Valentine’s Day evokes images of a stylized heart shape, but for a group of Georgia Institute of Technology researchers, the heart is a complex organ that interests them throughout the year.

Georgia Tech researchers are developing new ways to diagnose and treat heart problems -- from advanced imaging techniques and guidance for drug therapies to sophisticated surgical procedures. Georgia Tech’s emphasis on translational research accelerates the pace at which new heart-related discoveries are put to use in patient care.

Improving Heart Surgery

To advance the goal of minimally invasive cardiac surgery, researchers have developed a technology that simplifies and standardizes the technique for opening and closing the beating heart during surgery.

Apica Cardiovascular, a Georgia Tech and Emory University medical device startup, licensed the technology from the two institutions. The firm recently received a $5.5 million investment to further develop the system, which will make the transapical access and closure procedure required for delivering therapeutic devices to the heart more routine for cardiac surgeons. The goal is to expand the use of surgery techniques that are less invasive and do not require stopping the heart.

With research and development support from the Coulter Foundation Translational Research Program and the Georgia Research Alliance, the company has already completed a series of pre-clinical studies to test the functionality of the device and its biocompatibility. James Greene currently serves as the CEO of the company, which has offices in Galway, Ireland, and in Atlanta.

For more information on this work, visit http://gtresearchnews.gatech.edu/apica-cardiovascular/.

Diagnosing Heart Disease

Levent Degertekin is designing tiny devices micromachined from silicon that may make diagnosing and treating coronary artery diseases easier.

Degertekin, the George W. Woodruff Chair in Mechanical Systems, and Paul Hasler, a professor in the School of Electrical and Computer Engineering at Georgia Tech, micromachined intravascular ultrasound imaging arrays with integrated electronics. Placed on catheters inserted into the body, the devices image the arteries of the heart in three dimensions at high resolution using high-frequency ultrasound waves.

The system boasts a more compact design and three-dimensional imaging capability for guiding cardiologists during interventions, such as those for completely blocked arteries. The technology also offers higher resolution than current intravascular ultrasound systems, which help diagnose vulnerable plaque, a leading cause of heart attacks.

Funding for this research currently is provided by the National Institutes of Health. To commercialize the technology, the researchers have formed a startup company called SIBUS Medical, which is receiving assistance from VentureLab, a unit of Georgia Tech’s Enterprise Innovation Institute that nurtures faculty startup companies.

Detecting and Treating Atherosclerosis

With a five-year $14.6 million contract from the National Institutes of Health (NIH), Georgia Tech and Emory University researchers are developing nanotechnology and biomolecular engineering tools and methodologies for detecting and treating atherosclerosis. The award supports the interdisciplinary Center for Translational Cardiovascular Nanomedicine, which is led by Gang Bao, the Robert A. Milton Chair in Biomedical Engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

Atherosclerosis typically occurs in branched or curved regions of arteries where plaques form because of cholesterol build-up. Inflammation can alter the structure of plaques so they become more likely to rupture, potentially causing a blood vessel blockage and leading to heart attack or stroke.

The researchers are working to accomplish four goals:

• Using nanoparticle probes to image and characterize atherosclerotic plaques
• Diagnosing cardiovascular disease from a blood sample
• Designing new methods for delivering anti-atherosclerosis drugs and genes into the body
• Developing stem cell based therapies to repair damaged heart tissue

Additional researchers from the Coulter Department and from Emory University are also contributing to the project. For more information on this work, visit http://gtresearchnews.gatech.edu/cardiovascular-nanomedicine-center/.

Improving Drug Dosing Following a Heart Attack

A research team led by Georgia Tech mechanical engineering assistant professor Craig Forest is designing a device to quickly and accurately personalize a patient’s drug dosage to prevent blood clots that can cause heart attacks.

When someone experiencing heart attack symptoms arrives at an emergency room, he or she typically receives a standard dose of aspirin and/or clopidogrel to prevent further blood clotting. But that standard dose may not be the best dose for a given individual.

With Forest’s device, a small blood sample is sent through a microchip containing a network of microfabricated capillaries that mimic the branching coronary arteries around the human heart. Because the branches contain flow restrictions of different sizes, the failure of blood to flow through the branches with smaller restrictions indicates that a higher drug dose may be required.

Determining the necessary dose of anti-clotting drugs can be difficult. Too much of the drug may cause the patient to experience gastrointestinal bleeding. Too little drug may allow additional clot formation and set the stage for another heart attack. Forest’s device should help determine the right dosage for each patient.

Emory University Department of Emergency Medicine assistant professor Jeremy Ackerman and Georgia Tech Regents’ professor of mechanical engineering David Ku are working with Forest on this project, which is supported by the American Heart Association.

Examining Heart Valve Leakage

An estimated 1.6 million Americans suffer moderate to severe leakage through their tricuspid valve, a complex structure that closes off the heart’s right ventricle from the right atrium. If left untreated, severe leakage can affect an individual’s quality of life and can even lead to death.

Research teams led by Ajit Yoganathan, Georgia Tech Regents’ professor and Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering, have discovered causes for the tricuspid valve’s leakage and ways to predict the severity of leakage in the valve. These study results could lead to improved diagnosis and treatment of the condition.

A study published in the journal Circulation found that either dilating the tricuspid valve opening or displacing the papillary muscles that control its operation can cause the valve to leak. A combination of the two actions can increase the severity of the leakage, which is called tricuspid regurgitation.

Standard clinical procedures that detail when and how tricuspid valve repairs should be performed need to be developed and this study suggests several items that should be considered in developing those protocols, according to the researchers.

