by Holly Korschun
crudely stitched patchwork of body parts, the monster in Mary Shelley's Frankenstein is feared and scorned by all who encounter him. In his unending misery and rage, he exacts gruesome revenge on his master and loved ones.
An early fictional embodiment of experimental tissue engineering gone awry, the monster probably would have been much happier had his master had access to the tools of modern molecular genetics and cell biology. "I thought that if I could bestow animation upon lifeless matter, I might in process of time renew life where death had apparently devoted the body to corruption," says Frankenstein, the inventor. His overly ambitious quest to transcend the scientific limits of his time is a compelling argument for the Hippocratic oath.
"Everyone I talk to thinks the medical
implant industry will be revolutionized by
tissue engineering," says GTEC director
Robert Nerem, who also directs Georgia
Tech's Parker H. Petit Institute for
Bioengineering and Bioscience.
odern medical scientists at Emory and engineers at Georgia Tech are collaborating to imitate nature in a much more humane way -- using advanced techniques of molecular genetics and cell biology to incorporate living cells with synthetic and natural materials. The resulting tissue-engineered substitutes have the potential of repairing or replacing tissue damaged by disease or injury. Over the next decade these products are expected to gradually replace strictly artificial materials as the next generation of biomedical implants.
What that means is sizable savings in both lives and dollars.
Consider Michael Johnson, who will turn 40 in December and who has been fighting the effects of diabetes since he was 15. Daily insulin injections gave way to dialysis when his kidneys failed at age 32. In 1994, Johnson had his first kidney-pancreas transplant at Emory, but the pancreas was removed after it developed clotting problems. Johnson resumed his insulin injections until his new kidney failed in 1997 and he was forced back on dialysis. In late 1998, he had a second kidney-pancreas transplant. "This one is terrific," reports Johnson, whose wife is expecting their first child in December.
He figures the tab for his present good health to be the cost of 18 years of daily insulin injections, added to $6,000 a week for the months of dialysis, plus approximately $250,000 each for two transplants, and now $2,000 a month for the rest of his life for immunosuppressant medicines that keep his body from rejecting the transplant.
Tissue engineering holds enormous promise for millions of people like Johnson who suffer from common debilitating diseases such as diabetes, atherosclerosis, or bone loss due to injury, arthritis, or osteoporosis.
But creating tissue-engineered products requires a complex meshing of engineering and medicine, which is why the National Science Foundation (NSF) was attracted to the Georgia Tech/Emory Center for the Engineering of Living Tissues (GTEC), says director Robert Nerem. No other center has had the capability of studying the process of tissue-engineered implants all the way from engineered cells to human applications.
Interinstitutional teamwork is critical to GTEC's success, says Nerem, who has created joint scientific teams for three main initiatives:
Historic AllianceAt Georgia Tech, the development of
biomedical engineering has been a
major initiative for more than a decade,
with a growing involvement from Emory
issue engineering is translational research in one of its most important forms, points out Robert Rich, executive associate dean for research in the School of Medicine. "This is a spectacular process that goes all the way from basic engineering to the development of devices to actual applications for patients."
Tissue-engineered blood vessels, for example, could be exceedingly useful to cardiac surgeons for the half million bypass surgeries they perform each year. Finding acceptable vessels from the patient's own chest or legs is often a struggle, particularly with multiple bypasses. Synthetic materials used for large-diameter grafts are ineffective for the tiny vessels used in bypasses.
Long before GTEC, scientists with faculty appointments at both Emory and Georgia Tech were developing engineering strategies for artificial vessels. Since the early 1990s, Emory surgeon Elliott Chaikof (who also has a PhD in chemical engineering) has been designing a hybrid material that mimics elastin, one of the primary building blocks of arteries. And cardiologist Stephen Hanson has developed a system for delivering drugs through artificial blood vessels to help prevent clotting and abnormal tissue growth during coronary artery bypass.
