The Quest for Replacement Body Parts

Since 1967, when Christiaan Barnard successfully performed the first successful human to human heart transplant, it has been painfully obvious that there are not enough human hearts available to meet the demand. Surgeons have tried various approaches to replacing damaged and worn out hearts--including baboon hearts, refrigerator sized machine replacement hearts, and most reacently, the AbioCor totally implantable artificial heart system. While the AbioCor's batteries can be rechared through the skin, they will eventually have to be replaced. Machine hearts are subject to failure of various types, and experience with them is still only short term.

Eventually, hearts will be "printed", along with other replacement organs. Other organs, such as the urinary bladder, have already been synthetically produced and implanted. But the heart's fibrous skeleton is too complex for scientists to mimic in the lab--to this point.

So lab scientists are learning how to scavenge heart skeletons wherever they can. University of Minnesota scientists have taken dead animal hearts and removed the dead cells--leaving the fibrous infrastructure. By injecting immature heart cells into the scaffolding--in a stepwise manner--they were able to revitalize the heart to the point of beating.

The team took a whole heart and removed cells from it. Then, with the resulting architecture, chambers, valves and the blood vessel structure intact, repopulated the structure with new cells.

"We just took nature's own building blocks to build a new organ," says Dr Harald Ott, a co-investigator who now works at Massachusetts General Hospital. "When we saw the first contractions we were speechless."

The work has huge implications: "The idea would be to develop transplantable blood vessels or whole organs that are made from your own cells," said Prof Doris Taylor, director of the Centre for Cardiovascular Repair, Minnesota, principal investigator.

The method could be used to grow liver, kidney, lung and pancreas, indeed virtually any organ with a blood supply.

Telegraph

In the meantime, researchers continue to work on alternatives--including artificial hearts that spin like a turbine, producing a constant blood pressure rather than a pulse. Such turbine hearts are said to be efficient in small sizes, making it easier to fit size constraints. Such hearts would still have the problem of requiring a power supply.

Rather than replacing the heart, methods of regenerating the existing heart are being developed. Techniques of injecting stem cells into the patient's heart have already produced positive results in some cases. Likewise, procedures that attach "sheets of muscle blasts" to the patient's heart have been successful in Japan. Clearly, it would be preferable if the patient's own heart can serve as a scaffold for cell replacement.

In several pathological processes, however, the underlying structure of the patient's heart has been rendered dysfunctional. Without extensive remodeling surgery, the heart's infrastructure has to be replaced.

In approaching heart replacement, patients, physicians, and families have to weigh the benefits and risks. With the rapid growth in viable choices for replacement, this process will necessarily become more detailed and informed.

Bioprinting organs, and other ways of synthetically reproducing human organs, will be very expensive for a long time. That expense will push experimentation in different directions.

Tissue Engineering of Blood Vessels and Other Tissue

Tissue engineering is beginning to yield some useful products. Using skin tissue, scientists and bio-engineers can grow blood vessels for replacement and bypass surgeries.

From a snippet of a patient’s skin, researchers have grown blood vessels in a laboratory and then implanted them to restore blood flow around the patient’s damaged arteries and veins.

It is the first time blood vessels created entirely from a patient’s own tissues have been used for this purpose, the researchers report in the current issue of The New England Journal of Medicine.

Cytograft Tissue Engineering of Novato, Calif., made the vessels, in a process that takes six to nine months. Because they are derived from patients’ own cells, they eliminate the need for antirejection drugs. And because they are devoid of any synthetic materials or a scaffolding, they avoid complications from inflammatory reactions.

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Better scaffolds for growing tissues in the lab are being developed. The gel scaffold pictured above incorporates microchannels for nutrient fluid supply to the growing tissues--an artificial "blood" vessel.

The researchers have engineered tiny channels within a water-based gel that mimic a vascular system at the cellular scale and can supply oxygen, essential nutrients and growth factors to feed individual cells. The so-called gel scaffold can hold tens of millions of living cells per milliliter in a 3-D arrangement, such as in the shape of a knee meniscus, to create a template for tissue to form.

In theory, the system could accommodate many kinds of tissue.

"A significant impediment to building engineered tissues is that you can't feed the core," said Abraham Stroock, Cornell assistant professor of chemical and biomolecular engineering and one of the paper's senior authors. "Simply embedding this mimic of a microvascular system allows you to maintain the core of the tissue during culture." Gel scaffolds, he said, "are the culture flasks of the future."

