If a railroad engineer runs a freight train, an electrical engineer builds electric circuits and a custodial engineer is --well, a janitor-- what then is a tissue engineer? Engineer is one of those English words that have gotten slippery in their application. The Middle English engin comes from the Latin root ingenium for natural ability, or genius. Natural abilities were somehow ascribed to machines, called engines, the operators or designers of which were called engineers. This confusion between the natural and the mechanical is getting worse. Tissue engineers, the subject of this article, are people that design and build bioartificial organs among other things. Bioartificial, a word with oxymoronic qualities, refers to synthetic organs that contain living cells or tissues. A bioartificial liver, for instance, is a device which contains liver cells to detoxify the blood of a patient, along with purely mechanical filters, tubes and pumps.
Tissue engineering, broadly defined, covers a large fraction of the problems that medical science encounters. It includes 1) inducing the patient's own body to regenerate damaged tissue; 2) replacing the patients' cells or organs with living tissue from other sources, or 3) implanting prosthetic devices, such as an artificial heart, which functionally replace living organs or tissues. Already, physicians have found ways to enhance the body's limited abilities in the regeneration of skin, bones, cartilage, and nerves. Bioartificial livers, pancreas, and kidneys are in various stages of clinical development. Robert Langer and Joseph Vacanti, among the visionary fathers of tissue engineering, imagine a future in which severed limbs could be fully regenerated, failed organs could be replaced with living, laboratory generated equivalents, blindness could be cured with microelectronic vision chips, and fetuses could be brought to term in artificial wombs. This is not a far out future but one that could be realized in 30-50 years, in their view, given recent advances in understanding of tissue and organ culture, and in synthesizing biocompatible materials.
Technology, like politics, is the art of the possible. Advances in science are a necessary but not sufficient condition for advancements in technology. Also necessary are commitments of time and money, cultural adjustments in attitude, and sometimes, enabling changes in the regulatory environment.
The delicate balancing act required for technological advance is demonstrated by a small biotechnology concern called Osteotech in its efforts to help bone surgeons. While bones have an inherent ability to repair themselves, particularly traumatic fractures or bone cancer can leave voids that are impossible to for the body to heal in a satisfactory fashion. Traditionally, these voids have been filled with grafts, usually from taken from the patient; for instance, a piece of the hip is often used in back surgery. This requires the pain and expense of a second operation, however, and in sometimes the patient is not an adequate self-donor. In that case, "allograft" tissue, (in this case, bone) from another human donor is used, usually from a cadaver. Osteotech slices, freezes, and packages human bone in sizes convenient for surgeons.
The main attribute of bone, its structural strength, also makes it a hard material to work with. For this reason, Osteotech supplies Grafton, which comes in flexible strips, as a gel, or even Grafton bone putty. Grafton is "demineralized bone matrix;" human bone that has been chopped up, freeze-dried, acid extracted and further processed into its various forms. Grafton, however, is not a product that Osteotech "sells" to end users, because, under U.S. law, human tissue cannot be bought or sold. Technically speaking, Osteotech "processes" human tissue for non-profit organizations, such as the Red Cross or the Musculoskeletal Foundation, which then distribute it to surgeons. Last year, the federal Food and Drug Administration introduced an additional complication when it considered at length whether Grafton should be regulated as a "medical device" , and hence under FDA control. To the considerable relief of Osteotech and its stockholders, the FDA eventually concluded that Grafton was a human tissue graft ( regulated by local institutional review boards (IRBs)), thus saving the years and expense that would have been required to obtain FDA approval. It is likely that Grafton might easily be replaced with bone matrix from non-human sources, such as cattle, at much lower expense. Ironically, such a product, by the same logic that the FDA applied to Grafton, would be considered a "xenograft" or a tissue donation of non-human origin, which the FDA now regulates in a recent extension of its powers. Therefore, we are unlikely to see such a non-human derived Grafton-like product marketed in the U.S. very soon, if ever.
