Skin grafting is currently an incredibly important procedure for the thousands of people who survive devastating trauma with extreme, life-threatening burns. The practice of taking samples of skin, either from the inflicted patient or from an allogeneic source, and attaching them to the damaged area produces beneficial results that set the patient on the road to recovery. Skin grafts allow people who would otherwise be functionally or aesthetically debilitated due to their injuries to regain the utility and appearance of their epidermis. Over the past 40 years, the traditional methods of skin grafting, which involve the use of either a live or cadaver donor to directly harvest the grafts, have cemented themselves as routine, safe, and effective. Over the past 20 years, though, the pace of innovation and experimentation in the realm of skin grafting has significantly quickened. New techniques, procedures, and assistive products being used in the medical process of grafting are paving the way for more successful skin transplants and faster, more consistent healing. Although these reports of exciting research and development are focused on restorative measures for patients who have survived painful accidents, the advancements made may also be put to use in more superficial situations. There always exists the inevitable potential for medical progress to be used for superfluous, ultimately unnecessary reasons, and the case of skin grafting is no different. Many of the innovations presented in these articles could easily be transformed into the next 'hot procedure' for the more affluent members of the community.
In this blog, we provided and analyzed a collection of articles that we felt highlighted the newest, most ingenious, and most controversial innovations emerging in the field of skin grafting. The articles, appearing in various news, magazine, and scientific journal publications, widely range in topic; the use of cells which display malignant behavior in transplants, the method of actually spraying on skin cells for grafting, and the manipulation of color and tone in grafts are just some of the issues and advancements discussed in the articles themselves and our blog post responses. The format of the blog lists the articles chronologically according to their publication date—in this way, it is possible to trace the media's attention to and descriptions of the medical advancements in the field of skin grafting. Our blog responses critically analyze these lay-press representations of the innovations and their ethical and social implications.
In skin graft surgery, a variety of new techniques are being developed. These techniques are used in the actual grafting procedure to enhance post-operative care or to use skin to make other organs. One technique used on patients with extensive burns that cover 50 to 60% of their bodies involves extracting skin, allowing the epidermal cells to grow, and then spraying it back on the patient. This is different from the usual skin grafting procedure in which they stretch skin over the damaged area. This is an important advancement because it allows to autologous grafts on a wider range of patients. Post-operative care is very important in skin graft surgery, because if the graft is not a good match, it can become infected or be rejected. Another interesting practice involves the use of leeches during post-op care to encourage the flow of blood. By eliminating the pooled blood under the skin, the leeches make the graft healthier and allow it to heal and integrate with ease. The leeches also help because they have a blood thinner in their saliva and they numb the body while they feast. Another fairly recent technique that researchers are observing is the use of Therapeutic Ultrasound. From rabbit testing, TUS shows that tissue that has received this treatment has a larger number of new blood vessels and a significant increase in proliferating skin cells. In another medical arena over the last few months, skin cells have been harvested to grow the tissue needed to make blood vessels. If the use of these engineered blood vessels proves effective, this will be a revolutionary breakthrough in heart surgery; vessels will be artificially grown and the traditional harvesting of the saphenous vein or mammary artery for bypass will be unnecessary.
While embryonic stem cells have long been seen as the most effective and reliable source for skin cells, due to the plethora of moral and ethical controversy surrounding the deliberately aborting embryos, scientists and researchers are on the lookout for different sources. The makers of Cytograft in Argentina have discovered that taking a small swatch of skin from the back of the patient’s hand or the inner wrist are great sources for skin cells; once enzymes have been added to extract the necessary fibroblast cells, extracellular matrix, and serve as the framework for tissues. In America. a new kind of artificial skin, ICX-SKN, is being created from a matrix made from the skin cells that make new tissues in the body. Even the foreskin of circumcised babies has been used as a source for stem cells because they produce keratin in large amounts and never stop dividing. What is great about these new sources is that from one little piece of skin, scientists can create long grafts and engineer many new cells, ensuring that there will never be a shortage of skin cells. Now that so many sources have been discovered, the outlook for burn victims is increasingly positive.