The embedded microchannels allow fluid with oxygen, sugar and proteins to travel through the system. The researchers can control the distributions of these solutes over both time and space within the developing tissue, allowing the fine-tuning of the biochemical environment of the cells while the tissue develops. For example, the tissue may need to develop into bone on one side and cartilage on the other. Now the researchers can supply the right nutrients and proteins to certain parts of the growing tissue to ensure an intended outcome.

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As scientists and bio-engineers learn to mimic normal in vivo tissue growth processes in the lab, we will have more and better tissue and organ replacements available for transplant and regenerative purposes. Eventually, we will be able to grow better tissues and organs than the originals. Tissues more resistant to wear and degradation. Stronger muscles. More efficient nerves that are resistant to degenerative influences. Blood vessels that resist occlusive processes. Bones less prone to breaking etc.

Uterus Transplants?

A recent CNN article about womb transplants brings up a few interesting issues.

Approximately 1,800 heart-beating, but brain-dead, organ donors were identified through an existing donor network. The removal of several organs took place in about 150 of the donors. Nine had specifically consented to donate their uterus.

The uterus was removed without complications in eight donors. Tissue testing suggested that the organs were, in fact, suitable for transplantation.

The researchers point out that the transplant of organs that are not needed to preserve life raises ethical issues. Thus far, the only human uterine transplant that has been performed was "controversial and unsuccessful."

Nevertheless, they note that surgical techniques have improved and the successful retrieval of a usable human uterus brings the possibility of such transplants closer.

"Our hope," the team concludes, "is to eventually restore reproductive function through transplantation of a human uterus."

First of all, uterine transplants would require the administration of anti-rejection drugs, like all other transplants. Is it really wise to encourage women on anti-rejection drugs to become pregnant--no matter how badly they wish to have children?

Second, if you are going to harvest uteri for transplant, why not go to a larger source of living donors, rather than limited cadavers? Why not harvest the uteri of nuns and other healthy young women who have made a rational choice to forego childbirth? Assuming it is possible to handle rejection issues without drugs that may be dangerous to the fetus.

Third, why not learn to maintain the uterus and fetus ex corpore (out of body), and avoid the rejection issue altogether? There is a significant need for artificial wombs for gestating fetuses ex corpore, and what better to use than a living human uterus artificially maintained?

It is important for researchers to develop good means for long term "cold storage" of organs of all types. Vitrification and other preservation methods would help considerably with problems of organ transport to point of need. For donated uteri, workable vitrification would allow children to be born from a uterus long after the original donor had died.

It seems that both the researchers and the journalists reporting the story are thinking much too small, too short term. The genuine possibilities for expanding reproductive choice are much larger.

Becoming Cyborgs--One Organ At A Time

One of the most important steps in becoming a cyborg is developing a stable, working interface between electronic devices and nerve tissue. Nanotechnology has produced the nanotube, which not only serves as a scaffolding for the re-growth of damaged nerve tissue--nanotubes can also serve as interfaces between electronic chips and nerves.

Writing today in Advanced Materials, Nicholas Kotov of the University of Michigan and colleagues describe how they have used hollow, submicroscopic strands of carbon, carbon nanotubes, to connect an integrated circuit to nerve cells. The new technology offers the possibility of building an interface between biology and electronics.

Kotov and colleagues at Oklahoma State University and the University of Texas Medical Branch have explored the properties of single-walled nanotubes (SWNTs) with a view to developing these materials as biologically compatible components of medical devices, sensors, and prosthetics. SWNTs are formed from carbon atoms by various techniques including deposition and resemble a rolled up sheet of chicken wire, but on a tiny scale. They are usually just a few nanometers across and up to several micrometers in length.

The researchers built up layers of their SWNTs to produce a film that is electrically conducting even at a thickness of just a few nanometers. They next grew neuron precursor cells on this film. These precursor cells successfully differentiated into highly branched neurons.

A voltage could then be applied, lateral to the SWNT film layer, and a so-called whole cell patch clamp used to measure any electrical effect on the nerve cells. When a lateral voltage is applied, a relatively large current is carried along the surface but only a very small current, in the region of billionths of an amp, is passed across the film to the nerve cells. The net effect is a kind of reverse amplification of the applied voltage that stimulates the nerve cells without damaging them.