Tissue engineering innovations are regulated frequently as "medical devices" which means they have to be analyzed in terms of the 528 pages of federal guidance which pertain to such devices in the Code of Federal Regulations. These products occupy the same hazardous regulatory territory as, for instance, silicone breast implants, which have been the subject of intense dispute and product liability problems. With some justification, the FDA imposes strict licensing requirements before a product can be marketed. Before a product can even be tested clinically, an Investigational Device Exemption (IDE) must be filed. Testing can involve as many as three separate clinical trials. Companies cannot sell their products until they have received "Pre-marketing Approval" (PMA) from the FDA. Each step in the approval process can be associated with frustrating and inexplicable delays. Timing between filing and approval of PMAs is usually measured in years. These delays and other concerns prompted the conservative Cato Institute to write a blistering policy analysis entitled "Wrecking Ball: FDA Regulation of Medical Devices." According to that document, "the FDA is a full service government bureaucracy. Within broad and often vague statutory limits, it makes the rules; monitors compliance without inconveniences such as search warrants; and with wide discretion, punishes those it finds guilty. It is promulgator, police, judge, jury, and executioner all rolled into one." The American Institute for Medical and Biological Engineering (AIMBE) has also been vocal in calling for FDA reform. In a public policy statement, they recognize that "the newly evolving tissue engineering products cannot be regulated either as standard devices, as traditional biologics, or as conventional drugs. To allow timely introduction of these new technologies into medical practices requires that the FDA promptly implement a new approval pathway for this class of products." According to Grace Picciolo, a member of the FDA's Tissue Engineering Working Group, the FDA is not presently considering a separate track for tissue engineering products. She points out that it is something of a moot point, in any case. A product may be defined as either a drug, a device, or a biologic but each of the FDA's centers is free to impose another center's testing regime with respect to a particular product. Thus, a "device" might be regulated as if were a "drug" if the FDA deemed it necessary. Without legislative reform limiting the FDAs discretionary powers fears the AIMBE, "large device companies with international capabilities will continue to move their clinical trials, research, development, and manufacturing outside the United States. Smaller companies will continue to perish."
Regenerating Skin
After fifteen years of clinical testing, in March 1996, the FDA finally approved Artificial Skin, a product of Integra Life Sciences. Artificial Skin is the result of a long collaboration between Dr. John Burke, a trauma surgeon at Massachusetts General Hospital and Dr. Ionnis Yannis, a polymer chemist and biomedical engineer at MIT. The product is revolutionary in that it allows for the actual regeneration of skin badly damaged by burns or other trauma, rather than the formation of scar tissue.
A lizard that loses his tail will eventually grow a new tail. Flatworms are even more ingenious. No matter how they are cut up, new flatworms are regenerated. The tail grows a new head and the head grows a new tail. Even tiny pieces develop into whole (albeit smaller) flatworms. Regeneration is a skill that seems to decline with evolutionary complexity; humans are not very good at it, and the rudimentary skills we are born with decline with age. A three year old who loses his fingertip may grow a new one, but a teenager will not. The outer layer of skin, the epidermis, is chronically being damaged by the sun's rays, dehydration, injury, or inflammatory response. Indulge yourself too long in the sun and you will be burned. After a few painful days, however, the dead skin peels off, and a new, tender layer replaces it. Burn yourself badly in a fire, however, and the lower layer of skin, the dermis, is also destroyed. Until the advent of Artificial Skin, it was thought that the dermis would not regenerate.
Skin is an important vital organ, a very effective, breathable, moisture seal, without which our wet, pulpy insides would immediately dry out. Skin also protects us against all the bacteria, mold, and parasites for whom the human body represents opportunity. The injuries of severe burn patients must quickly be covered and traditionally, this has involved the use of cadaver skin. Obviously, this treatment brings with it the risk of viral infection and is very expensive and time-consuming; sometimes the cadaver skin has too be stitched together from small segments. John Burke was looking for a way to avoid this ghastly business for his patients and himself. He hoped to create an artificial covering that would take the place of cadaver skins. His first attempts to do this were, in his words, "the most glorious messes...absolute catastrophes." Burke needed someone who understood materials. Ioannis Yannas wanted to associate with "a medical person, who would be in contact with the patient population, who would know the exact needs of that population, so I could design a product with those specifications in mind." The surgeon and the chemist , together, invented the "skin regeneration template" which Integra now markets as "Artificial Skin." Artificial Skin far exceeds John Burke's initial expectations. Instead of merely being a temporary covering protecting the patient, Artificial Skin actually allows the body to create a new dermis over the burn site.
