The first case of sickle cell disease was identified in 1910 and today it affects more than 70,000 Americans. It is seen mostly in persons of African descent, but also in individuals of Middle Eastern, Mediterranean, Central and South American, and Asian Indian heritage. Approximately 10 percent of children with sickle cell disease suffer a stroke. Having experienced one stroke, they are at high risk of having another.

"Current therapies to prevent strokes in children with sickle cell disease have substantial side effects, so we need to create better ways to predict which patients need intervention," said Platt, who is also a Georgia Cancer Coalition Distinguished Cancer Scholar. "My goal is to use experimental and clinical data to develop a mathematical model for predicting stroke risk in pediatric patients with sickle cell disease to allow for earlier intervention."

Now in its fourth year, the 2010 NIH Director's New Innovator Awards will support 52 exceptionally creative new investigators who propose highly innovative projects that have the potential for unusually high impact.

"NIH is pleased to be supporting early-stage investigators from across the country who are taking considered risks in a wide range of areas in order to accelerate research," said Francis S. Collins, M.D., Ph.D., director of the National Institutes of Health. "We look forward to the results of their work."

Platt's research project will integrate cell biology, clinical pediatric hematology, enzyme kinetic modeling and dynamics, predictive statistical regression modeling, biomechanics, tissue remodeling and personalized medicine.

"Successful integration of all these areas would significantly advance the diagnosis and therapeutic intervention of strokes in children with sickle cell disease in a way that has not been seen in the one hundred years since this disease was first identified," said Platt.

The disease hits close to home for Platt, whose brother was recently diagnosed with sickle cell trait -- meaning he inherited a sickle cell gene from one of his parents and a normal gene from the other. In Georgia, one in every 1,300 children is born with sickle cell disease.

Sickle cell disease is a genetic condition present at birth. It involves an altered gene that produces abnormal hemoglobin -- the protein that carries oxygen in the blood. In sickle cell disease, red blood cells become hard, sticky and "C" shaped. Sickle cells die early, which causes a constant shortage of red blood cells.

The abnormal cells also clog the flow in small blood vessels, causing chronic pain and other serious problems such as infections and acute chest syndrome. Strokes, however, occur in large arteries with high blood flow rates and other biomechanical parameters known to cause plaque formation in atherosclerosis. The damage caused by sickled red blood cells in the arteries and links to remodeling of the arteries have not been extensively studied.

To understand the coordination of the mechanisms that produce structural changes in the arterial wall leading to stroke, Platt plans to model sickle cell disease from the molecular level to the human level based on clinical data, novel biomarkers and patient outcomes. First, he plans to develop a quantitative model that will detail the activation and inactivation of proteases -- enzymes that break down proteins -- in the artery walls of individuals with sickle cell disease.

"I will focus on incorporating different cathepsins, elastin and collagens into the model," said Platt. "I plan to use an assay recently developed in my laboratory that reliably detects and quantifies mature cathepsins using a technique called gelatin zymography."

After determining which proteases play a role in sickle cell disease, Platt will then determine how biomechanical conditions of sickle cell disease, such as altered blood flow and red blood cell stiffness, affect cell-mediated remodeling of arteries by these proteases. This will be done in collaboration with Coulter Department professor Gilda Barabino. With this information, Platt can link quantitative measures of blood flow and inflammatory markers found in sickle cell disease to the narrowing of artery openings and associated protease remodeling.

These markers will first be validated with animal models of sickle cell disease, in collaboration with Solomon Ofori-Acquah, an assistant professor of pediatrics at Emory University and the Children's Healthcare of Atlanta Aflac Cancer Center and Blood Disorders Service. Further validation will come from blood samples collected from individuals with sickle cell disease, which will be provided by Beatrice Gee, medical director of the Hematology and Sickle Cell Program at Children's Healthcare of Atlanta at Hughes Spalding and an associate professor of clinical pediatrics at the Morehouse School of Medicine.

