Tag Archives: synthetic trachea

Trachea transplants: an update

I got curious the other day about trachea transplants, a topic I first wrote about one an Aug. 22, 2011 posting featuring Andemariam Teklesenbet Beyene and wondered how things had worked out for him. For anyone who doesn’t know the story, ,

In early July 2011, there were reports of a new kind of transplant involving a body part made of a biocomposite. Andemariam Teklesenbet Beyene underwent a trachea transplant that required an artificial windpipe crafted by UK experts then flown to Sweden where Beyene’s stem cells were used to coat the windpipe before being transplanted into his body.

It is an extraordinary story not least because Beyene, a patient in a Swedish hospital planning to return to Eritrea after his PhD studies in Iceland, illustrates the international cooperation that made the transplant possible.

The scaffolding material for the artificial windpipe was developed by Professor Alex Seifalian at the University College London in a landmark piece of nanotechnology-enabled tissue engineering. Tim Harper in his July 25, 2011 posting provides more details about the scaffolding,

A team led by Professor Alexander Seifalian (UCL Division of Surgery & Interventional Science; professor of nanotechnology and regenerative medicine at University College London, UK), whose laboratories are headquartered at the Royal Free Hospital, created a glass mold of the patient’s trachea from X-ray computed tomography (CT) scans of the patient. In CT, digital geometry processing is employed to generate a 3D image of the inside of an object from a large series of 2D X-ray images taken around one single axis of rotation.

Then, they manufactured a full size y-shaped trachea scaffold at Professor Seifalian’s laboratories. The scaffold of the trachea was built using a novel nanocomposite polymer developed and patented by Professor Seifalian. Professor Seifalian worked together with Professor Paolo Macchiarini at Karolinska Institutet, Stockholm, Sweden (who also holds an Honorary appointment at UCL).

What I didn’t realize in 2011 was there had been some earlier transplants as Gretchen Vogel writes in her April 19, 2013  article (Trachea Transplants Test the Limits) which summarizes and critiques the work* on synthesized tracheas to date for Science magazine (the article is behind a a paywall),

More than a dozen ill people have received a bioengineered trachea seeded with stem cells during the past 5 years, but outcomes are mixed, and critics say the treatment may not do what its developers claim.

Although at first glance the trachea might seem like a simple tube, its thin but cartilage-reinforced walls must stand up to near-constant use as a person breathes, clears his throat, or coughs. Any transplant, therefore, has to be strong enough to withstand such pressures without collapsing. But a rigid prosthesis can rub against and damage the adjacent major blood vessels in the upper part of the chest, leaving a patient at risk for a fatal hemorrhage. At the same time, the natural blood supply for the trachea’s tissues is intricate, with vessels too small for surgeons to easily reconnect during a transplant operation. And because it is exposed to inhaled air, the wound between the implant and the remaining airway is especially vulnerable to infection.

Surgeons have tried for years to find ways around these challenges, without much success. When Castillo (Claudia Castillo,  first patient to receive a trachea transplant using her own stem cells) was hospitalized in Barcelona in March 2008, Macchiarini [Paolo Macchiarini], who was then at the University of Barcelona’s Hospital Clínic, and Birchall [Martin Birchall], then at the University of Bristol in the United Kingdom, had experimented with bioengineered transplants in pigs. They would take a trachea from a pig and remove its living cells to create a so-called decellularized scaffold. They seeded this with cells from the recipient pig: bone marrow cells on the outer layer, thought to help form new cartilage, and epithelial cells on the inside, which they hoped would regrow the trachea’s lining. They allowed the cells to grow on the scaffold for several days in a bioreactor designed to provide different conditions for the two types of cells. They hoped that the decellularized scaffold would not require immunosuppressive drugs to prevent its rejection and that the seeded cells would take over the removed cells’ roles, ultimately forming a living organ.

The main difference between the 2008 Castillo operation and the 2011 Teklesenbet Beyene,operation is the scaffolding. For Castillo, they used a cadaverous** trachea where living cells were removed to create a ‘decellularized’ scaffold. For Teklesenbet Beyene, they used a nanocomposite** polymer. According to Vogel, 14 people have had the operation using either the decellularized or the nanocomposite composite polymer as the base for a new trachea. There have been some problems and deaths although Castillo who is still alive did not respond to any of Vogel’s requests for a comment . As for Teklesenbet Beyene (from the article),

His current doctor, Tomas Gudbjartsson of Landspitali University Hospital in Reykjavik, tells Science that Beyene has had several stents, but is healthy enough that he was able to complete his studies last year [2012]. The researchers have mentioned other patients in passing in several papers, but no formal reports have been published about their health, and Science has not been able to independently verify the current status of all the patients.