While the use of the aforementioned mentioned skin graft techniques and procedures could be considered controversial, on a more fundamental level, the use of skin grafts is not controversial in the least. No one would begrudge a burn victim a healthier, less painful life, nor would they deny a patient suffering from ulcers the skin transplant that would cure them of their condition. The problem, then – the one true cause of controversy – is the source of the cells used to create skin grafts. There is a very limited source of skin cells that are continually viable and practical in all situations. Autologous skin transplants cannot be used on severe burn victims who lack enough healthy skin to cover their burns. Allogeneic transplants are avoided if there is a threat of an immune response, and while Epicel has recently gained FDA approval for the first xenogeneic skin transplant, using animals as possible sources of skin exposes humans to viral and bacterial infections that thus far have been restricted to other species – not to mention that animals rights activists will most certainly protest killing animals for the sake of human medical advancement. In order to overcome this lack of potent skin cells, the medical industry turned to the use of stem cells.
It is scientific fact that human neonatal foreskin fibroblasts in collagen gel form dermal skin-like tissue in vitro and that embryonic stem cells are the only human cells that are totipotent, which is to say that they can form all cell types, and have the potential to cure or treat all diseases with a significant cellular component. Therefore, it would seem ideal to use these totipotent cells in treating burn victims and other patients who require skin grafts. What makes the use of stem cells controversial is the fact that many conservative and religious groups view the destruction of a blastocyst as the murder of a human being. Thankfully, the use of two different techniques has allowed researchers to side-step this controversy.
The first method involves the harvest of adult epidermal stem cells from the skin of the patient or donor which have the capability to grow tissues with differentiated layers. These cells are attached to surgical gauze and grafted onto the patient. This creates viable transplant cells from unipotent stem cells and does not require the destruction of a blastocyst. This method is only used the most extreme cases, however. The second, more recent and exciting discovery is the creation of pluripotent stem cells from differentiated skin cells. Though this method has yet to yield transplantable skin grafts available for testing in clinical trials, and though the process of cell differentiation is currently unknown, the ability to grow any cell type without the destruction of the embryo has opened up several new avenues that can and will lead to the improved health and quality of life of burn victims everywhere.
Yet while the discovery of induced Pluripotent Stem Cells (iPS) should be greatly applauded – and the Yamanaka group congratulated with a trip to Stockholm next year – it is important to remember that this discovery, this supposed victory for both conservatives and liberals alike, did come at the terrible cost: the suffering of thousands of burn victims who would have benefited from stem cell therapy had this research been federally funded. Currently, President Bush is being lavishly praised for his continued stance against embryonic stem cell research. Supporters claim that had the president allowed such research, scientists would have had no incentive to look for alternatives to “embryo killing.” An examination of the facts, however, shows that the president deserves no such credit. Not only did President Bush limit stem cell research to a handful of aging stem cell lines, but he also prevented scientists who dared to do such research from using federally funded laboratories or equipment, or even consulting with federally supported scientists; his efforts thereby thwarted the research effort for about four to five years. Want definitive proof that the current administration’s efforts have nothing to do with the most recent breakthrough? The Yamanaka group who pioneered this method conducted their research in Japan, where they were unhindered by American regulations.
Regardless of who should ultimately receive credit, the discovery of iPS has freed skin grafting procedures and techniques from any surrounding controversies. All that remains is to look ahead and hypothesize as to what discoveries lay ahead. What advancements in skin grafting can be expected in the near future? To begin with, scientists will always have need fpr cells that grow faster – both in culture and when grafted to the patient’s skin. Continual growth would allow patients to not only develop thicker, stronger skin, but would also be extremely helpful for children who sustain severe burns and require skin that can grow as their bodies do. We can also expect future scientific discoveries to overcome immune barriers that currently prevent the widespread use of allogeneic and transgenic tissues.