Overall, Platt will integrate biochemical and biomechanical mechanisms of cardiovascular disease with predictive mathematical models that robustly interpret clinical biomarkers to develop a personalized medicine protocol that will predict strokes in individuals with sickle cell disease and reveal new mechanisms for therapeutic targets. If these methods are successful, they could be expanded to broader categories of cardiovascular disease, such as atherosclerosis, myocardial infarctions and heart valve stenosis.

While stem cell research is on the verge of broadly impacting many elements of the medical field - regenerative medicine, drug discovery and development, cell-based diagnostics and cancer - the bio-process engineering that will be required to manufacture sufficient quantities of functional stem cells for these diagnostic and therapeutic purposes has not been rigorously explored.

"Successfully integrating knowledge of stem cell biology with bioprocess engineering and process development into single individuals is the challenging goal of this program," said Todd McDevitt, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and a Petit Faculty Fellow in the Parker H. Petit Institute for Bioengineering and Biosciences at Georgia Tech.

McDevitt is leading the IGERT with Robert M. Nerem, professor emeritus of the George W. Woodruff School of Mechanical Engineering at Georgia Tech. Nerem is also director of the Georgia Tech/Emory Center (GTEC) for Regenerative Medicine, which will administer this award.

Ph.D. students funded by Georgia Tech's stem cell bio-manufacturing IGERT will receive interdisciplinary educational training in the biology, engineering, enabling technologies, commercialization and public policy related to stem cells. Their research efforts will focus on developing innovative engineering approaches to bridge the gap between basic discoveries made in stem cell biology and therapeutic stem cell-based technologies.

"This program provides a unique opportunity for engineers to generate standardized and quantitative methods for stem cell isolation, characterization, propagation and differentiation," said Nerem. "These techniques must be developed in a scalable manner to efficiently produce sufficient numbers of stem cells and derivatives in accessible formats in order to yield a spectrum of novel therapeutic and diagnostic applications of stem cells."

The Georgia Tech program is centered around three main research thrusts, which focus on several critical technologies that must be developed to enable the application and use of stem cell-based products:

* Creating reproducible, controlled and scalable methods to expand and differentiate stem cells with defined phenotypes and epigenetic states.
* Developing reliable, rapid and quantifiable methods to characterize the composition and function of stem cells to be generated.
* Designing low-cost systems capable of producing large populations of defined stem cells and derivatives.

Students in the program will be able to take advantage of the core facilities provided by the new Stem Cell Engineering Center at Georgia Tech, which is directed by McDevitt. Technologies developed by the students supported through this IGERT will be rapidly integrated into academic and industrial stem cell practices and cell-based products.

The award will support 30 new Ph.D. students over the next five years and brings together more than two dozen faculty members from Georgia Tech, Emory University, the University of Georgia and the Morehouse School of Medicine. In addition, plans are being made for students to participate in international research collaborations with the National University of Ireland at Galway, Imperial College London, the University of Cambridge and the University of Toronto.

"We anticipate this program will produce the future leaders and innovators in the field of stem cell bio-manufacturing who will contribute significantly at the interface of stem cell engineering, biology and therapy," added McDevitt.

The study shows that delivering stem cells on a polymer scaffold to treat large areas of missing bone leads to improved bone formation and better mechanical properties compared to treatment with the scaffold alone. This type of therapeutic treatment could be a potential alternative to bone grafting operations.

"Massive bone injuries are among the most challenging problems that orthopedic surgeons face, and they are commonly seen as a result of accidents as well as in soldiers returning from war," said the study's lead author Robert Guldberg, a professor in Georgia Tech's Woodruff School of Mechanical Engineering. "This study shows that there is promise in treating these injuries by delivering stem cells to the injury site. These are injuries that would not heal without significant medical intervention."

Details of the research were published in the early edition of the journal Proceedings of the National Academy of Sciences on January 11, 2010. This work was funded by the National Institutes of Health and the National Science Foundation.