High quality, low cost single-wall (SWCNT) & multi-walled (MWCNTs)
Kotov and his colleagues report that such devices might find use in pain management, for instance, where nerve cells involved in the pain response might be controlled by reducing the activity of those cells. An analogous device might be used conversely to stimulate failed motor neurons, nerve cells that control muscle contraction. The researchers also suggest that stimulation could be applied to heart muscle cells to stimulate the heart.

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In addition to neural-electronic interfaces, good cyborgs should also have a good supply of artificial organs, such as kidneys. Cyborgs, like conventional humans, may be injured, and will need replacement parts.

To make bioartificial kidneys, scientists grow cells harvested from donor kidneys not suitable for transplant and then insert them into a specially developed filter tube. Because the finished product contains live cells, it is treated like an organ for transplant, flown to the receiving hospital by helicopter in a temperature-controlled case. Humes founded a company, now known as RenaMed, to commercialize the device, which has not yet been approved by the Food and Drug Administration.

Early clinical trials of the device show that it can dramatically improve the health of patients with acute renal failure. According to the results of a trial released last year, patients treated with the device showed a 70 percent improved survival rate 28 days after treatment. (Scientists at RenaMed are currently analyzing interim results from a subsequent trial.)

However, the devices used in these trials were made with a manufacturing process that is only appropriate for growing small batches of cells. To run the larger clinical trials required for approval by the FDA and to supply needy patients if the device is approved, RenaMed will need to find a way to make and deliver the device on a much larger scale.

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Humans evolved over billions of years. Now that human medicine influences human evolution, humans may be close to a dead end of sorts. Cyborgs--part human, part machine--will be one way out of the rut in the short term. Genetic engineering of germ tissue will be another way humans will jump-start evolution. A combination of both approaches is most likely in the intermediate term.

Nanotechnology Developing Implantable Nano-Kidneys to Replace Dialysis

Dialysis is a poor substitute for working kidneys. But there is a perpetual shortage of donor kidneys for transplant. Technology Review looks at nanotechnology research that hopes to provide a better alternative to dialysis--an implantable nanotech kidney.

The common regimen of three half-day blood-cleansing sessions per week removes, on average, just 17 percent of the toxins that a healthy kidney would clear, so that only one-third of all dialysis patients survive more than five years of treatment.

Nanotechnology could offer an alternative, according to nephrologist William Fissell at the University of Michigan. He and colleagues are working on nano-pore membranes that could enable dialysis to be miniaturized into implantable devices that provide round-the-clock clearance of toxins, untethering dialysis patients from bulky pumps and clinics. "This is a fundamentally liberating technology," says Fissell.

....As currently practiced, dialysis is a crude procedure. Patients are hooked up intravenously to a powerful pump that circulates their blood through a cartridge of porous plastic fibers. Fluids, dissolved toxins, and salts pass through the fibers and are discarded, while the proteins and blood cells caught in the sieve are supplemented with electrolyte before returning to the patient. The filter's poor fluid dynamics are a function of their imprecision: filter manufacturing produces a wide range of pores, so to avoid having too many large pores, which would suck out valuable proteins, the fibers must be manufactured with a preponderance of very small pores. The machine's pump makes up the difference, forcing blood through these inefficient sieves.

In contrast, Fissell and Roy etch pores into ultrathin wafers of silicon with lithographic precision. The result is a homogenous array of pores, each capable of flow rates several orders of magnitude higher than the average pore in a conventional filter. The pores mimic the exquisitely precise yet efficient diaphragms that filter blood in a human kidney, resembling a panel of Venetian blinds, says Fissell.

Current prototypes contain roughly 10,000 pores per square millimeter, according to Fissell. Next-generation membranes, now being engineered, will have more than 100,000 pores or slits per square millimeter and provide more than 10 times the flow.

....Fissell's team is testing whether the kidney sorts not only by size but also by generating electrical charges that repel protein chains, which are also charged. They're modeling various chemical modifications to introduce charges on the surface of the silicon pores.

To make the system practical will require rendering the membranes biocompatible. Unmodified silicon strongly attracts proteins, and thus a silicon nano-pore membrane would rapidly clog if implanted in the body. Fissell's colleague at the University of Michigan, David Humes, has initiated animal studies with the nano membranes to identify surface treatments or alternative membrane materials that will prevent clogging in implants.