All of these methods, however, are largely reactive. The future, it seems, will bring not just advancements in our ability to respond to trauma, but also in a more proactive response to treatment. If parents will soon be able to select for cancer-resistant genes – or perhaps even genes for intelligence or good looks – then it certainly may become possible to select for genes that produce thicker, healthier skin: skin that is less prone to infection (or even acne), skin that is resistant to burns and frostbite, skin that heals more quickly. At some time, improving on existing technologies or ideas may not be feasible, efficient, or even possible. If medicine reaches that point, future scientific discoveries will concern themselves not with improving these procedures and assistive products, but with improving the human species itself. Whether that would destroy our humanity, whether it would take away our highly valued human ‘essence,’ remains to be seen.
Friday, December 14, 2007
Tuesday, November 20, 2007
Artificial Skin Breakthrough
Nupur Shridhar
First, a note concerning my previous blogs: I had previously recommended that scientists avoid using stem and fetal cells to avoid a moral debate and instead find some way to create those cells in a lab. Imagine my happiness when I discovered that scientists have only recently (and very recently, this article is published in the 20 November 2007 edition of SCIENCE magazine) discovered a way to turn skin cells into stem cells. For more details see here: http://sciencenow.sciencemag.org/cgi/content/full/2007/1120/1 or go get the article and read it.
Also here: http://www.cnn.com/2007/HEALTH/11/20/stem.cell.reax/index.html
In continuing with my theme of artificial cells that mimic the structure and function of natural cells, this article talks of the artificial skin cells created by British researchers in June of this year. This is the first successful trial involving laboratory-made living human skin that was fully and consistently integrated into the human body. This is a new development in artificial skins cells, since previously, skin substitutes in the past biodegraded too quickly in situ. The new skin, ICX-SKN, is created from a matrix produced by the same skin cells that create new tissue in the body. Thus, the artificial skin cells were designed with a template that was created by looking at the way the body naturally functions.
Current trials have shown that the new skin was able to close and heal a wound site in just 28 days. If artificial skins can become easily produced and prove to be just as effective as skin grafts, then doctors and surgeons would no longer have to worry about a dearth of viable skin cells for transplantation or grafting. Theoretically, there could be an endless supply of skin cells for every burn victim and plastic surgery patient - without risk of rejection (the cells wouldn't trigger an immune response) and a reduced risk of infection. So what's next? The article states that researchers now hope to create a whole range of cell-based implants that can fully regenerate lost tissue, not just help wound sites heal.
This clinical breakthrough has also inspired me to continuing working towards my goal of perhaps one day becoming a biomedical researcher or engineer. Perhaps "inspire" is too strong a word - too trite, too stereotypical. Rather, it had convinced me that investing in science pays off. Sometimes, as it was in this case, a researcher does not have to create a new mechanism or discover a new drug or procedure. Simply imitating the body's amazing ability to heal itself is enough.
The way in which these scientists approached creating an artificial skin cell (by looking at the matrix created when new cells are formed) reminds me of the article read earlier in class that outlined some of the cases where patients who had terminal cancer had miraculous recoveries. One line from the article that I remember rather distinctly stated that treatments from cancer need to do what the body did in those patients who recovered: it targeted the cancer cells with absolutely no side effects, and no current treatment, from surgery to chemotherapy, is as effective and efficient as the human body. In the case of patients who need skin grafts, then, who have suffered burns that are so severe that their bodies' natural mechanism of healing has been damaged, it makes sense to use artificial skin cells that would work the way their own cells would have had they not been damaged.
I am a student who often thinks about the moral consequences of any scientific discovery. Yet the use of artificial skin cells does not seem to offend anyone or cross any line. All burn victims deserve care, and if we can generate their cure in a test tube instead of surgically taking it from another part of their body, then we, as a community, should do so. Creating artificial skin cells was a result of working diligently, thinking creatively, and doing right. Hopefully, it will soon become common medical practice and affect thousands of people worldwide.
