December 2014 | VOL. 13, NO. 12 | www.McGowan.pitt.edu
Treating the potentially blinding haze of a scar on the cornea might be as straightforward as growing stem cells from a tiny biopsy of the patient’s undamaged eye and then placing them on the injury site, according to pre-clinical model experiments conducted by McGowan Institute for Regenerative Medicine affiliated faculty members James Funderburgh, PhD, Yiqin Du, MD, PhD, and researchers at the University of Pittsburgh School of Medicine. The findings, published in Science Translational Medicine, could one day rescue vision for millions of people worldwide and decrease the need for corneal transplants.
According to the National Eye Institute “Worldwide, corneal infectious diseases have compromised the vision of more than 250 million people and have blinded over 6 million of them.” Trauma, such as burns, are also a leading cause of corneal scarring, said senior investigator Dr. Funderburgh, professor of ophthalmology at Pitt and associate director of the Louis J. Fox Center for Vision Restoration of UPMC and the University of Pittsburgh, a joint program of UPMC Eye Center and the McGowan Institute.
“The cornea is a living window to the world, and damage to it leads to cloudiness or haziness that makes it hard or impossible to see,” Dr. Funderburgh said. “The body usually responds to corneal injuries by making scar tissue. We found that delivery of stem cells initiates regeneration of healthy corneal tissue rather than scar leaving a clear, smooth surface.”
Study lead author Sayan Basu, MBBS, MS, a corneal surgeon working at the L.V. Prasad Eye Institute in Hyderabad, India, joined Dr. Funderburgh’s lab in Pittsburgh. Dr. Basu had previously developed a technique to obtain ocular stem cells from tiny biopsies at the surface of the eye and a region between the cornea and sclera known as the limbus. Removal of tissue from this region heals rapidly with little discomfort and no disruption of vision. After collecting biopsies from banked human donor eyes, the team expanded the numbers of cells in a culture plate using human serum to nourish them. They conducted several tests to verify that they these cells were, in fact, corneal stem cells.
“Using the patient’s own cells from the uninjured eye for this process could let us bypass rejection concerns,” Dr. Basu noted. “That could be very helpful, particularly in places that don’t have corneal tissue banks for transplant.”
The team includes co-lead author Andrew J. Hertsenberg, BS, Martha L. Funderburgh, MSPH, Michael K. Burrow, BS, Mary M. Mann, MS, Kira L. Lathrop, MAMS, and Fatima N. Syed-Picard, PhD, all of Pitt; and Sheila M. Adams, PhD, and David E. Birk, PhD, both of the University of South Florida.
The project was funded by NIH grants EY016415, EY05129 and P30-EY08098, the Louis J. Fox Center for Vision Restoration, the Hyderabad Eye Research Foundation, and from Research to Prevent Blindness Inc.
Illustration: Stem cells found in the human limbus (the region between the cornea and the sclera, the white part of the eye) can be used to prevent the scarring of corneal tissue. Credit: C. Bickel/ AAAS.
The 14th Annual McGowan Institute for Regenerative Medicine Scientific Retreat is set to take place on March 8-10, 2015, at Nemacolin Woodlands Resort.
The poster session will begin on the evening of March 9, 2014, at which time there will be an informal mixer.
Under the leadership of McGowan Institute for Regenerative Medicine faculty member Dr. Fabrisia Ambrosio, Assistant Professor in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh, the program committee is planning an exciting group of speakers and topics.
Highlights from the 2014 Retreat can be found here.
Register online for the 2015 Retreat here.
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The annual Regenerative Rehabilitation Symposia series is a unique opportunity for students, researchers, and clinicians working in the interrelated fields of regenerative medicine and rehabilitation to meet, exchange ideas, and generate new collaborations and clinical research questions. Jointly organized by the University of Pittsburgh Rehabilitation Institute, the School of Health and Rehabilitation Sciences at the University of Pittsburgh, the McGowan Institute for Regenerative Medicine and the Rehabilitation Research and Development Center of Excellence at the Veterans Affairs Palo Alto Health Care System, the Fourth Annual Symposium on Regenerative Rehabilitation will be held on September 24-26, 2015 in Rochester, MN, hosted by the Mayo Clinic.