Artificial Skin is made in two layers; the upper layer is an elastic silicon membrane which provides the moisture barrier, functionally replacing the epidermis, and the lower level consists of an synthetic matrix of collagen fibers (purified from bovine tendons) and chondroitin sulfate (a type of large carbohydrate extracted from shark cartilage). This synthetic matrix was designed to approximate the supporting layer of protein and carbohydrate normally secreted by dermal cells. Dermal cells, as well as most tissues in the body, exist spread on surface called an "extracellular matrix" consisting of proteins and carbohydrates. Collagen is the major protein found in extracellular matrices in the body. It is also the protein from which we make gelatin. Because the protein is in a disordered state in gelatin, it has no particular structural strength. In extracellular matrices, however, collagen exists as a long, stretched out protein that arranges itself in triple helical bundles, similar to rope or twisted cable, although on a microscopic scale. Along these bundles are numerous small attachment sites for cells. Unexpectedly, Burke and Yannas found that when the synthetic matrix supplied by Artificial Skin was applied to a wound site, dermal cells from around the wound site migrate into to the artificial matrix and attach to the collagen fibers. The bovine collagen is slowly degraded and replaced with authentic human collagen synthesized by the dermal cells. Blood vessels grow into the wound to vascularize the new tissue. After the dermal layer has had a chance to repair itself, the outer membrane can be removed and replaced with very thin epidermal transplant, once again providing a natural moisture seal. The resultant skin is functionally and cosmetically superior to that achieved with other methods of treatment.
Is there any magic formula for making a collagen matrix that will attract dermal cells to colonize it? "Yes, and it is magical in a way that doesn't make sense to most biologists I know," says Dr. Yannas, the chemist. The collagen must have a "specific surface" which involves the right density of attachment sites for cells. The rate at which the matrix degrades is also very important. The matrix must persist while the "inflammation rages on," but ultimately it must be degradable so that it can be replaced by authentic human collagen. Additionally, the bovine collagen must be treated to remove or mask immunogenic sites that might cause the body to reject Artificial Skin in the same way that it would reject a foreign skin graft, for instance.
Artificial skin illustrates some of the general principles involved in tissue engineering. Tissue is organized by the underlying extracellular matrix. The matrix itself, was originally secreted by the cells, themselves, or put in place by their predecessors during the process of embryogenesis. In a deep wound, such as a severe burn, the protein matrix itself is missing or severely damaged, and the original cells in the wound have died. The burn site itself is temporarily occupied with immune system cells, like macrophages and lymphocytes, which keep infection from spreading but have no innate ability to manufacture skin. There are no appropriate cells left to replace the matrix correctly, and there is no matrix left to organize the tissue. Artificial Skin solves the problem by providing a synthetic matrix, or scaffolding, on which new tissue can arrange itself. Integra claims to have had excellent results at healing burns with Artificial Skin, even in older patients, whose skin is already thin and brittle with age. So pleased are they, in fact, according to vice-president Robert Towarnicki, that Integra is now conducting clinical trials to expand its use to cosmetic plastic surgery, that is, to treat scarring caused by previous wounds or burns. This is, of course, a vastly larger market than the original indication.
Although Integra is the first to gain FDA approval, two other biotechnology companies, Advanced Tissue Sciences (ATS) and Organogenesis, are also advancing their own form of engineered skin. Both of these companies actually grow living human "skin" in the laboratory, and use it to patch the sites of wounds. The ultimate source of their skin cells is human infantile foreskins harvested by circumcision. The cells in foreskin will grow and divide in tissue culture, increasing in number, if given an appropriate medium containing nutrients and growth factors. Infant foreskin has more potential for cell division than does that from an adult; cell cycle time increases with age, and the ultimate number of divisions is finite. An infant's foreskin can theoretically grow into a lawn that would cover something on the order of six football fields! (assuming you could incubate football fields in a humidified, sterile chamber at body temperature in a pH buffered solution containing vitamins, amino acids, epidermal growth factors, insulin, glucose, etc.) ATS has not had to acquire a new foreskin since 1989, despite ongoing clinical trials of its products. It's Dermagraft-TC would compete with Integra's Artificial Skin for the same indications, given FDA approval.
ATS and Organogenesis are also addressing the acute need for treatment of diabetic ulcers. Ulcers in the extremities, particularly the feet, result from poor circulation, very common in diabetic patients. ATS estimates that 500,000 patients are treated per year, and that over 55,000 amputations are performed because of inability to heal the wounds. ATS is allied with Smith and Nephew, PLC, a British pharmaceutical giant with over $1.5 billion in sales. The deal with Smith and Nephew is illustrative of the hurdles that small biotechnology companies face. ATS got $10 million up front and will receive $5 million more assuming they win FDA approval of Dermagraft for diabetic ulcer treatment. FDA pre-market approval of a medical device, however, does not obligate Medicare or private insurance companies to pay for that product, an important point in this age of dwindling budgets and managed health care. ATS will receive another $5 million if they successfully lobby Medicare into approving reimbursement for their product. Additional funds, up to $40 million would be given, pro-rated according to gross sales achieved, according to Marie Burke, director of investor relations for ATS.