In another study published in the journal Circulation: Cardiovascular Imaging, researchers found that the anatomy of the heart’s tricuspid valve can be used to predict the severity of leakage in the valve. Using 3-D echocardiograms from 64 individuals who exhibited assorted grades of tricuspid leakage, the researchers found that pulmonary arterial pressure, the size of the valve opening and papillary muscle position measurements could be used to predict the severity of an individual’s tricuspid regurgitation.

The study will change the focus and direction of future surgical therapies for tricuspid regurgitation to make them better and more durable, the researchers said.

Researchers from the Coulter Department, Emory University, Children’s Hospital Boston and Mount Sinai Medical Center contributed to these two studies.

For more information on this work, visit http://gtresearchnews.gatech.edu/tricuspid-valve-leakage/ and http://gtresearchnews.gatech.edu/tricuspid-regurgitation/. 

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Recent earthquake damage has exposed the vulnerability ofexisting structures to strong ground movement. At the Georgia Institute ofTechnology, researchers are analyzing shape-memory alloys for their potentialuse in constructing seismic-resistant structures.

“Shape-memory alloys exhibit unique characteristics that youwould want for earthquake-resistant building and bridge design and retrofitapplications: they have the ability to dissipate significant energy withoutsignificant degradation or permanent deformation,” said Reginald DesRoches, a professorin the School of Civil and Environmental Engineering at Georgia Tech.

Georgia Tech researchers have developed a model thatcombines thermodynamics and mechanical equations to assess what happens whenshape-memory alloys are subjected to loading from strong motion. The researchersare using the model to analyze how shape-memory alloys in a variety ofcomponents -- cables, bars, plates and helical springs -- respond to different loadingconditions. From that information, they can determine the optimalcharacteristics of the material for earthquake applications.

The model was developed by DesRoches, School of MechanicalEngineering graduate student Reza Mirzaeifar, School of Civil and EnvironmentalEngineering associate professor Arash Yavari, and School of Mechanical Engineeringand School of Materials Science and Engineering professor Ken Gall.

A paper describing the thermo-mechanical model was publishedonline Feb. 3 in the InternationalJournal of Non-Linear Mechanics. This research was supported by theTransportation Research Board IDEA program.

To improve the performance of structures during earthquakes,researchers around the world have been investigating the use of “smart”materials, such as shape-memory alloys, which can bounce back afterexperiencing large loads. The most common shape-memory alloys are made of metalmixtures containing copper-zinc-aluminum-nickel, copper-aluminum-nickel ornickel-titanium. Potential applications of shape-memory alloys in bridge andbuilding structures include their use in bearings, columns and beams, orconnecting elements between beams and columns. But before this class ofmaterials can be used, the effect of extreme and repetitive loads on thesematerials must be thoroughly examined.

“For standard civil engineering materials, you can usemechanics to look at force and displacement to measure stress and strain, butfor this class of shape-memory alloys that changes properties when it undergoesloading and unloading, you have to consider thermodynamics and mechanics,” explainedYavari.

The Georgia Tech team found that the generation andabsorption of heat during loading and unloading caused a temperature gradientin shape-memory alloys, which caused a non-uniform stress distribution in thematerial even when the strain was uniform.

“Shape-memory alloys previously examined in detail werereally thin wires, which can exchange heat with the ambient environment rapidlyand no temperature change is seen,” said Mirzaeifar. “When you start to examinealloys in components large enough to be used in civil engineering applications,the internal temperature is no longer uniform and needs to be taken intoaccount.”

To predict the internal temperature distribution ofshape-memory alloys under loading-unloading cycles, which could then be used todetermine the stress distribution, the researchers developed a model that usedthe surface thermal boundary conditions, diameter and loading rate of the alloyas inputs.

The team included ambient conditions in the model becauseshape-memory alloys for seismic applications could operate in a variety ofenvironments -- such as water if used in bridge structures or air if used inbuilding structures -- which would produce different rates of heat transfer. Theresearchers used a thermal camera to record the variation in surfacetemperature of shape-memory alloys experiencing loading and unloading.

Using their model, the researchers were able to accuratelypredict internal temperature and stress distributions for shape-memory alloys. Themodel results were verified with experimental tests. In one test, they foundthat a shape-memory alloy loaded at a very slow rate had time to exchange theheat created with the ambient environment and exhibited uniform stress. If it wasloaded very rapidly, it did not have enough time to exchange the heat, leadingto a non-uniform stress distribution.

“Our analytical solutions are exact, fast and capable of simulatingthe complicated coupled thermo-mechanical response of shape-memory alloysconsidering temperature changes and loading rate dependency,” said Mirzaeifar.

In future work, the researchers plan to examine morecomplicated shapes and the effects of combination loading -- tension, bendingand torsion -- to optimize shape-memory alloys for earthquake applications.

This project issupported by the Transportation Research Board of the National Academies (AwardNo. NCHRP-147). The National Academies has rights to the data and the contentis solely the responsibility of the principal investigators and does notnecessarily represent the official views of the National Academies.

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Inthe current issue of the journal Science,researchers at Michigan State University, the Georgia Institute of Technologyand the University of Texas at Austin demonstrate how a new virus evolves,which sheds light on how easy it can be for diseases to gain dangerousmutations.

Thescientists showed for the first time how the virus called “Lambda” evolved tofind a new way to attack host cells, an innovation that took four mutations toaccomplish. This virus infects bacteria, in particular the common E. coli bacterium. Lambda isn’tdangerous to humans, but this research demonstrated how viruses evolve complexand potentially deadly new traits, said Justin Meyer, MSU graduate student, whoco-authored the paper with Richard Lenski, MSU Hannah Distinguished Professorof Microbiology and Molecular Genetics.