The objectives of this event are:
- To promote the clinical translation of regenerative medicine scientific discoveries by communicating and disseminating research findings that demonstrate the synergistic relationship between regenerative medicine and rehabilitation;
- To provide a forum by which scientists and rehabilitation clinicians may interact, exchange ideas, and identify novel research directions relating to the field of regenerative rehabilitation; and
- To introduce the concept of regenerative rehabilitation to graduate students, medical students and medical residents in the rehabilitation field.
The McGowan Institute's Spring Distinguished Lecture Series has been announced.
The first Distinguished Lecturer is Gordana Vunjak-Novakovic, PhD, Mikati Foundation Professor of Biomedical Engineering and Medical Sciences, Columbia University. She will speak on “Tissue Engineering: Into the Era of Personalized Medicine.”
The lecture is scheduled for Monday, March 9, 2015 at 8:00 am during the 14th Annual McGowan Institute for Regenerative Medicine Scientific Retreat. For more information about the retreat, please click here.
The second Distinguished Lecturer is George Q. Daley, MD, PhD, the Samuel E. Lux IV Professor of Hematology/Oncology and Director of the Stem Cell Transplantation Program at Boston Children’s Hospital. He is also Professor of Biological Chemistry and Molecular Pharmacology, Medicine, and Pediatrics at Harvard Medical School, an investigator of the Howard Hughes Medical Institute, Associate Director of Children’s Stem Cell Program, founding member of the Executive Committee of the Harvard Stem Cell Institute, and past-President of the International Society for Stem Cell Research (2007-2008).
The lecture will be held at the University Club, Ballroom A. It is scheduled for Thursday, April 9, 2015 at 4:00 pm.
When the body forms new tissues during the healing process, cells must be able to communicate with each other. For years, scientists believed this communication happened primarily through chemical signaling. Now researchers at Carnegie Mellon University and the University of Pittsburgh have found that another dimension – mechanical communication – is equally if not more crucial. The findings, published in the Proceedings of the National Academy of Sciences, could lead to advancements in treatments for birth defects and therapies for cancer patients.
“It’s like 19th century scientists discovering that electricity and magnetism were the same force,” said McGowan Institute for Regenerative Medicine affiliated faculty member Lance Davidson, PhD, associate professor and Wellington C. Carl Faculty Fellow of Bioengineering at the University of Pittsburgh, who co-led the study. “The key here is using mechanical engineering tools and frameworks to reverse-engineer how these biological systems work, thereby giving us a better chance to develop methods that affect this cellular communication process and potentially treat various diseases related to tissue growth.”
“We answered this very important biological question by building a new tool that enabled us to see these mechanical processes at the cellular level,” said McGowan Institute for Regenerative Medicine affiliated faculty member Philip LeDuc, PhD, professor of Mechanical Engineering at Carnegie Mellon, who co-led the study with Dr. Davidson. The researchers developed a microfluidic control system that delivers chemicals at extremely low flow rates over very small, specific areas, such as integrated collections of individual cells. They hypothesized that in addition to using chemical signals to communicate with each other, embryonic or regenerative cells also used mechanical processes – pushing and pulling on each other – to stimulate and respond.
“In order to identify these mechanical processes, we really had to control small parts of a multi-cellular tissue, which today’s technology can finally allow us to do,” Dr. Davidson explained. For example, a tissue sample 2 millimeters across may contain up to 8,000 cells. The microfluidic device enables researchers to “touch” as few as three or four and view the mechanical processes using a high resolution laser scanning microscope to view proteins moving in cells.