Tissue in Three Dimensions
As important as it is, skin is basically a two-dimensional tissue, whereas most of the tissues and organs in our body are more complicated. Can engineers make tissue in three dimensions? Last year, as a test of this proposition, Linda Griffith-Cima and her colleagues at MIT created tissue that looked very like a human ear The rationale for this project was provided by Griffith-Cima's collaborator, Dr. Joseph Upton, a plastic surgeon who is frequently in the position of trying to reconstruct an ear for his patients. The outer ear is composed of cartilage and skin. Cartilage is synthesized by a specialized cell called a chondrocyte. Essentially, cartilage is extensive extracellular matrix material secreted by chondrocytes, and composed mainly of collagen, but also including large, spongy carbohydrate chains (glycose amino glycans) as well as some minor proteins. Griffith-Cima seeded isolated chondrocytes onto an artificial matrix composed of biodegradable suture material, shaped into the form of a human ear. After the chondrocytes attached to the matrix in the laboratory, the whole construct was transplanted under the skin on the back of a mutant laboratory mouse, called a nude mouse. In addition to having no hair, nude mice are lacking an immune system organ called the thymus, and as a result, they are almost totally immunodeficient. Nude mice will accept almost any type of graft (researchers have grown feathers on nude mice!). Once implanted in the mouse, the chondrocytes produced cartilage, dissolving the synthetic matrix in the process. The result: an apparent human ear growing out of the back of the mouse! It quickly became "the ear seen round the world."
For the aggressive leader of ATS, Gail Naughton, the press attention given to the vivid image of the ear seems to represent a challenge, or perhaps an opportunity to promote her company, which is also pursuing the possibilities of laboratory engineered cartilage. At the recent BioArtificial Organs conference, Naughton presented her response to the ear on the mouse's back--a very human looking ear implanted into a rabbit where the rabbit's floppy ear ought to be. The effect is grotesque, and calls up sci-fi warnings of technology gone awry. But the message gets through. Yes, tissue in three dimensions can be constructed, and yes, it is stable when placed in the animal (and presumably in a human being). The "human" ear on the rabbit was actually constructed from rabbit chondrocytes--human chondrocytes would have been rejected by the rabbit. The human ear shape was supplied by the synthetic matrix on which the cells were originally grown, and is retained in the transplanted animal even though the original biodegradable matrix has been dissolved and replaced with cartilage. Thus, "rabbit ear shape" is not an inherent property of rabbit chondrocytes. Shape is a property that can be "taught" by the matrix on which the cartilage secreting cells are grown.
From Tissues to Organs
Successes in regenerating skin and cartilage have led scientists to imagine the possibility of regenerating or reconstructing vital organs, for example, the liver. The problems are more difficult because the three dimensional architecture is complex and contains an assortment of different tissue types. The constituent cells will not automatically assume the correct structure without a matrix to guide them. Griffith-Cima has turned to a technique called "three-dimensional printing" (3DP) to create a biodegradable scaffold, which she is using to recreate miniature livers in the laboratory. 3DP is a computer aided design, computer aided manufacturing (CAD/CAM) technology wherein a three-dimensional blue-print programmed or scanned into the computer is translated into a three-dimensional structure by alternating layers of powder and adhesive in a precisely controlled fashion. Although Griffith-Cima admits it sounds like a Star-Trek replicator, it is actually more akin to the common ink-jet printers found in many offices, only engineered to work in three dimensions instead of two. Originally developed for ceramics, Griffith-Cima has altered 3DP to work with biodegradable suture-like materials (e.g. polyglycolic acid).
Griffith-Cima's "mini-liver" scaffolding has an "artery" at one end and a "vein" at the other, with a branching network in-between. So far, she has been able to show that liver cells seeded on to her scaffold will sort into "hepatocytes" , cells with the metabolic functions of the liver, and "endothelial cells", which line the capillaries and blood vessels, in a manner similar to what would be expected for a natural liver. Eventually, she hopes to have a laboratory generated liver which can be implanted in patients with liver dysfunction, reducing the need for liver transplants from organ donors. Occasionally, for inspiration, Griffith-Cima tours the wards of Childrens Hospital with her collaborator, Joseph Vacanti. She will regard her work as successful, she says, the first time a child is saved when one of her experimental livers. Vacanti is convinced that the laboratory cultured liver "is the best long term solution."