First, a note concerning my previous blogs: I had previously recommended that scientists avoid using stem and fetal cells to avoid a moral debate and instead find some way to create those cells in a lab. Imagine my happiness when I discovered that scientists have only recently (and very recently, this article is published in the 20 November 2007 edition of SCIENCE magazine) discovered a way to turn skin cells into stem cells. For more details see here: http://sciencenow.sciencemag.org/cgi/content/full/2007/1120/1 or go get the article and read it.
Also here: http://www.cnn.com/2007/HEALTH/11/20/stem.cell.reax/index.html
In continuing with my theme of artificial cells that mimic the structure and function of natural cells, this article talks of the artificial skin cells created by British researchers in June of this year. This is the first successful trial involving laboratory-made living human skin that was fully and consistently integrated into the human body. This is a new development in artificial skins cells, since previously, skin substitutes in the past biodegraded too quickly in situ. The new skin, ICX-SKN, is created from a matrix produced by the same skin cells that create new tissue in the body. Thus, the artificial skin cells were designed with a template that was created by looking at the way the body naturally functions.
Current trials have shown that the new skin was able to close and heal a wound site in just 28 days. If artificial skins can become easily produced and prove to be just as effective as skin grafts, then doctors and surgeons would no longer have to worry about a dearth of viable skin cells for transplantation or grafting. Theoretically, there could be an endless supply of skin cells for every burn victim and plastic surgery patient - without risk of rejection (the cells wouldn't trigger an immune response) and a reduced risk of infection. So what's next? The article states that researchers now hope to create a whole range of cell-based implants that can fully regenerate lost tissue, not just help wound sites heal.
This clinical breakthrough has also inspired me to continuing working towards my goal of perhaps one day becoming a biomedical researcher or engineer. Perhaps "inspire" is too strong a word - too trite, too stereotypical. Rather, it had convinced me that investing in science pays off. Sometimes, as it was in this case, a researcher does not have to create a new mechanism or discover a new drug or procedure. Simply imitating the body's amazing ability to heal itself is enough.
The way in which these scientists approached creating an artificial skin cell (by looking at the matrix created when new cells are formed) reminds me of the article read earlier in class that outlined some of the cases where patients who had terminal cancer had miraculous recoveries. One line from the article that I remember rather distinctly stated that treatments from cancer need to do what the body did in those patients who recovered: it targeted the cancer cells with absolutely no side effects, and no current treatment, from surgery to chemotherapy, is as effective and efficient as the human body. In the case of patients who need skin grafts, then, who have suffered burns that are so severe that their bodies' natural mechanism of healing has been damaged, it makes sense to use artificial skin cells that would work the way their own cells would have had they not been damaged.
I am a student who often thinks about the moral consequences of any scientific discovery. Yet the use of artificial skin cells does not seem to offend anyone or cross any line. All burn victims deserve care, and if we can generate their cure in a test tube instead of surgically taking it from another part of their body, then we, as a community, should do so. Creating artificial skin cells was a result of working diligently, thinking creatively, and doing right. Hopefully, it will soon become common medical practice and affect thousands of people worldwide.
Epicel is FDA approved
PR Newswire
October 29th, 2007
The FDA has granted Genzyme Corporation marketing approval for its product Epicel, which stands for cultured epidermal autograph. The rights were granted under the Humanitarian Device Exemption (HDE) for use in life threatening wounds due to severe burns. With its approval Epicel became the first xenotransplantation-classified product to be approved in the U.S. It is considered xenotranslplantation it includes animal cells.
The skin is taken from the patient and then grown on a layer of mouse cells, which expedite the growing process. The skin is grown in lengths which can then be used as grafts. The process takes 16 days to complete and then takes 3 to 4 weeks to incorporate after being attached. Epicel is meant for patients who have suffered damage to more than 30 percent of the body since they no longer have enough healthy skin to cover their burns, though it can also be used with split-thickness autografts. Dr. Rajiv Sood, medical director at Indiana University School of Medicine said that Epicel “has been the most important advance in burn care for the coverage of large total body surface area burn wounds in this decade”.