“We proved that mechanical processes are absolutely important along with chemical,” Dr. LeDuc said. When the researchers disabled the mechanical connections between the cells using microfluidics, the ability of cells to communicate with each other dropped substantially. Although the cells communicated through chemical signaling as well, the cells’ mechanical connections – their ability to push and pull on each other – were dominant in transmitting the signals.
Understanding this additional dimension could impact future research in tissue regeneration, from embryonic development to healing to cancer growth.
“If you are dealing with someone who has a birth defect, and their heart didn’t form correctly, the question is how do you target it?” Dr. LeDuc asked. “This discovery leads us to believe there is a mechanical way to influence tissue development and one day help the cells better communicate with each other to heal the body.”
University of Pittsburgh researchers recently received another $1.5 million from the National Science Foundation to continue a combined multi-university, private-industry effort to develop implantable medical devices made from biodegradable metals.
Body-degradable metals—usually magnesium based—are not new, having been originally considered in the late 19th century. “But,” says McGowan Institute for Regenerative Medicine director William Wagner, PhD, deputy director of the project and a principal investigator, “the question comes when you start to design medical devices for a specific application and a clinical partner says, ‘We want that to be gone in a month, or a month-and-a-half, or we want that to be there for a year.’” Then you have to figure out how to meet those specifications, he says.
To that end, the University of Pittsburgh team as well as collaborators at the University of Cincinnati (UC) and North Carolina Agricultural and Technical State University (N.C. A&T) are creating new alloys and new manufacturing processes that suit clinical demands. The consortium seeks to design devices that can adapt to changes in a patient's body and dissolve once healing has occurred, reducing the follow-up procedures and potential complications of major orthopedic, craniofacial, and cardiovascular procedures, and sparing millions of patients worldwide added pain and medical expenses.
Thus far, the consortium has created novel screws and plates for facial reconstruction, a stent to be used in kidney dialysis, a nerve guide, and a ring that will assist in pulling together and healing ruptured ligaments. The group has also created a tracheal stent for pediatric patients whose tracheas are underdeveloped at birth and prone to collapse. Once the stent is implanted, Dr. Wagner—professor of surgery, bioengineering, and chemical engineering in Pitt’s School of Medicine and Swanson School of Engineering—says it would dissolve, obviating the need for a second procedure on the young patient.
The universities have also involved several private enterprises in the project, including InCube Labs, nanoMag-Thixomat, ACell, OrthoKinetic Technologies, Fort Wayne Metals, General Nano, and IonBond.
Grant funding has also allowed Pitt to help N.C. A&T establish the first degree-granting program in bioengineering at a Historically Black College and University with the assistance of faculty members in Pitt's Department of Bioengineering and McGowan Institute for Regenerative Medicine. The program currently offers bachelor's and master's degrees and ultimately aims to offer a PhD.
“And there has been a lot of student exchange between the universities,” Dr. Wagner says. “It has been a good exercise for the trainees involved, as it spans the individual universities and reaches into active collaborations.”
In addition to undergraduate and graduate degrees, the research team, via the grant, has advanced STEM education to K-12 students in the Greensboro, North Carolina, Cincinnati, Ohio, and Western Pennsylvania regions by converting its work into a curriculum for aspiring engineers, with particular attention given to underrepresented groups. K-12 teachers are also invited to spend summer rotations in faculty-member laboratories to further broaden the transfer of scientific knowledge from the research effort.
University of Pittsburgh researchers—including McGowan Institute for Regenerative Medicine affiliated faculty members Stephen Wisniewski, PhD, senior associate dean and co-director of the Epidemiology Data Center at the University of Pittsburgh Graduate School of Public Health, and David Okonkwo, MD, PhD, associate professor of neurological surgery and clinical director of the Brain Trauma Research Center at Pitt’s School of Medicine—are key players in a national “dream team” that seeks to identify the best biological and imaging markers of traumatic brain injury (TBI) to improve the ability of clinical trials to find effective treatments for the condition, which annually affects 2.5 million people in the U.S., including athletes and soldiers.