The study was conducted in rats in which two bone gaps eight millimeters in length were created to simulate massive injuries. One gap was treated with a polymer scaffold seeded with stem cells and the other with scaffold only. The results showed that injuries treated with the stem cell scaffolds showed significantly more bone growth than injuries treated with scaffolds only.

Guldberg and mechanical engineering graduate student Kenneth Dupont experimented with scaffolds containing two different types of human stem cells -- bone marrow-derived mesenchymal adult stem cells and amniotic fluid fetal stem cells.

"We were able to directly evaluate the therapeutic potential of human stem cells to repair large bone defects by implanting them into rats with a reduced immune system," explained Guldberg, who is also the director of the Petit Institute for Bioengineering and Bioscience at Georgia Tech.

Micro-CT measurements showed no significant differences in bone regeneration between the two stem cell groups. However, combining the two types of stem cells produced significantly higher bone volume and strength compared to scaffolds without cellular augmentation.

Although stem cell delivery significantly enhanced bone growth and biomechanical properties, it was not able to consistently repair the injury. Eight weeks after the treatment, new bone bridged the gaps in four of nine defects treated with scaffolds seeded with adult stem cells, one of nine defects treated with scaffolds seeded with fetal stem cells, and none of the defects treated with the scaffold alone.

"We thought that the functional regeneration of the bone defects may have been limited by stem cells migrating away from the injury site, so we decided to investigate the fate and distribution of the delivered cells," said Guldberg.

To do this, Guldberg labeled stem cells with fluorescent quantum dots -- nanometer-scale particles that emit light when excited by near-infrared radiation -- to track the distribution of stem cells after delivery on the scaffolds and completed the same experiments as previously described.

Throughout the entire study, the researchers observed significant fluorescence at the stem cell scaffold sites. However, beginning seven to 10 days after treatment, signals appeared at the scaffold-only sites. Additional analysis with immunostaining revealed that the quantum dots present at the scaffold-only sites were contained in inflammatory cells called macrophages that had taken up quantum dots released from dead stem cells.

"While our overall study shows that stem cell therapy has a lot of promise for treating massive bone defects, this experiment shows that we still need to develop an improved way of delivering the stem cells so that they stay alive longer and thus remain at the injury site longer," explained Guldberg.

The researchers also found that the quantum dots diminished the function of the transplanted stem cells and thus their therapeutic effect. When the stem cells were labeled with quantum dots, the results showed a failure to enhance bone formation or bridge defects. However, the same low concentration of quantum dots did not affect cell viability or the ability of the stem cells to become bone cells in laboratory studies.

"Although in vitro laboratory studies remain important, this work provides further evidence that well-characterized in vivo models are necessary to test the ability of regenerative tissue strategies to effectively integrate and restore function in complex living organisms," added Guldberg. "Improved methods of non-invasive cell tracking that do not alter cell function in vivo are needed to optimize stem cell delivery strategies and compare the effectiveness of different stem cell sources for tissue regeneration."

Guldberg is currently exploring alternative cell tracking methods, such as genetically modifying the stem cells to express green fluorescent protein and/or other luminescent enzymes such as luciferase. He is also investigating the addition of programming cues to the scaffold that will direct the stem cells to differentiate into bone cells. These signals may be particularly effective for fetal stem cells, which are believed to be more primitive than adult stem cells, according to Guldberg.

Lessons learned from the current work are also being applied to develop effective stem cell therapies for severe composite injuries to multiple tissues including bone, nerve, vasculature and muscle. This follow-on work is being conducted in the Georgia Tech Center for Advanced Bioengineering for Soldier Survivability in collaboration with Ravi Bellamkonda and Barbara Boyan, professors in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

Other authors on the paper include Andres Garcia, professor and Woodruff Faculty Fellow in Georgia Tech's Woodruff School of Mechanical Engineering and the Petit Institute for Bioengineering and Bioscience; Georgia Tech research scientist Hazel Stevens, Georgia Tech graduate student Joel Boerckel; and National University of Ireland medical student Kapil Sharma.