“Wewere surprised at first to see Lambda evolve this new function, this ability toattack and enter the cell through a new receptor­ – and it happened so fast,”Meyer said. “But when we re-ran the evolution experiment, we saw the same thinghappen over and over.”

Thispaper comes on the heels of news that scientists in the U.S. and theNetherlands produced a deadly version of bird flu. Even though bird flu is amere five mutations away from becoming transmissible between humans, it’shighly unlikely the virus could naturally obtain all of the beneficialmutations all at once. However, it might evolve sequentially, gaining benefitsone-by-one, if conditions are favorable at each step, he added.

Throughresearch conducted at BEACON, MSU’s National Science Foundation Center for theStudy of Evolution in Action, Meyer and his colleagues’ ability to duplicatethe results implied that adaptation by natural selection, or survival of thefittest, had an important role in the virus’ evolution.

Whenthe genomes of the adaptable virus were sequenced, they always had fourmutations in common.

“Theparallelism shown in the evolutionary history of adaptable viruses was strikingand was far beyond what is expected by chance,” noted paper co-author Joshua Weitz, anassistant professor in the School ofBiology at Georgia Tech.

Incontrast, the viruses that didn’t evolve the new way of entering cells had someof the four mutations but never all four together, said Meyer, who holds theBarnett Rosenberg Fellowship in MSU’s College of Natural Science.

“Inother words, natural selection promoted the virus’ evolution because themutations helped them use both their old and new attacks,” Meyer said. “Thefinding raises questions of whether the five bird flu mutations may also havemultiple functions, and could they evolve naturally?”

Additionalauthors of the paper include Devin Dobias, former MSU undergraduate (now agraduate student at Washington University in St. Louis); Ryan Quick, MSUundergraduate; and Jeff Barrick, a former Lenski lab researcher now on thefaculty at the University of Texas at Austin.

Fundingfor the research was provided in part by the National Science Foundation,Defense Advanced Research Projects Agency, James S. McDonnell Foundation andBurroughs Wellcome Fund.

This research was supported in part bythe Defense Advanced Research Projects Agency (DARPA) (Award No.HR0011-09-1-0055) and the National Science Foundation (NSF). The content issolely the responsibility of the principal investigator and does notnecessarily represent the official views of DARPA or NSF.

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Writer: Layne Cameron

An estimated 1.6 million Americans suffer moderate to severeleakage through their tricuspid valves, which are complex structures that allowblood to flow from the heart’s upper right chamber to the ventricle. If leftuntreated, severe leakage can affect an individual’s quality of life and can evenlead to death.

A new study finds that the anatomy of the heart’s tricuspidvalve can be used to predict the severity of leakage in the valve, which is acondition called tricuspid regurgitation. The study, conducted by researchersfrom the Georgia Institute of Technology and Emory University, found that pulmonaryarterial pressure, the size of the valve opening and papillary muscle position measurementscould be used to predict the severity of an individual’s tricuspidregurgitation.

“By being able to identify and measure an individual’sparticular tricuspid valve anatomical features that we have shown arecorrelated with increased leakage, clinicians should be able to better target their repair efforts and create moredurable repairs,” said Ajit Yoganathan, Regents’ professor in theWallace H. Coulter Department of Biomedical Engineering at Georgia Tech andEmory University.

The study was published in the January issue of the journal Circulation: Cardiovascular Imaging. Funding for this work wasprovided by the American Heart Association and a donation from Tom and ShirleyGurley.

Yoganathan and recent Coulter Department doctoral graduate ErinSpinner teamed with Stamatios Lerakis, a professor of medicine (cardiology), radiologyand imaging sciences at Emory University, to non-invasively collect 3-Dechocardiograms from 64 individuals who exhibited assorted grades of tricuspid leakage.Subjects included 20 individuals with “trace,” 13 with “mild,” 17 with “moderate”and 14 with “severe” tricuspid regurgitation. The subjects with “mild” to“severe” leakage exhibited a mix of isolated right, isolated left, and bothright and left ventricle dilation.

From the 3-D echocardiography images of the heart theycollected, the researchers measured (1) the area of the annulus, which is thefibrous ring that surrounds the tricuspid valve opening; (2) the distancebetween the annulus and the three right ventricle papillary muscles, which keepthe valve shut when the ventricle contracts; and (3) the position of the papillarymuscles with respect to the center of the annulus. The clinicians also measuredpulmonary arterial pressure using standard clinical methods and assessed thegrade of tricuspid regurgitation from “trace” to “severe” with color Dopplerimaging.

In collaboration with Emir Veledar, an assistant professorand statistician in the Rollins School of Public Health at Emory University, theresearchers found statistical differences between individuals with ventricular dilationand the control subjects in the parameters of pulmonary arterial pressure,annulus area and papillary muscle displacement. They also found that all three factors were correlated with the gradeof tricuspid regurgitation.

“This study’s use ofadvanced cardiovascular imaging, and more specifically 3-D echocardiography, providednew insight into the pathophysiology of tricuspid regurgitation and a goodunderstanding as to why current surgical treatments for tricuspid regurgitationare not good enough,” explained Lerakis. “I believe this study will change thefocus and direction of future surgical therapies for tricuspid regurgitationonly to make them better and more durable.”

Based on the findings of this study, said Lerakis, future surgical therapiesshould not only be focused on the tricuspid annulus, but on the entiretricuspid valve apparatus, including the tricuspid valve papillary muscles andtheir three-dimensional location within the apparatus.

Individuals in the study with left ventricle dilation exhibitedsignificant displacement of one of the papillary muscles and patients with both ventricles dilated hadsignificant displacement of two papillary muscles. Subjects with rightventricle dilation showed significant displacement of all three papillarymuscles.  