Surgeon David Ku has been working in biomedical engineering at Tech and Emory since beginning his MD/PhD studies in 1978, when he first envisioned using engineering skills to address medical problems. His studies on how blood flows in vessels damaged by plaque buildup led to the dominant theory of why atherosclerosis develops where it does. His role within GTEC is to develop laboratory and animal models to test the artificial vessels developed by his colleagues.
"Combining engineering techniques with medicine allows scientists like me to address problems with solutions that could be useful to patients within 10 years, rather than the decades often required for many clinically applicable breakthroughs," he says.
Although tissue engineering brings to mind images of rubbery-looking artificial hearts and livers, tissue-engineered products do not necessarily resemble their natural counterparts. GTEC's bioartificial pancreas is not designed to be a whole transplantable organ, for example. It consists of cells, encased in a special membrane, that have been genetically engineered to do the work of pancreatic islet cells -- they secrete insulin in response to the level of glucose in the blood. A periodic injection of cells could eliminate the need for daily insulin shots for millions of diabetics. The engineered cells would provide more precise biofeedback and secrete only as much insulin as the body needs, rather than the sharp spikes of insulin delivered by injections.
The technology to grow new bone and cartilage has enormous potential for replacing the bone grafts used in half a million spinal fusion surgeries each year in the United States. Surgeons now must steal bone from the pelvis and graft it to the skeleton, a process that immobilizes patients for months and is unsuccessful 40% of the time. Replacement bone and cartilage also could save millions of people from the debilitating effects of osteoporosis and osteoarthritis.
GTEC scientists Scott Boden and Louisa Titus are learning to stimulate bone and cartilage growth using both genetics and biomechanics. Genes that promote bone growth can be encased within a biocompatible mesh or scaffold for implantation during spinal surgery. As new cells begin to grow, the scaffold provides the correct architecture for the new tissue, then eventually disintegrates as the cells form their own new scaffolding material.
Scientists also know that bone and cartilage grow stronger in response to physical stress, which is why heavier people have stronger bones, and bone begins to disappear in an underused limb. In order to strengthen new tissue-engineered bone and cartilage, scientists are testing mechanical loading techniques that place more weight on growing cells.
Surgeon Johnny Chen constructs bio-
engineered vessels for heart and leg
bypass surgery using pig carotid arteries
as the framework. He has successfully
tested his model vessel in six leg bypass
surgeries in dogs and plans trials in
monkeys and eventually humans.
ll these basic tissue engineering strategies, including cellular engineering, matrix construction, remodeling, and immune acceptance are referred to as "enabling technologies." Getting them all to work in tandem is the engineering equivalent of coordinating all the pieces in the child's game of Mousetrap. Everything must work together or nothing works at all.
As the inventor Frankenstein said, "Although I possessed the capacity of bestowing animation, yet to prepare a frame for the reception of it, with all the intricacies of fibres, muscles, and veins, still remained a work of inconceivable difficulty and labor."
The greatest successes in tissue engineering will be achieved by imitating nature as closely as possible, says Nerem, who also directs Tech's Parker H. Petit Institute for Bioengineering and Bioscience. The first challenge in all tissue-engineered products is to manipulate cells so that they perform certain functions that fit the desired product. For instance, to create artificial blood vessels, cells are genetically engineered to promote the growth of vessel walls. To create an artificial pancreas, scientists must train cells to perform the functions of islet cells, which secrete insulin. And cells used to promote bone growth are encouraged to express specific growth-promoting genes.
The engineered cells must be supported within a framework or "scaffold" that mimics natural tissue support systems. Depending on the product, this might be a human or animal blood vessel stripped of all but its basic building blocks (collagen or elastin) or a basic matrix that supports the growth of new bone or cartilage, like papier-mâché plastered on a wire frame. A membrane that encases engineered islet cells functions as a gatekeeper by allowing insulin to flow out and nutrients to flow in, but keeps out immune cells. The supporting materials must be strong and elastic and not clot producing. Finally, the engineered tissues must completely adapt themselves to their human host by remodeling -- a gradual integration that occurs over time much like the way step-families and their merged children adjust and adapt.