The press release from PR Newswire released October 29th, 2007 was very thorough in portraying Epicel in its entirety. It mentioned the antibiotics with which it was cultured and that traces of these antibiotics may still be on the graft. It also pointed out that the cells were grown in a medium of cells that have bovine and murine origin.
It also highlighted the danger of the grafts being xenotransplantation-classified. Since the cells were grown in the same culture as mouse cells, there is always the chance of contamination, even though the cells have been tested for bacteria, fungi and viruses. The press release also points out that since the effect of xenotransplantation is not yet known the patients who receive the graft should not donate blood or blood parts, tissue, breast milk, egg, sperm, or other body parts to be used in humans.
Epicel's approval is a big step. Though xenotransplantation is strictly regulated, at the moment there is no technology better than the Epicel cells. The FDA has been very strict about xenotransplantation and the only reason Epicel was approved is because there is not a better option. The HDE makes it possible for new procedures and technologies to be able to be distributed, but Genzyme should work to get general approval. If Epicel can get approval for widespread use then it would be a good option for all burn victims, and may even take over for cadaver donation.
Though the press release emphasized that the inclusion of mouse cells was a risk and that the recipients should not donate any part of their body, it left out a major component of transmission, child birth. With the inclusion of another species in the growing of the grafts there is always the chance that they will transmit a virus or pathogen that is not yet known in humans. If the patient then gets the virus they need to contain it to themselves and so they should not reproduce, in addition to bodily donation.
Yet if Epicel can be used effectively and prove that the xenotransplantation has no negative effects than it can be a very great resource for skin grafts. The harvested skin is the size of a postal stamp and can then be grown to cover the entire body. It would allow for there to be enough grafts available for all patients who need them.
Also the animal rights controversy that usually surrounds xenotransplantation doesn't really affect Epicel. Animal activists though in their plea that all animals are equal, don't really seem to care about mice. If the human cells were grown on animal cells other than mice, then there might be an issue, but as it stands right now there isn't.
-SH
October 29th, 2007
The FDA has granted Genzyme Corporation marketing approval for its product Epicel, which stands for cultured epidermal autograph. The rights were granted under the Humanitarian Device Exemption (HDE) for use in life threatening wounds due to severe burns. With its approval Epicel became the first xenotransplantation-classified product to be approved in the U.S. It is considered xenotranslplantation it includes animal cells.
The skin is taken from the patient and then grown on a layer of mouse cells, which expedite the growing process. The skin is grown in lengths which can then be used as grafts. The process takes 16 days to complete and then takes 3 to 4 weeks to incorporate after being attached. Epicel is meant for patients who have suffered damage to more than 30 percent of the body since they no longer have enough healthy skin to cover their burns, though it can also be used with split-thickness autografts. Dr. Rajiv Sood, medical director at Indiana University School of Medicine said that Epicel “has been the most important advance in burn care for the coverage of large total body surface area burn wounds in this decade”.
The press release from PR Newswire released October 29th, 2007 was very thorough in portraying Epicel in its entirety. It mentioned the antibiotics with which it was cultured and that traces of these antibiotics may still be on the graft. It also pointed out that the cells were grown in a medium of cells that have bovine and murine origin.
It also highlighted the danger of the grafts being xenotransplantation-classified. Since the cells were grown in the same culture as mouse cells, there is always the chance of contamination, even though the cells have been tested for bacteria, fungi and viruses. The press release also points out that since the effect of xenotransplantation is not yet known the patients who receive the graft should not donate blood or blood parts, tissue, breast milk, egg, sperm, or other body parts to be used in humans.
Epicel's approval is a big step. Though xenotransplantation is strictly regulated, at the moment there is no technology better than the Epicel cells. The FDA has been very strict about xenotransplantation and the only reason Epicel was approved is because there is not a better option. The HDE makes it possible for new procedures and technologies to be able to be distributed, but Genzyme should work to get general approval. If Epicel can get approval for widespread use then it would be a good option for all burn victims, and may even take over for cadaver donation.