The BioArtificial Liver
Already, patients with liver failure have been saved with laboratory devices which incorporate living hepatocytes, taken from pig livers. The simplest of these uses a whole pig liver maintained briefly in organ culture at the patient's bedside and perfused with the patient's blood, from which it removes the toxins. Although such an approach works for brief periods, the pig liver is under heavy attack from the patient's immune system, being rejected in the same way that a person rejects a transplanted organ. Another approach, the "bioartificial liver" involves culturing cells dissociated from the liver in hollow fibers or capsules, which separate the cells from the human blood by semi-porous membranes. Small molecules are able to pass through the pores, thus the liver cells are able to perform their detoxification function. About 5 years ago, Achilles Demetriou began using this sort of device to treat patients at Vanderbuilt University. Aside from the pig liver cells, the first of these "bioartificial" livers was built from off-the- shelf components, common laboratory artifacts like pumps and waterbaths. "It looked like it was built in a garage," says Demetriou. These days, Grace Biomedical, a division of W.R. Grace, supplies Demetriou with a much more impressive looking device, though it still operates on the same principles.
Using his bioartificial liver, Demetriou has an amassed an impressive record treating patients with fulminant liver failure, a disease which ordinarily has a 90% mortality rate. These patients are in an acute state of liver dysfunction resulting in "encephalopathy"--the brain literally swells up due to accumulated toxins, squeezing off the blood supply, leading to coma, and without an immediate liver transplant, these patients usually die. Of seventeen patients treated, Demetriou has successfully "bridged" fifteen to transplanted livers; that is he kept them alive as long as a week until a liver could be found. One patient was not a candidate for a new liver due to other complications, and so eventually died. The remaining patient had a rare blood type and a suitable liver could not be found. That patient, however, recovered liver function, and went home healthy, without a transplant.
There is reason for optimism that the bioartificial liver can eliminate the need for a transplanted liver in other patients with fulminant liver failure. Ironically, nobody knows what toxins accumulate in the brain, or how the liver operates to relieve intracranial pressure. "We are treating a disease we do not understand with a treatment we do not understand," according to Demetriou. Acute liver failure is usually due to a temporary event, like Tylenol overdose (a common means of attempted suicide) or hypersensitivity to other drugs. The liver is a fairly robust organ and could possibly regain function in many instances--if the patient doesn't go brain-dead first. This is an important point, one he hopes to impress on health maintenance organizations (HMOs) and insurance companies. Traditionally, these companies have been slow to adopt payment schedules for new technologies. Demetriou's bioartificial liver treatments require constant monitoring in expensive intensive care units. Worse yet, from the financial side, the treatments allow a patient who might have died access to a liver transplant, which costs in excess of half a million dollars. If Demetriou can show recovery of patients, in some cases, without a liver transplant, he stands a far better chance of having the bioartificial liver accepted by HMOs, Medicare and private insurance companies as standard medical practice in the U.S. For every 7 hours of treatment with the bioartificial liver, Demetriou figures he gains another 24 hours of life for his patients. Although the experiment hasn't really been tried yet, most in the field expect that using pig liver cells instead of human limits the amount of time that the device could be used on a human patient. In addition to its detoxification function, the liver supplies most of the non-cellular protein found in the blood. It is expected that eventually the patient will develop an immune response to the pig proteins secreted by the pig liver cells-- and Demetriou concedes he has detected porcine proteins in the blood of his patients.
Long term treatment of patients with chronic liver disease in a manner analogous to the hemodialysis treatment of kidney patients would probably require a bioartificial liver which used human cells. But where to get the cells? As it stands now, technology is not the limiting factor in treating liver patients; it is the number of human livers available. Every year, 30-50,000 people die of liver failure, while only about 3000 transplants are available. Geoffrey Block may have an answer to the human liver shortage. Recently, he and his co-workers at the University of Pittsburgh stimulated liver cells to divide and grow in laboratory culture, using a chemically defined culture medium. The secret? A few hormones--some of which are proprietary, and 75 different nutrients. Surprisingly, fully differentiated, functioning hepatocytes divide and grow, according to Block. It had been widely believed by many cell biologists and embryologists that these fully differentiated cells will not reproduce. Differentiated cells are replaced, it is thought, by the division of immature "committed progenitor" cells. While the latter can be cultured in the laboratory, they lack the liver cell functions that would be needed in a bioartificial liver. Block believes that his group has "dedifferentiated" the liver into growing, immature cells. He also claims that he can manipulate the cultures to develop again into functioning mature hepatocytes, which would be necessary for his work to be medically significant. Lola Reid of the University of North Carolina, who has done careful work on the developmental biology of liver, urges caution in interpreting Block's results. The "de-differentiation" of hepatocytes runs contrary to her own experience, which suggests that the liver cells mature in an ordered fashion in the body, starting with the division of immature stem cells. Demetriou, for his part, is skeptical that Block's laboratory cultured cells will ultimately provide the detoxification function necessary for use in the bioartificial liver, citing many previous claims in the literature of laboratory cultured, functioning hepatocytes that turned out to be premature. If Block is correct, however, "I'll buy the cells from him," says Demetriou.