Kidney transplant surgeons Chris Larsen
and Tom Pearson, along with an interdis-
ciplinary Emory team, are using a $7.5
million NIH grant to develop strategies
for immune tolerance that may lead to
permanent, long-term acceptance of
donor organs. These same strategies,
already tested in mice and rhesus mon-
keys, should help smooth the way to the
acceptance of engineered tissue transplants.
ne of the greatest challenges of tissue engineering is immune acceptance. Emory transplant immunologists Chris Larsen and Tom Pearson and their colleagues have devoted years of research to developing a strategy that selectively blocks the immune response to whole organ transplants, with the goal of eliminating the need for immunosuppressant drugs.
As kidney transplant surgeons, Larsen and Pearson are intimately involved with the struggles faced by patients and physicians trying to find donor organs in short supply. Emory is the ninth largest transplant center in the nation and performs between 300 and 350 solid organ transplants a year. According to LifeLink of Georgia, more than 65,000 people nationwide are waiting for an organ transplant. About 4,000 die each year while waiting for a donor organ.
Although tissue engineering is sometimes touted as the ultimate solution to organ shortages, this hope may contain more hype than reality, cautions Larsen, since whole tissue-engineered organs are not yet on the horizon. However, early applications of tissue engineering are likely to be in new areas for transplant with blood vessels and cell transplants. The strategy to promote immune tolerance of donor organs might very well allow greater tolerance of engineered tissues. And tissue engineering might present other new treatment options, like transplanting engineered liver cells, rather than a whole liver, for a patient whose liver enzymes are deficient.
Larsen and Pearson also believe that xenotransplants (transplants between animals and humans) have potential for easing the organ shortage. Developing a strategy for immune tolerance could eventually help humans accept these transplants from animals. Despite tremendous progress, however, major problems remain with xenotransplants, such as the potential transmission of diseases from animals to humans and immunologic differences between species.
Emory surgeon and researcher Changyi (Johnny) Chen has developed an artificial blood vessel using a pig carotid artery that he hopes to use as a human tissue transplant. The pig tissue would serve as a matrix for new cell growth, then as the vessel integrates within the human body, the pig vessel would eventually disintegrate, leaving behind fresh human tissue. Chen believes he has at least partly solved the problem of immune rejection by stripping the pig vessels of the vascular cells that would elicit the strongest immune response, leaving only the collagen and elastin shell. New human vascular cells could then be introduced along with growth factors.
Surgeon Collin Weber and pathologist Judith Kapp, who are recent additions to the GTEC team, have genetically engineered pig islet cells to treat diabetic patients. The cells are protected within special immune-resistant capsules designed by Chaikof. This group, along with Larsen and Pearson and radiologist Ioannis Constantinidis, hopes later this year to establish an islet transplantation program at Emory, working with Canadian researchers who recently were successful in transplanting islet cells into diabetic patients.
Cardiologist Zorina Galis studies the
mechanisms involved in blood vessel
"remodeling," in which native tissues
reorganize themselves during organ
development or in response to challenges
to make themselves feel more at home.
Knowing how native blood vessels re-
shape their extracellular scaffolding, like
remodeling a house to accommodate
change, will help avoid serious problems
such as clots and strokes in tissue-
espite the challenges, the question seems to be when, not if, tissue engineering will revolutionize the medical implant industry. Artificial skin substitutes are on the market already, most likely to be followed by cartilage substitutes within six to eight years, then by artificial blood vessels.
To be effective, says Nerem, tissue-engineered products must have "off-the-shelf" availability. This will require mass production, preservation, and transportability of tissues, which means that scientists must work closely with industry.