Though the press release emphasized that the inclusion of mouse cells was a risk and that the recipients should not donate any part of their body, it left out a major component of transmission, child birth. With the inclusion of another species in the growing of the grafts there is always the chance that they will transmit a virus or pathogen that is not yet known in humans. If the patient then gets the virus they need to contain it to themselves and so they should not reproduce, in addition to bodily donation.
Yet if Epicel can be used effectively and prove that the xenotransplantation has no negative effects than it can be a very great resource for skin grafts. The harvested skin is the size of a postal stamp and can then be grown to cover the entire body. It would allow for there to be enough grafts available for all patients who need them.
Also the animal rights controversy that usually surrounds xenotransplantation doesn't really affect Epicel. Animal activists though in their plea that all animals are equal, don't really seem to care about mice. If the human cells were grown on animal cells other than mice, then there might be an issue, but as it stands right now there isn't.
-SH
Monday, November 19, 2007
Blood Vessels Grown From Patient's Skin
Article: Blood Vessels Grown From Patient’s Skin
Author: Lawrence K. Altman
Found in: The New York Times
Published: October 9, 2007
Researchers at Cytograft Tissue Engineering of Novato, California have developed a six to nine month method of growing blood vessels – taken directly from a small section of the patient’s skin – in a laboratory with the intent of implanting them to restore blood flow around a patient’s damaged arteries and veins. This is the first time that blood vessels have been created solely from a patient’s own tissues and used to make skin grafts. This is such a huge accomplishment that the findings were published in the current issue of The New England Journal of Medicine.
Since the vessels are made from the patient’s own skin, there is no need for anti-rejection drugs, which are costly and require the patient to use them throughout his entire life to avoid long-term rejection. Furthermore, there is no risk of an inflammatory response because there are no synthetic materials or scaffolding in these vessels. Engineering these vessels is a huge feat since infection is the leading cause of graft failure (the second leading cause is shearing, where the pressure causes a graft to detach from the underlying tissue).
Doctors interested in pursuing this research project went to Argentina to conduct their studies because the medical costs are significantly lower than in America, and in Argentina, they didn’t have to deal with the strict regulations of the conservative Food and Drug Administration. Eight Argentinean patients, all of whom were receiving chronic kidney dialysis, were volunteers chosen for the study because their vessels were already worn out and because the dialysis shunts allowed for an easy way to monitor the functioning of the new vessels. On those brave eight patients, doctors performed the first human tests of the vessels. So far, none of these patients have suffered any major side effects, however, because the procedure is so new, the longest follow-up has only been for thirteen months. The long-term effects and possible
complications are not yet known, thus this procedure will not be in practiced as standard medicine for quite some time.
In the study in Argentina, surgeons cut an artery and a vein from the forearm and joined them in a link, also known as a shunt, which provided access for the repeated needle punctures required to connect the patient to a dialysis machine. These shunts can last a maximum of fifteen years, but when clots and infections develop inside the shunts that reduce or stop blood flow, new shunts must be created and installed immediately.
To obtain the skin necessary for the procedure, a fifteen-minute biopsy is all that is required. The patient is then put under local anesthesia while the surgeon removes a piece of skin, including a strip of a vein about an inch long from the back of the hand or the inner wrist. Technicians take that strip of skin and vein and use enzymes to extract fibroblast cells, the most common connective tissue found in humans and animals. These cells synthesize and maintain the extracellular matrix of tissues as well as provide the structural framework for many tissues, known as stroma. Additionally, fibroblasts play a critical roll in wound healing, which is incredibly important after a patient has undergone a skin graft procedure. In the actual graft, fibroblasts provide the mechanical backbone for the sheets that are later peeled and rolled into a tube. Technicians also extract endothelial cells from the inner lining of the vein. Endothelial cells line the interior surfaces of blood vessels, control the transit of white blood cells into and out of the bloodstream, and are involved in various processes such as angiogenesis (the formation of new blood vessels), atherosclerosis, and thrombosis (blood clotting). The fibroblast and endothelial cells are then grown by the millions as sheets in a laboratory. Under a microscope, this new vessel looks like a vein, but it has the strength of an artery, which is important because over time the body will be able to remodel the cells from a vein into a vessel with the elasticity of an artery.