Humes hopes to use the membranes to fashion a more sophisticated version of the implant that would contain living kidney cells--analogous to his "bioartificial" Renal Assist Device that's currently in phase two clinical trials (see "Saving Lives with Living Machines," July/August 2003). In an implantable version of the bio-artificial kidney, nano-pore membranes would protect the live kidney cells from immune cells and antibodies, which have thwarted most bio-artificial organ implants to date. The live kidney cells, in turn, would improve the function of the implant by reabsorbing and returning to the bloodstream some of the fluids and salts that pass through the nano-pore membrane. Eventually, bio-artificial implants that recover fluids and salts and divert the remaining ultrafiltrate to the bladder might even eliminate the need for external electrolyte and ultrafiltrate bags.

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Replacement organs that work well, and allow mobility, would improve the lives of hundreds of thousands of people. Whether from nanotechnology, stem cell research, or other advanced technology, most people in need of replacement organs would probably not quibble.

Oh, Brave New Womb

Scientists have been on the trail of the artificial uterus for decades. Since Aldous Huxley's Brave New World, science fiction writers have used the device (scroll) frequently. So, we have test-tube babies now, in vitro fertilisation, but no artificial wombs.

It is not for lack of trying. Hung Ching Liu, a fertilisation specialist, has been working on the problem for years, and making genuine progress.

In 2002, Liu stunned the world of reproductive medicine by claiming to have recreated a woman's womb, using uterine cells grown on a biodegradable scaffold bathed in a broth of hormones and nutrients.

When Liu placed fertilised human embryos created during IVF treatment inside, they nestled into the wall of the womb and began to attach themselves to the endometrial cells that make up the lining — just as in the early stages of pregnancy. Liu stopped the experiments after a week because regulations prevent human embryos being developed much further.

No such restrictions apply to animals and, in unpublished work, Liu says she has now grown mouse foetuses in her artificial womb for 17 of their 21—day terms. This is equivalent to about 31 weeks in humans, at which point babies have been viable for more than a month and can routinely be nurtured to normal development if born prematurely.

Just as with the human embryos, the tiny bundles of mouse cells nestled into the artificial womb lining and began to attach themselves. Liu watched as blood vessels formed, then miniature placentas and, eventually, the amniotic sac — an embryo's personal protective bubble.

A different approach has been taken by Yoshinori Kuwabara at Juntendo University in Tokyo. His team has removed foetuses from goats and placed them in clear plastic tanks filled with amniotic fluid stabilised at body temperature. In this way, Kuwabara has kept goat foetuses alive and growing for up to 10 days by connecting their umbilical cords to machines that pump in nutrients and dispose of waste.

While Liu's work is aimed at helping those having difficulty conceiving, Kuwabara's is designed to help women who suffer miscarriages or very premature births. In this way Liu is extending the time an embryo can exist in a laboratory before being placed in a woman's body; Kuwabara is trying to give a foetus a safe home if expelled too early from its natural womb.

Crucially, both believe artificial wombs capable of sustaining a child for nine months will become reality in a few years.

This Slate article looks at artificial wombs as a way of incubating embryonic tissue for use in regenerative medicine, not as a way to create a new person. There must be many uses for working artificial wombs, if you think about it.

Ethicists have lined up on every conceivable side of the issue. Some feminists see the development as an emancipation of women, and some see it as a threat to the existence of all women. Choose your sides. Some religious fundamentalists see artificial wombs as the end of abortion, and some see them as a threat to the idea of "human essence." Like a rorschach blot test, the artificial womb concept has a way of causing people to define themselves in unexpected ways.

Embryos have implanted inside the abdominal cavities of women, on the outer surface of viscera, and developed to a surprising degree. Here is a report of a successful abdominal pregnancy and delivery. This suggests that an artificial womb constructed of living tissue, well perfused with nutrient and oxygenating fluid, should do just as well as this woman's abdominal organs, and create much less risk for the mother. The problem of providing an in utero like environment should be solvable.

It will happen, sooner or later, ethics or no ethics, laws or no laws. What we choose to make of the possibilities created by the artificial womb is up to us.

Far into the future, I foresee an artificial womb in every home, where the proud parents-to-be can keep close track of thousands of parameters in the developing fetus. The A.W. could even be fitted with a 2-way communications (cell phone with remote antenna for radiation safety) device and high fidelity speakers so that the fetus can listen to Mozart, a soothing heartbeat, or even the mother's voice from half a world away, if need be.