This work was funded by grant number R01-AR051336 from the National Institutes of Health (NIH) and by grant number EEC-9731643 from the National Science Foundation (NSF). The content is solely the responsibility of the principal investigator and does not necessarily represent the official views of the NIH or NSF.

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Writer: Abby Vogel

Maybe they could regrow the tissue: Grow the cartilage, grow the blood vessels, grow the nerves and even grow the bone.

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Alexandra Peister and her collaborators received an NIH program project grant which will support research at Morehouse, Georgia Institute of Technology, University of Rochester, Emory University, and the University of Queensland in Australia. The grant will be funded for the next two years and will support research at Morehouse at a level of $36,000 per year. Co-Investigator, NIH Challenge Grant (American Recovery and Reinvestment Act funded): Engineered Delivery of Adult Versus Fetal Stem Cells for Bone Regeneration in collaboration with Georgia Tech. The grant will be funded September 2009.

.. . It’s a debate fraught with irony. Georgia has some of the nation’s leading researchers in the area of embryonic stem cells, scientists recruited and paid for by the state as eminent scholars; and state leadership has identified the life sciences as a strategic industry of interest. And yet, many of Georgia’s elected officialshave made it clear that they do not want new research in embryonic stem cells happening in Georgia,... “Induced pluripotent cells are a great success story, but it’s owed wholly to the fact that we had a starting basis in embryonic stem cells,” says Todd McDevitt, a Georgia Tech scientist who directs stem cell technology research in his lab and focuses most of his attention on ES cells... For Georgia Tech professor Bob Nerem, research needs to move forward in all areas. “At some point we will know about what makes the most sense from a patient point of view,” says Nerem, director of both the Parker H. Petit Institute for Bioengineering and Bioscience at Tech, and the Georgia Tech-Emory Collabora-tion for Regenerative Medicine (GTEC)... But for a young scientist like Todd McDevitt, whose lab at Georgia Tech has attracted some $2 million in federal funds and employs 10 other researchers, a differing opinion that has the potential to criminalize his work forces him to consider other options.

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McDevitt lab

Nerem lab

Organizers of the recently established Georgia Tech Center for Advanced Bioengineering for Soldier Survivability want to change that.

"The goal of the center is to rapidly move new technologies from the laboratory to patients so that we can improve the quality of life for our veterans as they return from the wars the United States is fighting," said center director Barbara Boyan, the Price Gilbert, Jr. Chair in Tissue Engineering at the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The center will leverage the expertise of Georgia Tech researchers in musculoskeletal biology and regenerative medicine to quickly move tools that are clinically valuable, safe and effective from laboratories to use in trauma centers. To reduce the amount of time from invention to clinical use, engineers and scientists in the center work in teams that include a clinician with experience in combat medical care and a medical device industry partner.

Support for the center is provided by the Armed Forces Institute of Regenerative Medicine, the U.S. Army Institute of Surgical Research's Orthopedic Trauma Research Program, the U.S. Department of Defense and industry.

Researchers in the center will initially focus on ways to improve the healing of wounds, segmental bone defects and massive soft tissue defects. Traumatic injuries that affect the arms, legs, head and neck require technologies for treatment at the time of injury and in the ensuing days and months.

"These combat injuries are complicated to treat because they are large and typically infected, so even determining when a soldier should be treated for optimal recovery is a challenge," said Boyan, who is also the associate dean for research in Georgia Tech's College of Engineering and a Georgia Research Alliance Eminent Scholar. "It is not known whether a regenerative therapy will be most effective if used immediately following injury or at some later time after scar tissue has been established at the wound site."

By developing models that accurately reflect the complex aspects of injuries sustained by soldiers in combat, the researchers will be able to test assumptions about when to employ specific strategies and how to ensure their effectiveness. The models must also allow them to examine the use of technologies on both male and female patients, and on complex tissues that consist of nerves, a blood supply and multiple cell types.