Both Birchall and Macchiarini have received grants for clinical trials,

In March [2013?[, Birchall received a £2.8 million ($4.3 million) grant from the United Kingdom’s Medical Research Council to conduct a trial of decellularized and stem cell–seeded upper trachea and larynx, with roughly 10 patients. Macchiarini has already completed two transplants in Russia as part of a clinical trial—funded with a $6 million grant from the Russian government—that he says should eventually enroll 20 or 25 patients. “We were allowed to do this type of transplantation only in extreme cases,” he says. “The clinical study for the first time gives us a chance to include patients who are not in such critical shape.”

Macchiarini is also the lead investigator on a 5-year, €4 million ($5.2 million) grant from the European Union to begin a clinical trial using decellularized tracheas and further develop the polymer scaffolds in large animal models. That project may need to be reorganized, however, following a legal dispute last year in Italy, where the transplants were supposed to take place—Macchiarini had a part-time position at Careggi Hospital in Florence. In September, however, Italy’s financial police accused him of attempted extortion, and briefly placed him under house arrest, for allegedly telling a patient that he could receive treatment in Germany for €150,000. Macchiarini and his lawyer say that he was simply informing the patient of possible options, not demanding payment. The main charges were soon dropped, but Macchiarini says that the charges stemmed from academic politics in Tuscany and he has severed ties with the hospital and university there. “There is no way to go back there.”

That last bit (in the excerpt) about academic politics in Tuscany seems downright Machiavellian (Wikipedia essay on Machiavelli here).

Getting back to the trachea transplants, there seems to be a major difference of opinion. While the researchers Macchiarini and Birchall have opted for human clinical trials other experts are suggesting that animal trials should be the next step for this research. I recommend reading Vogel’s article so you can fully appreciate the debate.

*’which a summary and critique of the work’ changed to ‘which summarizes and critiques the work’ for grammatical correctness on April 8, 2016.

**’pig trachea’ changed to ‘cadaverous trachea’ and ‘nanocompostie’ changed to ‘nanocomposite’ on April 19, 2016.

New type of scaffolding for tissue engineering

Since the international July 2011 coverage of Andemariam Teklesenbet Beyene’s synthetic trachea transplant (mentioned in my Aug. 2, 2011 posting), I’ve been quite interested in tissue engineering. Scientists at Northwestern University (US) have developed a new type of scaffolding for tissue engineering.

There’s a description in the Feb. 12, 2012 news release on EurekAlert of  tissue engineering and scaffolding and some of the disadvantages with the current technology,

Through tissue engineering, researchers seek to regenerate human tissue, such as bone and cartilage, that has been damaged by injury or disease. Scaffolds — artificial, lattice-like structures capable of supporting tissue formation — are necessary in this process to provide a template to support the growing cells. Over time, the scaffold resorbs into the body, leaving behind the natural tissue.

Scaffolds are typically engineered with pores that allow the cells to migrate throughout the material. The pores are often created with the use of salt, sugar, or carbon dioxide gas, but these additives have various drawbacks; They create an imperfect pore structures and, in the case of salt, require a lengthy process to remove the salt after the pores are created, said Guillermo Ameer, professor of biomedical engineering at the McCormick School of Engineering and professor of surgery at the Feinberg School of Medicine.

The new scaffolds are more flexible and can be tailored to ‘resorb’ at different times,

The new scaffolds, created from a combination of ceramic nanoparticles and elastic polymers, were formed in a vacuum through a process termed “low-pressure foaming” that requires high heat, Ameer said. The result was a series of pores that were highly interconnected and not dependent on the use of salt.

The new process creates scaffolds that are highly flexible and can be tailored to degrade at varying speeds depending on the recovery time expected for the patient. The scaffolds can also incorporate nano-sized fibers, providing a new range of mechanical and biological properties, Ameer said. [emphasis mine]

I wonder what “new range of mechanical and biological properties” will be enabled; I was not able to find any speculation.

In the meantime, here’s an image of the scaffolding from the McCormick School (at Northwestern University) http://www.mccormick.northwestern.edu/news/articles/article_1043.html,

For anyone who’s interested in an update on Andemariam Teklesenbet Beyene, according to this Dec. 9, 2011 posting on StemSave, he’s doing well.

ETA Feb. 14, 2012: Michael Berger at Nanowerk has written an article titled, Tissue engineering of 3D tubular structures, which provides some insight into another aspect of creating scaffolding, the tubular nature of many of our organs.

