Toddler’s death prompts reflection on bioengineered tissue transplants

Tissue engineering

{credit}Robert A. Lisak{/credit}

There was sad news over the weekend that the youngest patient to ever receive a bioengineered trachea seeded with her own bone marrow–derived stem cells had died. Hannah Warren, who was born without a windpipe, received the artificial trachea at Children’s Hospital of Illinois in Peoria in April. It was only the sixth procedure of its kind and the first to be performed in the US. She would have turned three next month.

Doctors involved in the girl’s treatment told the New York Times that her death was not related to the bioengineered organ. Rather, her native tissue around the esophagus didn’t heal properly, necessitating another operation. She ultimately died from complications of that second operation. “The trachea was never a problem,” said Paolo Macchiarini, a surgeon at the Karolinska Institute in Stockholm, who led the girl’s tracheal implant and has spearheaded the protocol around the world.

The news got me thinking about a feature article I wrote two years ago about a similar procedure in which a toddler, about the same age as Hannah Warren, received a tissue-engineered blood vessel to correct a congenital heart defect known as a ‘single-ventricle anomaly’. The problem is fatal without surgical correction.

The bioengineered blood vessel, like the artificial trachea, starts out as a tube of plastic fibers. Doctors then add a patient’s own cells, taken from the bone marrow, and implant the construct after just a few hours of incubation. Twenty-five people received this treatment in Japan throughout the late 1990s and early 2000s, but this was the first such procedure in the US.

So how is that child doing today? “I am happy to report our first patient is still doing well nearly two years after her surgery,” Christopher Breuer told me in an email this week.

Breuer and his colleague Toshiharu Shinoka completed the operation in August 2011 at the Yale-New Haven Hospital in Connecticut. The two pediatric surgeons have since moved to Columbus, Ohio, where they codirect the Tissue Engineering Program at Nationwide Children’s Hospital. They continue to see their one patient from the blood vessel trial every six months and talk to her parents on the phone about once a month. But the move to Ohio has temporarily delayed further study enrollment.

They should be recruiting participants again soon, though. “We have recently completed construction of our new facilities,” says Breuer, “and will hopefully be enrolling more patients later this year.”

As for the bioengineered tracheas, Macchiarini told the Times that he would continue with similar operations, including one scheduled for Stockholm this week. It’s clear that with Hannah Warren’s death, the risks of the procedure will be foremost in researchers’ thoughts.

Bioengineered kidney makes urine after transplantation

Here’s research that could take the piss out of disease—and it’s no joke. For the first time, scientists reporting in Nature Medicine have created lab-grown kidneys in rats that produce urine after transplantation.

If the work can be replicated in humans, patients suffering from end-stage kidney disease could one day have “an organ that’s grown on demand—a tailored organ that can be transplanted and replaces the failing organ,” says study author Harald Ott, a bioengineer at the Massachusetts General Hospital in Boston.

Stem cell tracking system promises more targeted regenerative therapies

Ultrasound MachineStem cells hold enormous potential for repairing or regenerating damaged tissue. But delivery of these cells to their target location remains a major obstacle. Now, researchers at the Stanford University School of Medicine in California have developed a novel nanoparticle-based system that allows stem cells to be tracked in real time in a living mouse for up to a year after injection. This work, if replicated in humans, could finally allow scientists to verify if these cells are going where they’re intended.

“Delivering stem cells to specific tissues is a very big challenge, since basically all investigators have to shoot blindly,” says Sanjiv Gambhir, director of Stanford’s molecular imaging program who led the work published online today in Science Translational Medicine. “For these cell therapies to succeed, you need imaging systems.”

Gambhir and his team started with a type of nanoparticle already used in clinical trials to guide cancer drug delivery. They then attached two imaging agents to the nanoparticle: gadolinium, a contrast agent picked up by magnetic resonance imaging (MRI), and a fluorescent compound called fluorescein. Although the resulting composite nanoparticle was less than a micron in diameter, it aggregated once absorbed by a cell, making it large enough be imaged by ultrasound and MRI.

After injecting bone marrow stem cells labeled with these particles into the hearts of healthy mice, the researchers found that they could track the cells using a standard ultrasound device. The MRI contrasting agent allowed the team to monitor long term survival or deposition patterns of labeled stem cells without harming the animals. And when necessary, the fluorescent tag allowed for accurate post-mortem examinations as well. Nanoparticle imaging also demonstrated remarkable sensitivity, as the researchers were able to visualize as few as 75,000 stem cells with ultrasound, and a few hundred thousand with MRI.

Although the materials utilized in the study have already been used in clinical trials, Gambhir acknowledges that this new composite nanoparticle requires strenuous safety testing before it could be ready for human use. Still, he was encouraged by the finding that the nanoparticles did not affect stem cell differentiation or division.

