of regenerative medicine and tissue engineering to develop new treatments for wounded soldiers. Today, the lives of thousands of injured U.S. troops in Iraq and Afghanistan have been saved because of body armor, shorter evacuation times, and improved battlefield medicine. But when these soldiers return home, they are missing limbs. They are burned, scarred, and otherwise disfigured. As recently reported in PittMed, the injured-to-killed ratio in all American wars, from the Revolution to Gulf War I, was 2.5 to 1. In Afghanistan and Iraq, that number is around 9 to 1.

There are more than a dozen projects at the McGowan Institute that are a part of AFIRM focusing on effective wound-healing technologies. A few of these projects include the following principal investigators and their AFIRM-related research:
•    Kacey Marra, PhD, Assistant Professor of Surgery: Dr. Marra is working on a technique that will train severed nerves to regrow.

•    Charles Sfeir, DDS, PhD, Associate Professor, Department of Oral Medicine and Pathology; Prashant Kumta, PhD, Edward R. Weidlein Chair, Swanson School of Engineering and Professor in the Departments of BioEngineering, Chemical and Petroleum Engineering, and Mechanical Engineering and Materials Science; and Elia Beniash, PhD, Associate Professor, School of Dental Medicine: This craniofacial team is exploring a calcium phosphate powder that can be mixed with any liquid—water, saline, even blood—and daubed onto an exposed wound to regrow bone. The substance would behave a lot like Plaster of Paris and may even be applied with a finger.

•    William Wagner, PhD, Deputy Director of the McGowan Institute for Regenerative Medicine, Professor of Surgery, Bioengineering and Chemical Engineering, and Director of Thrombosis Research for the Artificial Heart and Lung Program: Dr. Wagner is studying a biocompatible patch to treat compartment syndrome, caused when injury-induced inflammation—say, in biceps shredded by shrapnel—causes enough pressure that blood vessels constrict and the tissue dies. Surgical incisions release the pressure. Dr. Wagner’s patch, seeded with stem cells or special growth proteins, can be sewn directly onto the incised compartment and stimulate regrowth.

Read more…

Novel Treatment for Lung Disease

McGowan Institute for Regenerative Medicine faculty member Jay Kolls, MD, Chief, Division of Pediatric Pulmonary Medicine, Allergy and Immunology, and Professor of Pediatrics and Immunology, School of Medicine, discovered a protein target that may lead to therapies to treat bacterial pneumonia and play a vital role in creating a vaccine to prevent the disease. Dr. Kolls’ work today points toward a future treatment more effective than antibiotics that comes without the risk of creating antibiotic resistance. As reported by Joe Miksch, PittMed, through Dr. Kolls’ efforts, a novel treatment for pneumonia will one day emerge from a new cell line.

In his years of research, Dr. Kolls linked interleukin-17, T Helper type 17 cells, neutrophil responses, cytokines, interleukin-22, lypocalin-2 (an iron-stealing protein), antimicrobial peptides, invading bacteria that scavenge iron from the body in order to survive. In his studies, by increasing the level of interleukin-22 in the lung tissue of mice infected with Mycobacterium tuberculosis, he was able to cure the rodents. More interleukin-22, Dr. Kolls found, meant that there were more iron-stealing proteins and progressively more resilient lung epithelial cells, which could better handle the insults and injuries caused by the pneumonia bacteria. Dr. Kolls says he thinks the process will work the same way in humans. Doses of recombinant interleukin-22 could be used as a prophylactic treatment against tuberculosis, he says, priming the immune system for a fight.

It will be as much as a decade before interleukin-22–related therapies are approved to treat or prevent tuberculosis in people. “We could use it as a prophylactic regimen; it could be used as a vaccine,” Dr. Kolls says. “There’s a 5- to 10-year timeline before this could probably happen, but we’ve learned a lot, and we’re making progress.”

Read more. . .

Pittsburgh Protocol for Immunosuppression After Hand Transplant

Composite Tissue Allotransplantation (CTA) is the umbrella term for transplantations composed of multiple tissues like the hand or face. More than 32 patients have received hand transplants at institutions around the world. The longest surviving hand transplant patient is the first U.S. recipient at almost 10 years.

Rejection of the new hand following a transplant is a major concern for the team of specialists involved with a transplant. For this reason, an immunosuppression protocol is followed. Induction therapy with antibodies together with multi-drug maintenance therapy represents the standard employed around the world in human hand transplantation. Such drug regimens, while effective, have caused complications like infection and drug toxicity, among others, jeopardizing the benefits gained from otherwise successful hand transplantation.