The $17 million initiative, called the TBI Endpoints Development (TED) Award, is funded by the U.S. Department of Defense (DOD) and includes many universities, the U.S. Food and Drug Administration (FDA), companies, and philanthropies. It is overseen by the University of California, San Francisco (UCSF).
“This project is going to redefine how we measure the outcomes for traumatic brain injury studies,” said TED investigator Dr. Wisniewski. “We need a more robust, detailed way to determine what challenges a person faces when he suffers a traumatic brain injury, and that is what we're setting out to accomplish with this ambitious study.”
Under Dr. Wisniewski's leadership, Pitt Public Health will run the data analysis for the project, meaning the school will compile data from previous studies and analyze it to see what existing methods for measuring traumatic brain injuries prove most promising. That information will be used as a launch point for clinical evaluation in real-life situations.
Dr. Okonkwo is co-leading the second branch of the project to test those findings through the previously announced $18.8 million National Institutes of Health (NIH) project called Transforming Research and Clinical Knowledge in TBI, or TRACK-TBI.
The project is specifically designed to overcome the difficulty in demonstrating the effectiveness of TBI drugs and medical devices by actively involving the FDA in clinical-trial design from the outset. It also fosters collaboration between the DOD, the NIH, foundation-funded research networks, industry co-sponsors such as General Electric, and patient advocacy groups to try to develop procedures, outcomes measures, and standards for interpreting clinical data.
“TBI is really a multifaceted condition, not a single event,” said UCSF neurosurgeon Geoffrey T. Manley, MD, PhD, principal investigator for the new award and chief of neurosurgery at San Francisco General Hospital and Trauma Center, a UCSF partner hospital. “TBI lags 40 to 50 years behind heart disease and cancer in terms of progress and understanding of the actual disease process and its potential aftermath. More than 30 clinical trials of potential TBI treatments have failed, and not a single drug has been approved.”
As reported by Karen Ferrick-Roman, Duquesne University Fall 2014 Magazine, pain costs Americans up to $635 billion each year for medical treatment and in lost productivity, says the Institute of Medicine of the National Academies. That hefty price tag is equivalent to the first 10 years of spending for homeland security, illustrating a nationwide problem of giant proportions. Today, an estimated 116 million Americans live with chronic pain.
With the goal to introduce new ideas into pain research and bring people together across disciplines who typically would not work on pain or even collaborate, the Chronic Pain Research Consortium was co-founded on May 16, 2011, at Duquesne University by McGowan Institute for Regenerative Medicine affiliated faculty members Jelena Janjic, PhD, Assistant Professor of Pharmaceutics in the Graduate School of Pharmaceutical Sciences and Mylan School of Pharmacy at Duquesne University, and John Pollock, PhD, Full Professor of Biological Science at Duquesne University, out of love and passion for patient care, multidisciplinary science, and a holistic view of life and medicine. Since that time, Duquesne University scientists study all aspects of chronic pain, from molecular mechanisms to mind-body interaction and psychological impact of pain on relationships and quality of life. The team includes pharmacists, nurses, physical and occupational therapists, neurobiologists, neuropharmacologists, molecular biologists, medicinal chemists, and pharmacuetical scientists.
Most pain studies focus only on biology or behavior, drug delivery or microscopic cell anatomy, but the research of Drs. Janjic and Pollock incorporates each of these areas to personalize pain treatment. Their methods could enable doctors to pinpoint where pain is originating, then provide medication to that precise location—allowing a smaller dose of medication to be effective in curtailing pain while creating few side effects. This could be a breakthrough for treating pain, Dr. Pollock explains, because soreness in one location might actually be caused by a pinched nerve or issue elsewhere.
“The process relies on the interplay between the immune system and the nervous system to work,” he says.