The researchers first plan to test the system in larger animal studies with other populations of stem cells. Ghambir believes it could be ready for human testing within the next five years. “This enables cell therapy to understand why it’s failing. This allows you to connect the dots,” he says.

Check out the video of labeled stem cells being injected into a mouse heart below (stem cells circled in red):

New techniques could improve reprogrammed-immune-cell treatment of HIV and cancer

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Recent experiments exploring the use of patients’ own genetically reprogrammed immune cells toward the treatment of chronic diseases such as HIV and cancer have had encouraging and sometimes high-profile results. Yet, these studies have only been conducted in a limited number of individuals, and outcomes have been inconsistent, ranging from complete remission to complete inefficacy.

Now, two teams of researchers have demonstrated a method of using patients’ cells to create long-lived immune cells that target specific HIV and cancer antigens, and appear to resist degradation over time. Their work was published today in two separate papers in Cell Stem Cell.

“Our method has realized the functional rejuvenation and unlimited production of mature cytotoxic T cells with desired antigen-specificity for the first time in vitro,” says Shin Kaneko a stem cell biologist at Kyoto University in Japan and a co-author of the HIV-related study.

Difficulties in previous attempts to extract and reengineer T cells from patients are thought to be due in part to a phenomenon known as ‘cellular senescence’, a type of aging process. Naïve, quiescent T cells can survive for decades in the body. But active T cells, particularly those expanded outside the body in the laboratory, can gradually lose the ability to proliferate and be effective. This can lead to insufficient numbers of active immune cells to combat disease.

“Replicative senescence is likely to be a major issue for adoptive cell therapy,” says Carl June, an immunologist at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “[These papers] address this issue and are exciting demonstrations of the progress in cell and developmental biology.”

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Mouse stem cells manipulated to create egg-producing ovary

From recent news about uterus transplants to controversy over the possibility of so-called ‘three-parent children’, the lengths to which modern medicine will go to achieve conception are increasingly expanding. Creating an ovary that can itself produce viable eggs might soon be added to that list.

In a study published online today in Science, Japanese researchers report that embryonic stem cells from mice can be manipulated to form an ovary that produces viable eggs, the second known method of creating a viable gamete from stem cells.

The scientists, led by Katsuhiko Hayashi at Kyoto University in Kyoto, Japan, used both stem cells and fibroblasts taken from mouse embryos. They then manipulated the function of specific genes to create cells that were very similar to primordial germ cells, which become eggs. The manipulated cells were divided into two groups, with some being cultured in vitro with gonadal cells, a germ cell native to the ovary, and some not, ultimately creating two different types of “reconstituted ovaries.”

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Court ruling: FDA can regulate stem cell clinics

Cross posted from the Nature News blog on behalf of Monya Baker.

The FDA can block U.S. clinics that offer cultured cell products, according to a ruling of a U.S. district court this week.

Though championed by politicians like Governor of Texas Rick Perry, clinics marketing stem-cell procedures worry many healthcare advocates because these procedures are often heavily marketed but not thoroughly tested in clinical trials. (See Stem cell therapy takes off in Texas from nature.com and warnings compiled by the International Society for Stem Cell Research)

If cells are harvested and returned to a patient with “minimal manipulation”, the procedures are not regulated, but further processing classifies cell treatments as a drug, which requires FDA approval.

Read more on the Nature News blog.

First vein grown from human stem cells successfully transplanted into a young girl

First came bladders. Then pulmonary arteries. Followed by urethras, arteriovenous shunts and tracheas. Now, in another first for the world of tissue-engineered body parts, Swedish surgeons have successfully transplanted a bioengineered vein into a 10-year-old girl suffering from portal vein obstruction.

“This is a very good start for demonstrating what impact regenerative medicine can have on patients by using a biological matrix and seeding it with a patient’s own cells,” says Juliana Blum, cofounder and senior director of business operations at Humacyte, a North Carolina–based company developing bioengineered blood vessels for dialysis patients.

A team led by Suchitra Sumitran-Holgersson at the University of Gothenburg took a 9 centimeter-long snippet of vein from the groin of a deceased donor, stripped it of all cells and then reseeded the resulting hollow tube with stem cells taken from the recipient’s own bone marrow. Two weeks later, the surgeons transplanted the engineered conduit into the young girl. She remained healthy for close to a year, although a second procedure was then needed to lengthen the first graft after the vein started to constrict. Ever since the second transplant, in February of this year, the girl’s energy levels have improved and the blood flow to her kidneys are back to normal.

“The girl is somersaulting now,” says Sumitran-Holgersson, who reported the findings today in The Lancet. “Her parents told me, ‘We have a completely different child.’”