McGowan Institute faculty member Andrew Lee, MD, director of the Division of Plastic Surgery and Reconstructive Surgery, and the other members of the UPMC Hand Transplant Team (McGowan Institute faculty member Stefan Schneeberger, MD, director of the CTA Program; McGowan Institute faculty member Vijay Gorantla, MD, PhD, administrative director of the CTA Program; and Gerald Brandacher, MD, scientific director of the CTA Program) are proposing the use of the Pittsburgh Protocol for immunosuppression after hand transplant. It is composed of two elements: treating the patient with antibodies on the day of transplant, followed by a donor bone marrow infusion several days later. When used in solid organ transplants at UPMC, this protocol allows patients to be treated with low doses of a single maintenance drug.

In the last decade, around 80 different CTA surgeries have been performed with success. Since its inception, CTA has faced and endured much speculation, debate, controversy, and scrutiny. Early world outcomes have confirmed that satisfactory to excellent function can be achieved with these types of procedures. The goal now is successful avoidance of the risks of high-dose multiple drug therapy to prevent rejection. Strategies like the Pittsburgh Protocol that aim to minimize maintenance immunosuppression have been studied in organ transplantation at UPMC. Realization of such protocols in clinical CTA will herald a new era of reconstructive transplant surgery to treat complex and major tissue defects.

Evolution of New Brain Area Enables Complex Movements

According to McGowan Institute for Regenerative Medicine faculty member Peter Strick, PhD, professor in the department of neurobiology and senior career scientist at the Veterans Affairs Medical Center, and fellow neuroscientists, a new area of the cerebral cortex has evolved to enable man and higher primates to pick up small objects and deftly use tools.

The brain’s primary motor cortex turns out to have neighboring “old” and “new” parts. In most animals, including cats, rats, and some monkeys, the old primary motor cortex controls movement indirectly through the circuitry of the spinal cord, explained senior author Dr. Strick. But in man, the Great Apes, and some monkeys, another area of the motor cortex developed and is now home to a special set of cortico-motoneuronal (CM) cells, he said. These cells directly control spinal cord motor neurons, which are the nerve cells responsible for causing contraction of shoulder, elbow, and finger muscles. The direct control exerted by CM cells bypasses the limitations imposed by spinal cord circuitry and permits the development of highly complex patterns of movement, such as the independent finger action needed for playing an instrument or typing.

“What we’ve shown is that along with evolution of direct control over motor neurons, a new cortical area has evolved that’s right next to the old one,” Dr. Strick said. “We still have much the same spinal machinery the frog has, but the new cortical area with CM cells endows humans with the superior hand skills to manufacture and use tools – an especially human trait.”

He and co-author Jean-Alban Rathelot, Ph.D., a research associate in Dr. Strick’s lab, based their conclusions on a series of experiments in which rabies virus was injected into single muscles in the shoulders, elbows, or fingers of monkeys. The virus, chosen because of its unique ability to travel between networked nerve cells, was tracked to locate CM cells in the primary motor cortex.

Dr. Strick noted that the direct connection from the cortex to motor neurons is not present at birth, but develops during the first few months of life and becomes fully mature around 2 years of age. Thus, the progress of an infant’s motor skills is a display of the establishment of these connections.

Fat Cell Therapy Benefits Man’s Best Friends

McGowan Institute faculty member J. Peter Rubin, MD, is co-director of the University of Pittsburgh Adipose Stem Cell Center. Studies there focus on the isolation, growth and differentiation, biology, and therapeutic applications of stem cells derived from adipose tissues. Dr. Rubin and the Center’s researchers are isolating, characterizing, and testing adult stem cells from fat (or adipose tissue) for use in therapeutic applications in humans. Today, some of the potentially promising regenerative medicine applications using fat-derived stem cells are already in use in horses and dogs.
In 2002, Vet-Stem, Inc. was formed to bring regenerative medicine technology to the veterinary profession. The goal was to be the conduit for the latest developments in human medical technology and provide easy-to-use services and products to the practicing veterinarian. Recently, Dr. Rubin weighed in on the science and therapeutic benefits of adipose stem cells for some of man’s best friends.

"This is a very interesting therapy and one where the results have been fairly striking," Dr. Rubin said. "It's definitely based on evidence, and they are showing good data to support these changes for a number of years now. I believe the results are real."