The researchers also found that patients with a dilated rightventricle were more likely to have a dilated annulus and exhibited the highestpulmonary arterial pressures and highest levels of tricuspid regurgitation. However,not all patients with a dilated right ventricle had significant increases inannulus area, providing evidence that the right ventricle may become dilatedwithout the annulus being affected.

“We think an increase in pulmonary arterial pressure causedgeometric changes in the ventricle, which resulted in alterations to theannulus and papillary muscles,” explainedYoganathan. “The combination of displacement of all three papillarymuscles and annular dilatation may account for the patients with isolated rightventricle dilatation having the largest percentage of severe tricuspid regurgitation.”

Knowing which parameters are responsible for significant tricuspidregurgitation and having a non-invasive imaging technique to measure theseparameters should help clinicians target repairs to the specific cause of an individual’stricuspid leakage, according to Yoganathan.

In future studies, the researchers plan to study papillarymuscle displacements in individuals with specific diseases to see if differentdisease manifestations exhibit different characteristics.

“Although it has long been accepted that pulmonaryhypertension may result in tricuspid regurgitation, this study is one of thefirst to provide a clinical correlation between the two,” said Yoganathan, whois also the Wallace H. Coulter Distinguished Faculty Chair in BiomedicalEngineering. “We want to know whether treating an individual’s pulmonary hypertension,and thus decreasing one’s pulmonary arterial pressure, can reverse thegeometric changes that are causing tricuspid regurgitation and return the annulusand papillary muscles to their original positions.”

Emory University sonographers Jason Higginson, Maria Pernetzand Sharon Howell also contributed to the study.

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Technology developed by researchers at the Georgia Institute of Technology and Emory University for delivering drugs and other therapeutics to specific locations in the eye provides the foundation for a startup company that has received a $4 million venture capital investment.

The Atlanta-based startup, Clearside Biomedical, plans to develop microinjection technology that will use hollow microneedles to precisely target therapeutics within the eye. If the technique proves successful in clinical trials and wins regulatory approval, it could provide an improved method for treating diseases that affect the back of the eye, including age-related macular degeneration.

The technology was developed in collaboration between the research groups of Mark Prausnitz, a Regents' professor in Georgia Tech's School of Chemical and Biomolecular Engineering, and Henry Edelhauser, a professor in the Department of Ophthalmology at Emory School of Medicine. Research leading to development of the technology was sponsored by the National Institutes of Health (NIH).

"We expect that targeting drug delivery within the eye will be helpful because we should be able to concentrate drugs at the disease sites where they need to act, and keep them away from other locations," said Prausnitz. "This could reduce side effects and possibly also decrease the dose required."

Prior to this development, drugs could be delivered to the retinal tissues at the back of the eye in three indirect ways: (1) injection by hypodermic needle into the eye's vitreous humor, the gelatinous material that fills the eyeball, (2) eye drops, which are limited in their ability to reach the back of the eye, and (3) pills taken by mouth that expose the whole body to the drug.

The technology developed by Georgia Tech and Emory uses a hollow micron-scale needle to inject therapeutics into the suprachoroidal space located between the outer surface of the eye -- known as the sclera -- and the choroid -- a deeper layer that provides nutrients to the rest of the eye. Preclinical research has demonstrated that fluid can flow between the two layers, where it can spread out to the entire eye, including structures such as the retina that are now difficult to reach.

By targeting this suprachoroidal space using microscopic needles, the researchers believe they can reduce trauma to the eye, make drugs more effective and reduce complications. The new delivery method could help advance a new series of drugs being developed to target the retina, choroid and other structures in the back of the eye.

"This is a significant advance in the field of ophthalmology," said Edelhauser. "Until now, it has been difficult to target drug delivery to specific locations within the eye. This new microneedle technology enables precise drug targeting to the suprachoroidal space and other locations within the eye."

In research reported in the January 2011 issue of the journal Pharmaceutical Research, the Georgia Tech-Emory team demonstrated for the first time that this technique can be used to deliver nanoparticles and microparticles to specific parts of the eye. In later research, they also showed that microneedle injections into the suprachoroidal space rapidly resulted in concentrations of drugs and particles that could be maintained for several months.

Between two and three million eye injections are made each year, many of them to treat age-related macular degeneration (AMD). The researchers believe that the microneedle-based technique could be useful for treating both AMD and glaucoma, as well as other ocular conditions related to diabetes.

The $4 million in funding for Clearside Biomedical will come from Hatteras Venture Partners, a venture capital firm based in Research Triangle Park, N.C. Hatteras focuses on seed and early-stage investments in companies developing products in biopharmaceutical, medical device, diagnostic and related human health areas.

"Clearside Biomedical represents an ideal fit for Hatteras Discovery as the platform technology is highly innovative, based on elegant science and the lead product is expected to be in clinical trials in the United States in less than 18 months," said Christy Shaffer, Ph.D., venture partner and managing director of the Hatteras Discovery Fund.

So far, the technique has been tested only in animals. The Hatteras funding will allow the company to conduct additional efficacy and safety testing needed to seek regulatory approval. The company's first product is expected to address macular edema and retinal vein occlusion.

Clearside was formed with the assistance of Georgia Tech's VentureLab program, which helped obtain early-stage seed funding from the Georgia Research Alliance. Georgia Tech VentureLab also helped the founders connect with the company's president and CEO, Daniel White, a veteran ophthalmic entrepreneur. Before joining Clearside, White was a co-founder of Alimera Sciences, an Atlanta company that is developing ophthalmic pharmaceuticals.

Two researchers from the Prausnitz lab who have been involved in development of the ocular drug delivery technique will also join the company. They are Samirkumar Patel, a postdoctoral researcher and Vladimir Zarnitsyn, a research scientist.