Ordinarily, when adults suffer the same problem as the girl who received the tissue-engineered blood vessel—a condition in which the vein that carries blood from the spleen and intestines to the liver is blocked—surgeons opt to transplant a patient’s own vein from the leg.  But this option is not feasible for young children because of the potential growth problems that can result from grafting in a still maturing body.

Christopher Breuer, a pediatric surgeon at the Yale University School of Medicine in New Haven, Connecticut, says the study represents an important next step for tissue-engineered technology. “This is a new application,” he notes. “This is the first time a bioengineered vein has been used in the portal circulation.”

As researchers try to make these procedures more routine, however, the use of stem cells on bioengineered grafts could face regulatory delays. “Whether real or not, regulatory agencies consider the risk of tumorogenesis or alterations in DNA a serious problem,” says Todd McAllister, cofounder and chief executive of Cytograft Tissue Engineering, a Novato, California company developing tissue-engineered blood vessels for people on dialysis for end-stage kidney disease.

Breuer, for one, is trying to overcome those obstacles. He is leading the first clinical trial in the US testing a tissue-engineered vascular product: a bioengineered blood vessel for children with a congenital heart defect. For more on his approach, see our 2011 news feature, ‘Taking tissue engineering to heart’.

Image courtesy of  Lightspring via Shutterstock

Update: More evidence that bone marrow swaps could improve organ transplant options

Drug-free kidney transplants could one day be an option even for people without immune-matched donors, according to a pair of papers published today.

In January, I wrote a news feature about an experimental protocol to help recipients of kidney transplants avoid having to take immunosuppressive drug therapy for life. The approach, investigated for more than a decade by doctors in Massachusetts and California, involves giving bone marrow or just a subset of marrow-derived stem cells from the same people who donate the kidneys in an effort to induce tolerance to the foreign organ.

In one of the two papers published today, the same California team reports in the American Journal of Transplantation that 11 of 16 people who underwent the procedure since 2005 with tissue-matched siblings as donors achieved long-term normal kidney function and successfully weaned off their immunosupressants, and a twelfth study subject is now in the process of tapering the drug regimen. In unpublished results, the Massachusetts group has achieved similar success in seven of ten people who were only half matches with their donors. Both groups, however, have not always seen levels of donor immune cells sustained over the long haul—and this means that the risk of organ rejection can return.

But other research groups that have incorporated the drug cyclophosphamide, a chemotherapy medication used to treat lymphoma, have seen more lasting effects. For example, the second paper published today from a team led by Suzanne Ildstad, director of the University of Louisville’s Institute for Cellular Therapeutics in Kentucky, and Joseph Leventhal, a kidney transplant surgeon at the Northwestern Memorial Hospital in Chicago, describes a way to boost the level of donor immune cells in the recipient for the long term—so much that it completely takes over the recipients’ native bone marrow.

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VIDEO: Stem cell discovery puts women’s reproduction on fertile ground

Researchers have discovered a population of human ovarian stem cells with the potential of forming new eggs during a woman’s reproductive years. The findings, reported online today (26 February) in Nature Medicine, could lead to new therapies that help extend female fertility into late middle age and beyond.

“For women’s reproductive health these findings have so many ramifications,” says study author Jonathan Tilly, a reproductive biologist at the Massachusetts General Hospital and the Harvard Medical School in Boston. “If we can get to the stage of generating functional human eggs outside the body, it would essentially rewrite human assisted reproduction.”

Results from two patients signals possible efficacy of stem cell-based eye therapy

Geron may have been the first company to launch a US trial with regulatory clearance involving a human embryonic stem cell (hESC)-derived product. But Advanced Cell Technology (ACT) made history itself today, becoming the first biotech to report results about such a product in a major peer-reviewed journal.

In July of last year, ACT started treating subjects with retinal pigment epithelial cells derived from hESCs in each of its two ongoing US trials—one for a rare form of blindness that typically begins in childhood, the other for a common cause of blindness in the elderly. Now, a team led by Robert Lanza, chief scientific officer of the Marlborough, Massachusetts-based company, offers a four-month status report on the first participant in each trial. Writing in The Lancet, the researchers describe how the transplanted retinal cells appear safe and both study subjects experienced some improvement in vision.

“The results are impressive,” Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, wrote in an accompanying commentary. The authors “have realized the potential to use hESCs therapeutically in human beings.”

In a conveniently timed press release, ACT also announced today that the first participant in the company’s European trial was treated on Friday at the Moorfields Eye Hospital in London. With all this forward momentum, the company, which was profiled in a January 2012 news feature in Nature, hopes it can avoid the fate of Geron. In November, the Menlo Park, California-based biotech announced that it was abandoning its hESC work to focus instead on cancer drugs. Earlier this month, the company also said that it had hired a brokerage firm to help find a buyer for its stem cell portfolio.