Genetic Therapy
Dr. Block is excited about his experiments for another reason. The liver has long been thought of as an ideal target for genetic therapy; it is the largest organ in the body, , and it is specialized for delivering secretion products into the blood stream. Suppose, for instance, that a patient is hemophiliac, that is, he doesn't produce blood clotting factor, a protein that is encoded by a gene, a piece of DNA. A portion of his liver could be removed, a procedure which would do him no harm, as the liver would regenerate to full size (virtually the only organ with that capability). The excised liver cells could then be genetically engineered such that a new gene specifying the clotting factor protein was introduced. The cells could then be re-implanted in the liver, and clotting factor would then be secreted by engineered cells. The problem, so far, has been that hepatocytes would not undergo cell division outside the body. Cells that are not actively replicating their chromosomes will not take up and express the genetically engineered DNA used by molecular biologists for genetic therapy. If Dr. Block has persuaded liver cells to divide in culture, this problem may be solved.
The Bioartificial Pancreas
Instead of using genetic therapy, as Dr. Block suggests, foreign cells that secreted a particular protein could be used to replace the patients own-- if a way was found to protect the cells from the host's immune system. This is exactly the idea behind the "bioartificial pancreas" which researchers hope will replace insulin injections as a therapy for diabetics. The insulin-secreting cells form pancreatic islets, usually taken from a pig, are placed in semi-porous capsules and implanted in the body. The capsules must be biologically and chemically inert; that is, their chemical composition cannot induce inflammation or other reaction from the body, and they must resist decomposition. The capsules must contain pores small enough to exclude the mobile cells of the immune system, macrophages and lymphocytes, but large enough to allow a physiological release of insulin in response to blood glucose levels. Obviously, long term survival of the cells is also a requirement. According to Anthony Sun, of the University of Toronto, diabetic monkeys have become insulin independent using the bioartificial pancreas for periods longer than two years. Other researchers have shown similar results in dogs and rats. Islet cells have been recovered after a year of implantation and shown to be still viable. A limited trial using human beings that was carried out in China was so successful, according to Dr. Sun, that patients tried to bribe the doctors to continue the experimental procedure. Clinical trials have now been only recently approved by the FDA in the United States using microencapsulated porcine cells in human patients.
Time Line
When can we expect the fruits of tissue engineering to be turned into medical practice?. Robert Langer believes that in addition to Integra's Artificial Skin, ATS and Organogenesis will have approval for some applications of their "skin equivalents" in the next couple of years and that engineered cartilage will become available for athletic injuries and reconstructive surgery in a couple of years. Originally, he had thought that the bioartificial liver might take ten years to gain approval, but he's revising that estimate downward. Vacanti guesses the liver will take five years for approval. Demetriou, who is intimately involved with the project, and Lola Reid, who is not, both believe perhaps two years is a possibility. Clinical trials for the bioartificial pancreas have not yet begun in the United States, so the time frame has more uncertainties. The implantable liver envisioned by Griffith-Cima and Vacanti is still in the dream category.
The difficulty in forecasting the introduction of tissue engineering products lies less with anticipating clinical problems, and more with guessing the extent of the inevitable delays as applications pile-up in the FDA's bureaucracy. The FDA's Grace Picciola thinks that regulators are ahead of the game with respect to tissue engineering if only because the field is so new that few products have yet to emerge from the clinics. Nonetheless, she complains of downsizing, cutbacks, understaffing, and a lack of funds available, for instance, to attend the scientific meetings so necessary to keep up with advances in the field. Dr. Langer, typically optimistic, characterizes the FDA as now "very co-operative" and predicts that "eventually everything, all the tissues, will be engineered." For surgeons like John Burke or Joseph Vacanti, that promises a far, far better system than one in which parts have to be scavenged off dead bodies in order to patch up their patients. ~
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