A vascular surgeon in Buenos Aires, Dr. Sergio Garrido, implanted the Cytograft vessels in ether the forearm or the upper arm of the patient while he was under general anesthesia in surgery that took a little over an hour (the intravenous fluid line was inserted in another area from the malfunctioning shunt). The Cytograft vessel, only five and a half to eleven and three-quarters of an inch long, feels a little more delicate than a vein.
Cytograft reported that the vessels do have great potential for patients with damaged blood vessels due to diabetes, arteriosclerosis, and birth defects. Dr. Toshiharu Shinoka, director of pediatric cardiovascular surgery at Yale, plans to conduct studies with the new vessel because of its enormous potential in the vascular surgical field. In Japan, where Dr. Shinoka has previously practiced, the vessels were grown from cells on a scaffold that degraded and were absorbed in the body. He was also particularly enthusiastic about the new types of cells because they may prove to be beneficial for infants and children with congenital heart defects; the vessels will be able to grow with the child – since they have the elasticity of an artery – eliminating the problem of repeating skin graft procedures as the child grows. Dr. Shinoko and Cytograft have agreed to start these studies within the next two years.
Vessels in the arm would be much easier to repair in an emergency than vessels implanted deeper in the body. Researchers hope that these new vessels will allow them to save the toes and lower legs of people with poor blood circulation due to arteries damaged by diabetes or arteriosclerosis, as well as use these vessels to treat patients who need coronary bypass surgery.
Since the vessels are grown in a laboratory, there are limits to the length the vessel, meaning that multiple short segments of the vein have to be sewn together in order to create longer vessels. Researchers plan to make a two-foot long graft from four shorter ones for lower limb grafts. To test the lower limb grafts, Cytograft is currently searching for willing patients in Poland and Slovakia. Cytograft realizes that in order to make these procedures more widely-used they need to experiment on humans in the United States, and has applied to the Food and Drug Administration for approval to conduct studies of the vessels in the United States provided that at least ten patients in Poland and Slovakia are healthy six months after treatment.
Because these procedures are so new and experimental, the cost of treating one patient is an astonishing $15,000-$25,000. However, these prices are expected to drop if the procedures become more common, and hopefully Medicare and private insurance companies will agree to cover the procedure!
Author: Lawrence K. Altman
Found in: The New York Times
Published: October 9, 2007
Researchers at Cytograft Tissue Engineering of Novato, California have developed a six to nine month method of growing blood vessels – taken directly from a small section of the patient’s skin – in a laboratory with the intent of implanting them to restore blood flow around a patient’s damaged arteries and veins. This is the first time that blood vessels have been created solely from a patient’s own tissues and used to make skin grafts. This is such a huge accomplishment that the findings were published in the current issue of The New England Journal of Medicine.
Since the vessels are made from the patient’s own skin, there is no need for anti-rejection drugs, which are costly and require the patient to use them throughout his entire life to avoid long-term rejection. Furthermore, there is no risk of an inflammatory response because there are no synthetic materials or scaffolding in these vessels. Engineering these vessels is a huge feat since infection is the leading cause of graft failure (the second leading cause is shearing, where the pressure causes a graft to detach from the underlying tissue).
Doctors interested in pursuing this research project went to Argentina to conduct their studies because the medical costs are significantly lower than in America, and in Argentina, they didn’t have to deal with the strict regulations of the conservative Food and Drug Administration. Eight Argentinean patients, all of whom were receiving chronic kidney dialysis, were volunteers chosen for the study because their vessels were already worn out and because the dialysis shunts allowed for an easy way to monitor the functioning of the new vessels. On those brave eight patients, doctors performed the first human tests of the vessels. So far, none of these patients have suffered any major side effects, however, because the procedure is so new, the longest follow-up has only been for thirteen months. The long-term effects and possible
complications are not yet known, thus this procedure will not be in practiced as standard medicine for quite some time.