Research leading to the development of the technology has been supported by the National Institutes of Health (NIH). The content of this article is solely the responsibility of the principal investigators and does not necessarily represent the official view of the NIH.

Henry Edelhauser, Samirkumar Patel, Mark Prausnitz, Vladimir Zarnitsyn, Emory University and Georgia Tech have financial interests in Clearside Biomedical and its ocular platform. Edelhauser, Patel, Prausnitz and Zarnitsyn own equity in Clearside and the terms of this arrangement have been reviewed and approved by Emory University or Georgia Tech in accordance with their conflict of interest policies.

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Writer: John Toon

The promise of stem cell research for drug discovery and cell-based therapies depends on the ability of scientists to acquire stem cell lines for their research.

A survey of more than 200 human embryonic stem cell researchers in the United States found that nearly four in ten researchers have faced excessive delay in acquiring a human embryonic stem cell line and that more than one-quarter were unable to acquire a line they wanted to study.

"The survey results provide empirical data to support previously anecdotal concerns that delays in acquiring or an inability to acquire certain human embryonic stem cell lines may be hindering stem cell science in the United States," said Aaron Levine, an assistant professor in the School of Public Policy in the Ivan Allen College of Liberal Arts at the Georgia Institute of Technology.

Results of the survey were published in the December issue of the journal Nature Biotechnology. Funding for the study was provided by the Kauffman Foundation's Roadmap for an Entrepreneurial Economy Program.

Levine administered the web-based survey in November 2010 to more than 1,400 stem cell scientists working at U.S. academic and non-profit medical research institutions. Almost 400 respondents from 32 states completed the survey. Of those, 205 respondents reported using human embryonic stem cells in their research, and their responses were used in this study.

The surveyed scientists cited four main reasons for their problems accessing human embryonic stem cell lines: difficulty obtaining material transfer agreements, failure to acquire research approval from internal institutional oversight committees, cell line owners that were unwilling to share and federal policy considerations.

"Bureaucratic challenges may be inevitable in this ethically contentious and politically sensitive field, but policymakers should attempt to mitigate these issues by doing things like encouraging institutions to accept third-party ownership verification and providing clearer guidance on human embryonic stem cell research not eligible for federal funding," said Levine, who is also a member of the Georgia Tech Institute for Bioengineering and Bioscience.

The broad patents assigned to the initial inventors of the method used to isolate embryonic stem cells and numerous narrower patents claiming specific human embryonic stem cell-related techniques are also factors complicating access to human embryonic stem cell lines, according to Levine.

When survey respondents were asked how many of the more than 1,000 existing human embryonic stem cell lines they used, 76 percent reported using three or fewer lines and 54 percent reported using two or fewer lines in their research. More than half of the 130 respondents cited access issues as a major reason they chose to use specific cell lines in their research.

"These results illustrate that many human embryonic stem cell scientists in the United States are not conducting comparative studies with a diverse set of human embryonic stem cell lines, which raises concern that at least some results are cell-line specific rather than broadly applicable," said Levine. "Federal and state funding agencies may want to consider encouraging research using multiple diverse human embryonic stem cell lines to improve the reliability of research results."

Embryonic stem cell lines are being used to develop new cellular therapies for various diseases, to screen for new drugs and to better understand inherited diseases. It's crucial that diverse lines are available for this research to ensure that all individuals benefit from the results.

While availability was cited as the most common factor affecting scientists' choices regarding which cell lines to use, other considerations included suitability for a specific project, familiarity with specific lines, a desire to reduce complications in the laboratory, cost, the extent of relevant literature and the preferences of scientists' colleagues.

Three of the initial human embryonic stem cell lines derived at the University of Wisconsin in the late 1990s were the lines most commonly used by respondents. Cell lines H1, H9 and H7 were used by 79, 68 and 26 percent of respondents, respectively. Scientists also reported using more than 100 other lines, but each of these was used by fewer than 12 percent of respondents.

"Other research communities in the life sciences have experienced material access problems and they addressed them, in part, by creating centralized information and data sharing hubs, including public DNA sequence databases, tissue banks and mouse repositories. The stem cell research community has taken promising steps in this direction, but this analysis should encourage the community to continue and, if possible, accelerate these efforts," added Levine.

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When RNA component units called ribonucleotides become embedded in genomic DNA, which contains the complete genetic data for an organism, they can cause problems for cells. It is known that ribonucleotides in DNA can potentially distort the DNA double helix, resulting in genomic instability and altered DNA metabolism, but not much is known about the fate of these ribonucleotides.

A new study provides a mechanistic explanation of how ribonucleotides embedded in genomic DNA are recognized and removed from cells. Two mechanisms, enzymes called ribonucleases (RNases) H and the DNA mismatch repair system, appear to interplay to root out the RNA components.

"We believe this is the first study to show that cells utilize independent repair pathways to remove mispaired ribonucleotides embedded in chromosomal DNA, which can be sources of genetic modification if not removed," said Francesca Storici, an assistant professor in the School of Biology at the Georgia Institute of Technology. "The results also highlight a novel case of genetic redundancy, where the mismatch repair system and RNase H mechanisms compete with each other to remove misincorporated ribonucleotides and restore DNA integrity."

The findings were reported Dec. 4, 2011 in the advance online publication of the journal Nature Structural & Molecular Biology. The research was supported by the Georgia Cancer Coalition, National Science Foundation and Georgia Tech Integrative BioSystems Institute.

Storici and Georgia Tech biology graduate students Ying Shen and Kyung Duk Koh conducted the study in collaboration with Bernard Weiss, a professor emeritus in the Department of Pathology and Laboratory Medicine at Emory University.