This regenerative cell therapy has demonstrated successful therapeutic outcomes in horses with tendon and ligament injuries, fractures, and joint disease. This same therapy is now being used to treat osteoarthritis in dogs. Since 2005, selected veterinary clinics have treated dogs with osteoarthritis and orthopedic soft tissue injuries. Initial studies demonstrate that intra-articular administration of this cell-based therapy significantly decreases pain and improves comfort in the majority of cases. Duration of the benefit from a single injection varies from several months to more than 1 year. Depending on how many joints need injections, the cost ranges from $2,400 to $3,000.

Fat, or adipose tissue, contains an abundant number of adult stem cells, over 10 times more than in bone marrow. These cells not only regenerate adipose tissue, but they can reconstruct a variety of injuries and defects by being coaxed to develop into nerves, bone, or cartilage—areas of research being conducted at the Adipose Stem Cell Center.

Read more…

Therapy Option for Short Bowel Syndrome Patients

McGowan Institute for Regenerative Medicine faculty member Julie Fuchs, MD is an assistant professor of surgery and practices in the Division of Pediatric Surgery at Children’s Hospital of Pittsburgh of UPMC. An area of interest within Dr. Fuchs’ research efforts is in exploring novel treatments for short bowel syndrome and liver failure. Short bowel syndrome (SBS, also short gut syndrome or simply short gut) is a malabsorption disorder caused by the surgical removal of more than two thirds of the small intestine, or, rarely, due to the complete dysfunction of a large segment of bowel. Most of these cases are acquired, although some children are born with a congenital short bowel. Babies born with SBS lack the ability to digest food or absorb nutrients.

In newborn infants, the 4-year survival rate on total parenteral nutrition (TPN) is approximately 70%. TPN is often referred to as IV nutrition (feeding directly into a venous catheter). Some studies suggest that much of the mortality is due to a complication of the plant-based TPN, especially chronic liver disease. Much hope is vested, however, in Omegaven, a type of fish oil-based TPN feed, in which recent case reports suggest the risk of liver disease is much lower. Omegaven is rich in omega-3 fatty acids.

At Children's, Omegaven has been used in about two dozen patients and is "very promising," said Dr. Fuchs. "We've had very good results, but we're planning to study it long term in more detail."

Omegaven - which typically costs $50 to $100 a day - is not approved in the United States but is made available to individual patients with permission of the FDA. Today, that means parents must make the choice to give their very sick baby an experimental treatment. Omegaven’s German manufacturer, Fresenius Kabi, supports clinical investigations needed for Omegaven to gain federal approval for use on children facing liver failure because of IV nutrition.

First Paired Kidney Transplant Performed

McGowan Institute for Regenerative Medicine faculty member Ron Shapiro, MD is director of the kidney, pancreas, and islet transplant program at the UPMC Thomas E. Starzl Transplantation Institute and professor of surgery and Robert J. Corry Chair in Transplantation Surgery at the University of Pittsburgh, School of Medicine. On December 10, Dr. Shapiro and a team of UPMC doctors participated in UPMC’s first kidney paired donation in collaboration with Temple University Hospital and the Paired Donation Network. The couples, a husband and wife from Pittsburgh and two sisters from Philadelphia, donated kidneys to each others’ loved ones in a two-way surgical swap. Such paired exchanges are still uncommon. All donors and recipients are recovering well.

The Pittsburgh recipient, Galina Komar, and her husband, Vyacheslav Komar, the original intended donor, were not ABO compatible. Instead, Mr. Komar traveled to Temple and donated his kidney to Mimi Weber of Philadelphia. The exchange then enabled Ms. Weber’s sister, Wendy, who could not donate to her sister because of incompatible blood types, to donate her kidney to Mrs. Komar at UPMC Montefiore.

The independent matches between the Komar and Weber families were identified after each couple had been through the preliminary screening processes at UPMC and Temple. This exchange was facilitated by the Center for Organ Recovery and Education (CORE) and the Gift of Life through their affiliation with the national donor registry.

The Paired Donation Network, administered locally by CORE, allows individuals to give of themselves to benefit another person through living donation. Though their intended donor is medically eligible to become a live donor, they have immunological or ABO incompatibilities with the recipient. This program offers patients with end-stage renal failure the hope of finding a compatible living donor. By agreeing to exchange recipients—giving the kidney to an unknown, but compatible individual—the donors provide two patients with healthy kidneys where previously no living donor transplant would have been possible. Through the registry, recipient and donor pairs are matched, thus creating two harmonious pairs.