"Surgeons perform half a million bypass surgeries each year, the majority of which require multiple vessels," he explains. "In many cases surgeons can use the patient's native vessels, but at least 150,000 patients have vessels that are unsatisfactory. If three companies shared the market for artificial blood vessels, each company would need to manufacture 50,000 vessels each year, or 1,000 per week."
GTEC's Industrial Educational Partners Program was designed to provide a dialogue between industry and the academic program and to promote collaborative research -- eventually taking tissue engineering beyond the limitations of the laboratory. Currently 14 companies plus the Sandia National Laboratory are members of the partners program. These include Advanced Tissue Sciences, AtheroGenics, Johnson & Johnson, Medtronic, Organogenesis, St. Jude Medical, Smith and Nephew, and Tissue Informatics. Each company contributes $10,000 annually for "a seat at the table" where technological advances are discussed, including a yearly symposium covering current research, and interactions with bioengineering students who could turn into future employees.
The industrial partners provide their perspective to academic research scientists by communicating the critical barriers to commercializing tissue-engineering products, points out Steve Shaya, a corporate director of science and technology at Johnson & Johnson.
"The NSF's intention in awarding the engineering research center grant to Tech and Emory was to promote the industrialization of research. The dialogue with industry has provided a focus on a broad range of key problems," says Shaya.
Orthopaedist Scott Boden uses animal
models to test genetically engineered bone
cells containing a gene that encourages
growth of bone tissue. After Boden dis-
covered the gene LMP-1 in 1997, Sofamor
Danek licensed from Emory the rights to
manufacture and market products related
to LMP-1 with the potential to treat bone
arly in the evolutionary process of tissue engineering we saw academia focus on generating this new science, while ignoring the problems of production," Shaya says. "Knowing how to produce a blood vessel that is flexible, holds blood, and avoids clots is a wonderful scientific accomplishment, but if that same vessel can't be preserved for several days or transported long distances, or manufactured in mass quantities, then the job isn't complete.
"Our company has an interest in the particular areas of artificial skin, bone, and cartilage, but the basic principles of tissue engineering, like cryopreservation [freezing] and immune acceptance, are applicable to all types of products, and breakthroughs will apply to any platform."
Shaya was working with tissue engineers at Georgia Tech even before the NSF grant, and he believes creating the partnership with Emory was critical to the program's success. "The educational partners felt strongly that without clinical input for tissue-engineering targets and clinical evaluation of developments, the program would be far less relevant," he says.
EmTech Biosciences, the Emory-Tech biotech incubator which opened in July at the new Emory West campus, should provide many additional opportunities for translating GTEC's fledgling technologies into marketable tissue-engineered products.
Enhancing research in biomedical and tissue engineering fits squarely within the Woodruff Health Science Center's goals of expanding interdisciplinary and translational research and solidifying relationships with constituents outside the university, including government agencies, business and biotechnology leaders, and other universities.
Radiologist Ioannis Constantinidis is
developing advanced magnetic resonance
imaging spectroscopy as a noninvasive
way of monitoring engineered pancreas
cells and studying their interactions with
the artificial capsules that contain them.
Miniature MRI equipment allows him to
image cell implants in small animals to
study properties of the anatomy and
glucose metabolism of the implants.
TEC's educational program focuses on developing scientific leadership for the future of tissue engineering. A year-long Undergraduate Research Scholars Program is open to rising juniors and seniors at Georgia Tech, Emory, Morehouse College, and Spelman College. A National Science Foundation Research Experience for Undergraduates hosts 10 interns from around the country at GTEC for 10 weeks during the summer. GTEC scientists also are developing web-based learning modules for students in kindergarten through graduate school and educational programs for industry.
Emory graduate research experiences within GTEC frequently overlap with the joint Emory-Tech department of biomedical engineering (BME). The department currently has 10 faculty members, but will more than double that over the next five or six years, thanks to a recent $16 million award from the Whitaker Foundation.