"We wanted to understand how cells of the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae tolerate the presence of different ribonucleotides embedded in their genomic DNA. We found that the structure of a ribonucleotide tract embedded in DNA influenced its ability to cause genetic mutations more than the tract's length," said Storici.

With double-stranded DNA, when wrong bases are paired or one or few nucleotides are in excess or missing on one of the strands, a mismatch is generated. If mismatches are not corrected, they can lead to mutations.

The researchers found that single mismatched ribonucleotides in chromosomal DNA were removed by either the mismatch repair system or RNase H type 2. Mismatched ribonucleotides in the middle of at least four other ribonucleotides required RNase H type 1 for removal.

"We were excited to find that a DNA repair mechanism like mismatch repair was activated by RNA/DNA mismatches and could remove ribonucleotides embedded in chromosomal DNA," explained Storici. "In future studies, we plan to test whether other DNA repair mechanisms, such as nucleotide-excision repair and base-excision repair, can also locate and remove ribonucleotides in DNA."

Using gene correction assays driven by short nucleic acid polymers called oligonucleotides, the researchers showed that when ribonucleotides embedded in DNA were not removed, they served as templates for DNA synthesis and produced a mutation in the DNA. If both the mismatch repair system and RNase H repair mechanisms are disabled, ribonucleotide-driven gene modification increased by a factor of 47 in the yeast and 77,000 in the bacterium.

Defects in the mismatch repair system are known to predispose a person to certain types of cancer. Because the mismatch repair system is conserved from unicellular to multicellular organisms, such as humans, this study's findings open up the possibility that defects in the mismatch repair system could have consequences more critical than previously thought given the newly identified function of mismatch repair to target RNA/DNA mispairs.

The results also provide new information on the capacity of RNA to play an active role in DNA editing and remodeling, which could be the basis of an unexplored process of RNA-driven DNA evolution.

This project was supported by the National Science Foundation (NSF) (Award No. MCB-1021763). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

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Media Relations Contacts: Abby Robinson (abby@innovate.gatech.edu; 404-385-3364) or John Toon (jtoon@gatech.edu; 404-894-6986)

Writer: Abby Robinson

More than 1,800 visitors can move smoothly through the Georgia Aquarium's new AT&T Dolphin Tales exhibit, entering and leaving through the same set of doors. Their experience is not by accident though -- before the exhibit opened, logistics experts at the Georgia Institute of Technology carefully studied how guests would move and recommended ways to improve their experiences while minimizing congestion.

"We offered Georgia Aquarium leaders accurate predictions on how the new AT&T Dolphin Tales exhibit would impact guest flow within the aquarium and how to optimize the operations logistics, efficiency and show schedules for the new exhibit," said Eva K. Lee, a professor in the H. Milton Stewart School of Industrial and Systems Engineering at Georgia Tech.

The new 84,000-square-foot AT&T Dolphin Tales attraction, which opened in April 2011, includes a theater with performances of Atlantic Bottlenose dolphins in a Broadway-style production with live actors and trainers, all set to an orchestral soundtrack. The exhibit also features a lobby area where visitors can be face-to-face with the dolphins through a 25-foot viewing window.

"We knew that managing the flow of guests through the new AT&T Dolphin Tales exhibit was going to be more difficult than the other aquarium galleries because guests would be entering and exiting the exhibit through the same space," said Brian Davis, director of education and guest programs at the Georgia Aquarium. "The logistical predictions and recommendations Georgia Tech provided us were extremely accurate and enabled us to ensure an amazing guest experience while remaining fiscally responsible."

To provide recommendations to the Georgia Aquarium on how to optimize visitor flow through the new exhibit, Lee and Georgia Tech graduate student Chien-Hung Chen created RealOpt-ABM, a large-scale modeling and decision support software suite that could model guest movement through the entire aquarium.

With this software, the researchers predicted guest flow through the new exhibit and the impact of the new exhibit to surrounding areas and overall visitor flow. They were also able to determine the best strategies for show scheduling, resource allocation, space usage, and theater loading and unloading. RealOpt-ABM produced recommendations that were implemented for operations design of the new exhibit, according to Joe Handy, vice president of guest experience at the Georgia Aquarium.

According to Lee, the software's success lies in its integrated simulation and optimization approach and its inclusion of human cognitive and behavioral elements. The software's computational speed also allowed for rapid solution strategies and on-the-fly reconfigurations. Facility layout, physical design and activities at specific points of interest were captured in sub-models, which were aggregated and coupled to form the overall model.

"RealOpt-ABM incorporated advances in agent-based simulation that capture the stochastic nature of the events within the aquarium, optimization of resource allocation and show schedules, and modeling of human cognitive decisions that affect show preference and guest behavior," explained Lee.

To validate the model, Lee, research engineer Niquelle Brown and 10 Georgia Tech students analyzed guest flow and behavior patterns in the entire aquarium before the new exhibit opened. Through time-motion studies in 2010, they collected guest flow data and captured the decisions guests made, such as turning left or right when they arrived at an intersection and how long guests spent in each exhibit area. The data showed that guest movement changed based on the time of day and what time guests arrived at the museum.

Using RealOpt-ABM, the researchers accurately predicted the amount of time required to load and unload the AT&T Dolphin Tales theater, depending on the number of guests, which led to a recommendation that performances be separated by at least 90 minutes to minimize congestion. The researchers also recommended that on days with fewer than 6,000 aquarium attendees, only two shows should be offered. This recommendation was based on the need to maintain the comfort and health of the dolphins while minimizing unnecessary operations costs.