Read more…

Regenerative Medicine Podcast Update

The Regenerative Medicine Podcasts continue to gain listeners and explore pertinent topics. Remember to tune in and keep abreast of new interviews. The most recent podcasts are:

#62 – Sanjeev G. Shroff, PhD – Dr. Shroff is the Associate Chair of the Department of Bioengineering at the University of Pittsburgh; Professor and Gerald McGinnis Chair in Bioengineering; Professor of Medicine; and Senior Investigator, Magee-Women’s Research Institute. Dr. Shroff shares highlights of his scientific studies on vascular stiffness and cardiovascular function as well as large-scale mathematical simulations of biological systems for research, education, and engineering design.

#63 – Major General (ret.) Gale S. Pollock – Major General (ret.) Pollock is the executive director of the nation’s first Center for Ocular Regeneration and Vision Restoration (CORVR), a division of the UPMC eye center. Major General Pollock discusses her goals for CORVR as well as current studies being done to improve quality of life for those with eye injuries and blindness.

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

Publication of the Month

Authors:	Wescoe KE, Schugar RC, Chu CR, Deasy BM.
Title:	The Role of the Biochemical and Biophysical Environment in Chondrogenic Stem Cell Differentiation Assays and Cartilage Tissue Engineering.
Summary:	The field of regenerative medicine offers hope for the development of a cell-based therapy for the repair of articular cartilage (AC). Yet, the greatest challenge in the use of stem cells for tissue repair, is understanding how the cells respond to stimuli and using that knowledge to direct cell fate. Novel methods that utilize stem cells in cartilage regeneration will require specific spatio-temporal controls of the biochemical and biophysical signaling environments. Current chondrogenic differentiation research focuses on the roles of biochemical stimuli like growth factors, hormones, and small molecules, and the role of the physical environment and mechanical stimuli, such as compression and shear stress, which likely act through mechanical receptors. Numerous signals are associated with chondrogenic-like activity of cells in different systems, however many variables for a controlled method still need to be optimized; e.g., spatial and temporal application of the stimuli, and time of transplantation of an engineered construct. Understanding the necessary microenvironmental signals for cell differentiation will advance cell therapy for cartilage repair.
Source:	Cell Biochem Biophys. 2008;52(2):85-102.

Grant of the Month

PI	Rick Koepsel
Co-Investigators	Sharon Marx and Gabriel Amitai
Title	Temperature responsive modification of microfiber tissue perfusion devices.
Description	Tissue perfusion devices based on hollow fibers have been developed for use in bioreactors and for wound healing. In both cases the perfusion devices are in direct contact with cells and tissues. The hollow fiber tubing that makes up the devices is fabricated from hydrophilic materials, which resist the direct attachment of cells and proteins in the short term but over time cells will attach to the devices. With cells and tissue attached to the device, removal of the device can disrupt the structure of the tissue that was the intended when the device was implanted. This project will extend the development of tissue perfusion devices by providing smart polymer coatings which, when activated, will facilitate the removal of the device. Smart polymers are materials that exhibit a response to a physical stimulus. For this project we will concentrate on the temperature responsive polymer poly (N-isopropylacrylamide) (pNIPAAm). As with many temperature responsive materials, pNIPAAm in aqueous solution changes structure at a temperature called the lower critical solution temperature (LCST). In the case of pNIPAAm the LCST is about 320C, below the LCST the polymer is soluble in aqueous solution while above the LCST a change in the polymer structure causes the polymer to be come hydrophobic and form micelles in solution. When pNIPAAm is immobilized on a surface it still responds to temperature. A surface coated with pNIPAAm is hydrophobic below the LCST but becomes hydrophilic above the LCST. Cells grown on tissue culture dishes coated with pNIPAAm will attach and proliferate normally while the dishes are kept at 370C but when the temperature is lowered below the LCST the cells are sloughed off of the surface. If the cells have grown to a confluent monolayer, they will come off the surface as a cohesive sheet showing that the underlying protein layer to which the cells are attached is also sloughed from the surface. Applying a layer of pNIPAAm to the hollow fiber perfusion tubing should therefore allow a temperature change to eliminate the adhesions between the cells or tissues and the perfusion device allowing the device to be removed with considerably less trauma to the insertion site.
Source	PTEI/DOD
Term	11/1/08 – 10/31/09
Amount:	$203,752

Newsletter Comments or Questions: McGowan@pitt.edu