"Since the processes of bone, vascular and neural formation are naturally linked during normal tissue development, growth and repair, our approach is to harness this knowledge by developing delivery strategies that present the right biologic cues in the right place at the right time to promote functional regeneration of multiple integrated tissues," said associate director of the center Robert Guldberg, a professor in Georgia Tech's Woodruff School of Mechanical Engineering.

To enhance tissue repair and regeneration following a traumatic injury, the researchers are focusing their efforts on stem cells. Even though stem cells have tremendous potential for repairing such defects, effective methods do not yet exist for delivering them to an injury site and of ensuring that they survive and remain at that site long enough to impact the regeneration process.

"Clinicians currently inject stem cells into a vein and hope that the cells will migrate to sites of injury and remain at those sites long enough to participate in the repair process. While some cells certainly do migrate to injury sites, the actual percentage is very small and those that arrive at the site do not remain to engraft with the host tissue," explained Boyan.

This limited effect may be the result of the injection process, according to Boyan, so researchers in the center are developing ways to protect the cells from damaging forces they might encounter when inserted into the body.

"Studies in our laboratory have shown that when stem cells are encapsulated in microbeads, they can be injected by needle without loss of cell viability and they remain at the injury site for at least two months," said Boyan.

Protecting the cells during insertion is just the first step toward improved tissue repair. The researchers must also examine whether the stem cells will turn into cells typical of the implanted tissue and if they produce or should be paired with molecules that can enhance the healing of the implanted tissues.

Center researchers are also investigating whether bone marrow-derived stem cells can be used in the body to heal large defects in bone and cartilage if they are inserted in fiber mesh scaffolds and silk sponges during a surgical procedure.

Additional projects in the center include assessing tissue viability, preventing the growth of bone in the soft tissues of the body and improving pre-hospital care of orthopedic injuries. Since effective treatment of traumatic injuries is an important goal for the general public as well as the military population, the researchers also hope to adapt their technologies for use in hospitals.

Other researchers in the center include Ravi Bellamkonda, a professor in the Coulter Department; Andres Garcia, the Woodruff Faculty Fellow in the Woodruff School of Mechanical Engineering; Robert Taylor, a professor in the Coulter Department and Emory's Division of Cardiology; Zvi Schwartz, a visiting professor in the Coulter Department; and U.S. Army surgical medicine consultants Michael Yaszemski and David Cohen.

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Media Relations Contacts: Abby Vogel (404-385-3364); E-mail: (avogel@gatech.edu) or John Toon (404-894-6986); E-mail: (jtoon@gatech.edu).

Writer: Abby Vogel

January 13, 2009. The Georgia Tech Emory Center for the Engineering of Living Tissues (GTEC), a National Science Foundation Engineering Research Center, celebrated its tenth year of innovative research. When founded in 1998, GTEC's focus was on replacing tissues or growing cell-based substitutes outside the body for implantation into the body. As GTEC has evolved over the last decade, its approach has broadened from a focus on tissue engineering to one that includes tissue regeneration.

Now, a decade after the $25 million National Science Foundation award, GTEC is internationally recognized for its strengths and novel applications in the emerging field of Regenerative Medicine. The center

President-elect Obama

"Engineering Graded Tissue Interfaces"

Jennifer E. Phillips, Kellie L. Burns, Joseph M. Le Doux, Robert E. Guldberg and Andr

Biological factors are not the only influence on stem-cell behaviour

A training grant, entitled "Graduate Training for Rationally Designed, Integrative Biomaterials" or "GTBioMAT" was awarded by the National Institutes of Health to the Georgia Tech/Emory Biomaterials Research Team. Ravi Bellamkonda, PhD, Principal Investigator and Director and Julie Babensee, PhD, Co-Director, will be responsible for the overall management and implementation of the program