The first step is to envision the pain with Drs. Janjic and Pollock’s non-invasive fluorescence imaging and MRI imaging achieved in collaboration with Carnegie Mellon University, pinpointing the origins of pain-inducing inflammation. Next, researchers specifically locate the immune cells involved in pain, then target them with medication.
Dr. Janjic has pioneered targeted drug delivery to treat pain, developing nanodroplets that, when injected intravenously, accumulate at the inflamed areas. This process could have a huge impact for people with inflammation-related pain, including osteoporosis and arthritis.
“We’re helping to fulfill a completely unmet need in pain research,” says Dr. Janjic.
Dedicated to the evaluation and care of voice disorders, the UPMC Voice Center offers a wide range of services and is a unique resource for both the general public and those who use their voices professionally. Its mission is to prevent injury and rehabilitate patients who have voice problems and to provide cutting edge research. The Voice Center is staffed by a select group of medical experts—including McGowan Institute for Regenerative Medicine affiliated faculty member Clark Rosen, MD, director of the UPMC Voice Center and professor of otolaryngology in the University of Pittsburgh School of Medicine—who utilize state-of-the-art technology, including a voice analysis laboratory, to provide patients with a wide range of medical, surgical, and behavioral treatments for all voice disorders.
Voice disorders are often signs of other medical problems. In order to offer a truly comprehensive approach to the diagnosis and treatment of even the most complex voice disorders, the Voice Center staff consults with specialists in gastroenterology, internal medicine, neurology, psychiatry, psychology, physical therapy, and other disciplines.
To treat voice disorders, the Voice Center offers a combination of behavioral, medical, and surgical approaches:
- Thyroplasty, arytenoid adduction, and vocal cord augmentation—to restore your voice following vocal cord paralysis
- Vocal cord microsurgery—specialized microsurgery to treat vocal cord lesions such as polyps, cysts, and scars
- BOTOX® injections of vocal cords—to reduce tight, squeezed phonation and voice breaks caused by spasmodic dysphonia or essential tremor
- Laryngeal reconstruction—to repair a narrowed or injured throat or windpipe
- Laryngeal microspot laser surgery—a precise laser treatment of vocal cord problems such as bleeding
- Voice therapy—to rehabilitate and maximize the physiology of voice production
- Singing voice therapy—to rehabilitate the injured singing voice
The Voice Center also provides voice health care services for professional and amateur vocal performance groups such as the Pittsburgh Opera as well as performing arts centers at regional high schools and universities. To provide these health care services, the Voice Center at UPMC Mercy brings together two teams of surgeons and voice therapists. Their goal is to keep professionals like singers, teachers, and public speakers out of the operating room. And Dr. Rosen says Pittsburgh is once again leading the way.
“That combination of having those two disciplines…is unique in Western PA and is very rare throughout the world,” said Dr. Rosen.
McGowan Institute for Regenerative Medicine affiliated faculty member Anna Balazs, PhD, was selected as this year’s recipient of the Greater Pittsburgh Area Women Chemists Committee’s (WCC) Award for Excellence in the Chemical Sciences. The award “recognizes the achievements of female chemists and chemical engineers in the greater Pittsburgh area who have a record of accomplishment in their field.” According to the committee’s chair, Dr. Balazs’ packet was “nothing short of extraordinary.” Dr. Balazs was recognized at the Awards Banquet of the 2014 American Chemical Society Central Regional Meeting (CERM 2014) held in Pittsburgh on October 30, 2014.
Dr. Balazs is a Distinguished Professor of Chemical Engineering and the Robert v. d. Luft Professor, Department of Chemical & Petroleum Engineering, University of Pittsburgh. She also serves as an Adjunct Professor in Pitt’s Department of Chemistry.