Graduate student Chad Johnson thought the combination of GTEC and the joint department was a good stepping stone to becoming a biomedical engineer -- his goal since the age of 15. Johnson graduated from the University of Minnesota in chemical engineering and hopes to receive his PhD from Tech and Emory in 2003. He works in the laboratory of cardiologist Zorina Galis, who is both a GTEC scientist and a BME faculty member. As a Medtronic scholar, Johnson receives partial support and educational benefits from the company. Galis and Johnson and their colleagues are working with tissue-engineered blood vessels fashioned from human or genetically modified smooth muscle cells. First they mold a gel solution made from collagen into a tubular shape, then mix in the engineered cells, like making jello, then putting in fruits. Their ultimate goal is to make sure the vessels will adapt well to their new host surroundings. "Cells like to change their microenvironments to make themselves feel at home," explains Johnson. "Our goal is to match their mechanical properties so they mimic the properties of the native vessels around them. This is called 'compliance match.'"
Apart from dual-institution parking hassles and lots of travel time, working at Tech and Emory has given Johnson the chance to deal with engineers, who want to see how things work and are more science oriented, and with medical people who are application-based and want to know how the work applies to treatment. "This keeps me grounded in the end product," he says, "and makes me aware that science is done for a reason, not just for its own sake."
GTEC's future appears bright. During a recent site visit, the NSF noted outstanding integration between the faculties of Georgia Tech and Emory, as well as excellent support from both administrations and from state government agencies. It approved full funding for GTEC for an additional year but also recommended hiring an assistant director, who could complement Nerem's expertise in engineering with equally strong expertise in biology and medicine. Next year's site visit will determine long-term future funding.
Mary Shelly provided us with the classic cautionary tale of scientific overreaching and human arrogance. At GTEC, collaborators at Emory and Georgia Tech are helping to weave a new tale: one of scientific progress and human ingenuity that points to a future of new possibilities and better lives for millions.
Holly Korschun is senior medical writer for health sciences communications at Emory. Illustrations by Christopher Hickey, photos by J. D. Scott.
Expect research to increase exponentially now that the Whitaker Foundation has injected a whopping $16 million into the Tech/Emory collaboration. Through the foundation's leadership development award, BME will nearly triple its current size by adding 17 faculty and will create fellowships in its new joint PhD program. The funds will also support major renovations at Emory and construction of a new building at Georgia Tech.
Importantly, the award will help the department realize its full potential in education and research, says Don Giddens, chair of BME, which was created just three years ago and is based in both the College of Engineering at Georgia Tech and the School of Medicine at Emory. Both universities jointly contribute to and benefit from research in biomedical engineering with the potential for major breakthroughs in medicine, basic science, and applied technology. The program is the first partnership of its kind between a public and a private university and ranks seventh nationally in the U.S. News & World Report listing of "America's Best Graduate Schools."
|The award comes as BME is already expanding its offerings. Beginning this fall, its new joint PhD degree program will incorporate both life sciences and engineering to provide students a deep understanding of biomedical systems in a multidisciplinary environment. Faculty represent engineering, physics, and computational sciences from Georgia Tech and biological, life, and clinical sciences from Emory.
BME currently participates in an MD/PhD degree program with the medical degree awarded by Emory and the bioengineering doctorate awarded by Georgia Tech. It also grants a traditional PhD in bioengineering, offered through Georgia Tech.
Building on the distinct and complementary strengths of both institutions, BME faculty now focus on education and research in cardiovascular biomechanics and biology, cellular and tissue engineering, neurosciences/engineering, biomedical imaging, and biomedical modeling and computing.
The mission of the Whitaker Foundation is to promote better human health through advancements in medicine and rehabilitation. The foundation, created in 1975, honors the memory of Uncas Whitaker, founder and chief executive officer of AMP, the world's largest manufacturer of electrical connectors and connecting devices. Whitaker was an inventor, engineer, and philanthropist who encouraged and supported collaborative medical research involving engineers, scientists, and physicians.
Copyright © Emory University, 2000. All Rights Reserved.
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Web version by Jaime Henriquez.