In the study in Argentina, surgeons cut an artery and a vein from the forearm and joined them in a link, also known as a shunt, which provided access for the repeated needle punctures required to connect the patient to a dialysis machine. These shunts can last a maximum of fifteen years, but when clots and infections develop inside the shunts that reduce or stop blood flow, new shunts must be created and installed immediately.
To obtain the skin necessary for the procedure, a fifteen-minute biopsy is all that is required. The patient is then put under local anesthesia while the surgeon removes a piece of skin, including a strip of a vein about an inch long from the back of the hand or the inner wrist. Technicians take that strip of skin and vein and use enzymes to extract fibroblast cells, the most common connective tissue found in humans and animals. These cells synthesize and maintain the extracellular matrix of tissues as well as provide the structural framework for many tissues, known as stroma. Additionally, fibroblasts play a critical roll in wound healing, which is incredibly important after a patient has undergone a skin graft procedure. In the actual graft, fibroblasts provide the mechanical backbone for the sheets that are later peeled and rolled into a tube. Technicians also extract endothelial cells from the inner lining of the vein. Endothelial cells line the interior surfaces of blood vessels, control the transit of white blood cells into and out of the bloodstream, and are involved in various processes such as angiogenesis (the formation of new blood vessels), atherosclerosis, and thrombosis (blood clotting). The fibroblast and endothelial cells are then grown by the millions as sheets in a laboratory. Under a microscope, this new vessel looks like a vein, but it has the strength of an artery, which is important because over time the body will be able to remodel the cells from a vein into a vessel with the elasticity of an artery.
A vascular surgeon in Buenos Aires, Dr. Sergio Garrido, implanted the Cytograft vessels in ether the forearm or the upper arm of the patient while he was under general anesthesia in surgery that took a little over an hour (the intravenous fluid line was inserted in another area from the malfunctioning shunt). The Cytograft vessel, only five and a half to eleven and three-quarters of an inch long, feels a little more delicate than a vein.
Cytograft reported that the vessels do have great potential for patients with damaged blood vessels due to diabetes, arteriosclerosis, and birth defects. Dr. Toshiharu Shinoka, director of pediatric cardiovascular surgery at Yale, plans to conduct studies with the new vessel because of its enormous potential in the vascular surgical field. In Japan, where Dr. Shinoka has previously practiced, the vessels were grown from cells on a scaffold that degraded and were absorbed in the body. He was also particularly enthusiastic about the new types of cells because they may prove to be beneficial for infants and children with congenital heart defects; the vessels will be able to grow with the child – since they have the elasticity of an artery – eliminating the problem of repeating skin graft procedures as the child grows. Dr. Shinoko and Cytograft have agreed to start these studies within the next two years.
Vessels in the arm would be much easier to repair in an emergency than vessels implanted deeper in the body. Researchers hope that these new vessels will allow them to save the toes and lower legs of people with poor blood circulation due to arteries damaged by diabetes or arteriosclerosis, as well as use these vessels to treat patients who need coronary bypass surgery.
Since the vessels are grown in a laboratory, there are limits to the length the vessel, meaning that multiple short segments of the vein have to be sewn together in order to create longer vessels. Researchers plan to make a two-foot long graft from four shorter ones for lower limb grafts. To test the lower limb grafts, Cytograft is currently searching for willing patients in Poland and Slovakia. Cytograft realizes that in order to make these procedures more widely-used they need to experiment on humans in the United States, and has applied to the Food and Drug Administration for approval to conduct studies of the vessels in the United States provided that at least ten patients in Poland and Slovakia are healthy six months after treatment.
Because these procedures are so new and experimental, the cost of treating one patient is an astonishing $15,000-$25,000. However, these prices are expected to drop if the procedures become more common, and hopefully Medicare and private insurance companies will agree to cover the procedure!
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