Dr. Balazs received a MS from the Massachusetts Institute of Technology (MIT) and went on to earn her PhD from the same university. Her postdoctoral research was completed at Brandeis University, MIT, and the University of Massachusetts. She has also held the position of visiting professor at the Scripps Research Institute in Southern California, the University of Texas at Austin, and Oxford University in the United Kingdom.
The research interests of Dr. Balazs center on statistical, mechanical, and computer modeling of complex chemical systems and developing theories for the properties of polymer blends and the behavior of polymers at surfaces and interfaces.
Congratulations to McGowan Institute for Regenerative Medicine faculty member Yoram Vodovotz, PhD, a co-author of the recently released book, “Translational Systems Biology: Concepts and Practice for the Future of Biomedical Research.” The text provides a foundational description of the barriers facing biomedical research today and the immediate future, and how these barriers could be overcome through the adoption of a robust and scalable approach that will form the underpinning of biomedical research for the future. Dr. Vodovotz is a Professor in the Department of Surgery with secondary appointments in the Departments of Computational & Systems Biology, Bioengineering, Immunology, Communication Science and Disorders, and the Clinical and Translational Science Institute. He also is the Director of the Center for Inflammation and Regenerative Modeling at the McGowan Institute.
The Regenerative Medicine Podcasts remain a popular web destination. Informative and entertaining, these are the most recent interviews:
Image adapted from Kutten JC, McGovern D, Hobson CM, Luffy SA, Nieponice A, Tobita K, Francis RJ, Reynolds SD, Isenberg JS, Gilbert TW. “Decellularized Tracheal Extracellular Matrix Supports Epithelial Migration, Differentiation, and Function.” Tissue Engineering Part A, 2014 [epub ahead of print]. doi:10.1089/ten.tea.2014.0089.
|Authors:||Aaron D. DeWard, Julie Cramer, Eric Lagasse|
|Title:||Cellular Heterogeneity in the Mouse Esophagus Implicates the Presence of a Nonquiescent Epithelial Stem Cell Population|
|Summary:||Because the esophageal epithelium lacks a defined stem cell niche, it is unclear whether all basal epithelial cells in the adult esophagus are functionally equivalent. In this study, we showed that basal cells in the mouse esophagus contained a heterogeneous population of epithelial cells, similar to other rapidly cycling tissues such as the intestine or skin. Using a combination of cell-surface markers, we separated primary esophageal tissue into distinct cell populations that harbored differences in stem cell potential. We also used an in vitro 3D organoid assay to demonstrate that Sox2, Wnt, and bone morphogenetic protein signaling regulate esophageal self-renewal. Finally, we labeled proliferating basal epithelial cells in vivo to show differing cell-cycle profiles and proliferation kinetics. Based on our results, we propose that a nonquiescent stem cell population resides in the basal epithelium of the mouse esophagus.|
|Source:||Cell Reports. Volume 9, Issue 2, p701–711, 23 October 2014.|
|PI||William Wagner (Jagannathan Sankar, lead PI)|
|Title||NSF Engineering Research Center for Revolutionizing Metallic Biomaterials|
|Summary:||The Engineering Research Center for Revolutionizing Metallic Biomaterials (ERC-RMB) will pursue revolutionary advances in metallic biomaterials and the underlying sciences and technologies, leading to engineered systems that will interface with the human body to prolong and improve quality of life. This research effort is coupled with the development of a vibrant, diverse workforce well-prepared for the global challenges and opportunities of the 21st century. The ERC proposes to develop the fundamental knowledge and technology needed to advance biocompatible and biodegradable metal-based, implantable systems with feedback control for reconstruction and regeneration. The research and technology development will be aided by industrial input and clinical assessments. The ERC’s education program is designed to develop innovative and adaptive engineers. Seamlessly integrated undergraduate and graduate bioengineering programs will be established at North Carolina A&T State University (NCAT) to support this goal.
Major goals of the ERC-RMB are:
|Source:||Engineering Research Center-National Science Foundation|
|Term||08/20/14 - 08/31/16|
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