RealOpt-ABM also detailed the optimal number and location of ticket scanners and traffic controllers and the best time to open the theatre doors so that the waiting time and queue length were acceptable. The study also predicted that unless other provisions were made, a large percentage of the new exhibit's lobby area would be occupied by baby strollers that were not allowed in the theater. Lee's team recommended the creation of valet stroller parking in the main lobby of the aquarium to avoid logistics bottlenecks and congestion in the exhibit lobby area.

This logistics research project is one of six finalists for the 2011 Daniel H. Wagner Prize for Excellence in Operations Research Practice, which is given by the Institute for Operations Research and the Management Sciences (INFORMS). The winner will be selected on Nov. 14 at the INFORMS Annual Meeting, following presentations by the finalists.

"Effective strategies for managing guest flow are imperative for the successful operation of the aquarium and we trust Georgia Tech's logistics advice 100 percent," said Davis. "As the Georgia Aquarium continues to grow and expand, we will always look to Georgia Tech's expertise to maximize the experience for our guests."

Research News & Publications Office
Georgia Institute of Technology
75 Fifth Street, N.W., Suite 314
Atlanta, Georgia 30308 USA

Media Relations Contacts: Abby Robinson (abby@innovate.gatech.edu; 404-385-3364) or John Toon (jtoon@gatech.edu; 404-894-6986)

Writer: Abby Robinson

The Georgia Institute of Technology will receive funding through Grand Challenges Explorations, an initiative created by the Bill & Melinda Gates Foundation that enables researchers worldwide to test unorthodox ideas that address persistent health and development challenges. Mark Prausnitz, Regents' professor in Georgia Tech's School of Chemical and Biomolecular Engineering, will pursue an innovative global health research project focused on using microneedle patches for the low-cost administration of polio vaccine through the skin in collaboration with researchers Steve Oberste and Mark Pallansch of the U.S. Centers for Disease Control and Prevention (CDC).

Grand Challenges Explorations funds scientists and researchers worldwide to explore ideas that can break the mold in how we solve persistent global health and development challenges. The Georgia Tech/CDC project is one of 110 Grand Challenges Explorations grants announced November 7th.

"We believe in the power of innovation -- that a single bold idea can pioneer solutions to our greatest health and development challenges," said Chris Wilson, director of global health discovery for the Bill & Melinda Gates Foundation. "Grand Challenges Explorations seeks to identify and fund these new ideas wherever they come from, allowing scientists, innovators and entrepreneurs to pursue the kinds of creative ideas and novel approaches that could help to accelerate the end of polio, cure HIV infection or improve sanitation."

Projects that are receiving funding show promise in tackling priority global health issues where solutions do not yet exist. This includes finding effective methods to eliminate or control infectious diseases such as polio and HIV as well as discovering new sanitation technologies.

The goal of the Georgia Tech/CDC project is to demonstrate the scientific and economic feasibility for using microneedle patches in vaccination programs aimed at eradicating the polio virus. Current vaccination programs use an oral polio vaccine that contains a modified live virus. This vaccine is inexpensive and can be administered in door-to-door immunization campaigns, but in rare cases the vaccine can cause polio. There is an alternative injected vaccine that uses killed virus, which carries no risk of polio transmission, but is considerably more expensive than the oral vaccine, requires refrigeration for storage and must be administered by trained personnel. To eradicate polio from the world, health officials will have to discontinue use of the oral vaccine with its live virus, replacing it with the more expensive and logistically-complicated injected vaccine.

Prausnitz and his CDC collaborators believe the use of microneedle patches could reduce the cost and simplify administration of the injected vaccine. Use of the patches, which carry vaccine into the body by dissolving into the skin, could eliminate the need for administration by highly-trained personnel and the "sharps" disposal problems of traditional hypodermic needles. Because skin administration produces an immune response with smaller doses of vaccine than traditional deep intramuscular injection, the researchers expect to reduce the per-person cost of vaccine. And by incorporating dried vaccine into the microneedles, they hope to eliminate the need for vaccine refrigeration -- a challenge in remote areas of the world.

"We envision vaccination campaigns in which minimally-trained personnel go door-to-door administering microneedle patches rather than oral polio vaccine," Prausnitz explained. "Our goal for this study will be to provide the data to scientifically justify moving the microneedle patch for polio vaccination into a human trial."

In research that will complement the Grand Challenges Exploration grant, Prausnitz and his team have also received funding from the World Health Organization (WHO) to support development of the polio vaccine application for microneedle patches. And in a project sponsored by the U.S. National Institutes of Health (NIH), Prausnitz and other Georgia Tech researchers are collaborating with Emory University scientists on development of a microneedle patch for administering flu vaccine.

About Grand Challenges Explorations: Grand Challenges Explorations is a US $100 million initiative funded by the Bill & Melinda Gates Foundation. Launched in 2008, Grand Challenge Explorations grants have already been awarded to nearly 500 researchers from over 40 countries. The grant program is open to anyone from any discipline and from any organization. The initiative uses an agile, accelerated grant-making process with short, two-page online applications and no preliminary data required. Initial grants of $100,000 are awarded two times a year. Successful projects have an opportunity to receive a follow-on grant of up to US $1 million. To learn more about Grand Challenges Explorations, visit www.grandchallenges.org.

About The Georgia Institute of Technology: The Georgia Institute of Technology is one of the world's premier research universities, ranked second among all U.S. colleges and universities in the amount of engineering research conducted. Ranked seventh among U.S. News & World Report's top public universities, Georgia Tech's more than 20,000 students are enrolled in its Colleges of Architecture, Computing, Engineering, Liberal Arts, Management and Sciences. Georgia Tech is among the nation's top producers of women and minority engineers. The Institute offers research opportunities to both undergraduate and graduate students and is home to more than 100 interdisciplinary units plus the Georgia Tech Research Institute.

Research News & Publications Office
Georgia Institute of Technology
75 Fifth Street, N.W., Suite 314
Atlanta, Georgia 30308 USA

Media Relations Contacts: John Toon (404-894-6986)(jtoon@gatech.edu) or Abby Robinson (404-385-3364)(abby@innovate.gatech.edu).

The U.S. Food and Drug Administration (FDA) has awarded the Georgia Institute of Technology, Children's Healthcare of Atlanta, Emory University and Saint Joseph's Translational Research Institute (SJTRI) a two-year, $1.8 million grant to foster the development of medical devices focused on the special needs of children. The award will launch the new Atlanta Pediatric Device Consortium, which will provide assistance with engineering design, prototype development, pre-clinical and clinical studies and commercialization for novel pediatric medical devices.

"By developing, testing and refining medical devices specifically for children, we hope to produce safer, more effective devices that will improve their lives," said Barbara Boyan, the Price Gilbert, Jr. Chair in Tissue Engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The consortium will be led by Boyan, along with consortium co-directors Kevin Maher, a cardiologist and researcher specializing in pediatrics with appointments at the Children's Healthcare of Atlanta Sibley Heart Center and Emory University, and Wilbur Lam, a pediatric hematologist/oncologist and bioengineer with appointments at Emory, the Aflac Cancer Center of Children's Healthcare of Atlanta and Georgia Tech.

Historically, devices designed for adults have been used in children. However, differences in body size and immune system responses between adults and children, and the lack of appropriate models to assess how a device might function in a growing child, can result in poor device performance and responses that are less than optimal.

"There is little information as to what devices are working well for children and what complications occur," explained Boyan, who is also a Georgia Research Alliance Eminent Scholar. "In addition, the high cost of clinical trials for a small market like pediatrics has made conducting pediatric trials cost-prohibitive for many manufacturers."

The consortium will try to reduce these barriers by creating a product development pathway that will provide support for commercialization of devices for pediatric health care from initial concept to the completed product.

To do this, the consortium will build on partnerships the institutions have with the Georgia Tech Translational Research Institute for Biomedical Engineering and Science (TRIBES), which focuses on the need for engineering systems that result in commercial products; the Global Center for Medical Innovation (GCMI), which includes a prototyping design and development facility; and the Advanced Technology Development Center (ATDC) at Georgia Tech, a startup accelerator that helps Georgia technology entrepreneurs launch and build successful companies. Consortium institutions will also partner with SJTRI and the National Institutes of Health-sponsored Atlanta Clinical & Translational Science Institute (ACTSI) for pre-clinical, first-in-child testing and clinical assessments.

Additional consortium leadership will be provided by Franklin Bost, professor and director of design instruction in the Coulter Department; David Ku, a Regents professor with appointments in the Georgia Tech School of Mechanical Engineering and College of Management, and Emory's Department of Surgery; and Nicholas Chronos, president of SJTRI.

The consortium will provide assistance for pediatric medical devices from academic institutions and small businesses. The three technologies that will be investigated initially are:

• A smartphone attachment designed for at-home ear examinations;
• A renal dialysis device; and
• A gel designed to delay the re-fusion of a child’s skull bones after surgery for craniosynostosis.

The first innovation is the RemOtoscope -- a smartphone attachment designed by Lam for at-home ear examinations. Ear infections result in more than 15 million doctor office visits each year in the United States because diagnosing them requires direct observation of the child's eardrum and ear canal with a device called an otoscope. Lam envisions a physician remotely guiding placement of the device and diagnosing the condition via real-time video consultation with parents at home. The smartphone capabilities will also enable the transmission of other relevant clinical information to guide the physician in making the correct diagnosis.

The second device the consortium will bring into the pipeline is a renal dialysis device designed especially for children with kidney failure. There is currently no FDA-approved continuous bedside dialysis device for children. When critically ill children need kidney dialysis, doctors are forced to adapt adult-size dialysis equipment. These adapted adult devices can withdraw too much fluid from a pediatric patient, leading to dehydration, shock and loss of blood pressure. Matthew Paden, a pediatric critical care physician at Children's Healthcare of Atlanta and Emory realized this problem and has collaborated with Ajit Yoganathan, a Georgia Tech Regents professor and the Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering, to develop the device.

The consortium will also investigate the development of a gel designed to delay the re-fusion of a child's skull bones after surgery for craniosynostosis. Craniosynostosis affects approximately one in every 2,500 babies in the United States and is caused by the premature closure of gaps between skull bones. The gel is being developed by Boyan; Joseph Williams, clinical director of craniofacial plastic surgery at Children's Healthcare of Atlanta and clinical assistant professor in the Department of Plastic and Reconstructive Surgery at Emory University; and Coulter Department M.D./Ph.D. student Chris Hermann, senior scientist Rene Olivares-Navarrete, visiting professor Zvi Schwartz and associate professor Niren Murthy.

Future projects will be selected through the consortium's seed grant competition, which will provide awards between $25,000 and $50,000 to inventors in the partnering institutions and the business community to develop a pediatric medical device through the consortium. Entries are due Nov. 1, 2011.

Additional devices will also be identified through technology development and commercialization programs, including the Coulter Department capstone design class, the TI:GER (Technological Innovation: Generating Economic Results) program in the Georgia Tech College of Management, Georgia Tech's comprehensive center for technology commercialization called VentureLab and the Goizeuta Business School at Emory.

Research News & Publications Office
Georgia Institute of Technology
75 Fifth Street, N.W., Suite 314
Atlanta, Georgia 30308 USA

Media Relations Contacts: Abby Robinson (abby@innovate.gatech.edu; 404-385-3364) or John Toon (jtoon@gatech.edu; 404-894-6986)

Writer: Abby Robinson