Printing bones

Apparently all you need is an inkjet printer and some researchers from Washington State University (WSU) at Pullman to create new bone. From the Nov. 29, 2011 news item (written by Eric Sorenson of WSU) on Nanowerk,

Washington State University researchers have used a 3D printer to create a bone-like material and structure that can be used in orthopedic procedures, dental work and to deliver medicine for treating osteoporosis. Paired with actual bone, it acts as a scaffold for new bone to grow on and ultimately dissolves with no apparent ill effects. [emphasis mine]

The authors report on successful in vitro tests in the journal Dental Materials (“Effects of silica and zinc oxide doping on mechanical and biological properties of 3D printed tricalcium phosphate tissue engineering scaffolds” [behind a paywall]) and say they’re already seeing promising results with in vivo tests on rats and rabbits. It’s possible that doctors will be able to custom order replacement bone tissue in a few years, said Susmita Bose, co-author and professor in WSU’s School of Mechanical and Materials Engineering.

The printer works by having an inkjet spray a plastic binder over a bed of powder in layers of 20 microns, about half the width of a human hair. Following a computer’s directions, it creates a channeled cylinder the size of a pencil eraser.

After just a week in a medium with immature human bone cells, the scaffold was supporting a network of new bone cells.

Here’s a video of Dr. Bose discussing the inkjet printer that produces bone-like material,

The Nov. 30, 2011 news item about the bone scaffolding work on BBC News adds more detail,

Prof Bose’s team have spent four years developing the bone-like substance.

Their breakthrough came when they discovered a way to double the strength of the main ceramic powder – calcium phosphate – by adding silica and zinc oxide.

To create the scaffold shapes they customised a printer which had originally been designed to make three-dimensional metal objects.

It sprayed a plastic binder over the loose powder in layers half as thick as the width of a human hair.

The process was repeated layer by layer until completed, at which point the scaffold was dried, cleaned and then baked for two hours at 1250C (2282F).

Earlier this year I highlighted a story about a trachea transplant where they used scaffolding to grow trachea cells in much the same way the WSU team is using a scaffolding to grow bone cells. Here are the posts about the trachea transplant and scaffolding from the first to the last,

Body parts nano style

Making nanotechnology-enabled body parts

More on synthetic windpipe; Swedes and Italians talk about nanoscience and medicine

More on synthetic windpipe; Swedes and Italians talk about nanoscience and medicine

There was a Swedish-Italian workshop on nanoscience and medical technology held in Stockholm, Sweden, Sept. 29 and 30, 2011. It rates a mention here largely because there’s some additional information about the synthetic windpipe transplant that took place in June 2011 in Sweden. From the Oct. 14, 2011 news item on Nanowerk,

A very important session was devoted to “tissue engineering”, i.e. the creation of artificial tissues and organs to replace diseased or damaged ones, thus reducing the need for human organs from donors for transplantation, whose availability is always difficult to predict. A “keynote lecturer”, in this field was held by Prof. Paolo Macchiarini, who recently joined the Karolinska Institute in Stockholm (the Institute that awards the Nobel Prize in Medicine each year).

Prof. Macchiarini presented the results of his recent surgery works, performed at the Karolinska, where for the first time a synthetic trachea (windpipe) made of porous nanocomposites was transplanted into a human patient. This was the base for the trachea reconstruction using stem cells from the patient himself, thus eliminating any possible problem of rejection. The artificial structure was designed to dissolve in a few months, leaving a totally natural organ. [emphasis mine] It is clear that this could be a first step in a revolution in regenerative medicine, reducing the need for conventional transplants, but it is also clear that the Prof. Macchiarini was able to perform this action thanks to the collaboration of experts in nanotechnology for the design of the scaffold, bioreactors for the growth of stem cells and biological tissues and dedicated infrastructure in Stockholm.

I must have missed it when the event (trachea transplant) was first made public (mentioned in my Aug. 2, 2011 posting) but I never realized the biocomposite was meant to dissolve.

Here’s a little more about the workshop, from the news item,

During the workshop, 18 Swedish and 18 Italian experts offered a comprehensive overview of the most prominent activities in the two Countries in several fields: bio-sensors, bio-electronics, contrast media for imaging and bio-analysis, nanoparticles for drug delivery eventually combined with diagnosis possibilities (known in the field as “theranostics”).

Several companies from both countries, including Bracco, Finceramica and Colorbbia from Italy as well as AstraZeneca and Spago Imaging from Sweden, presented their recent results in the field and gave a clear overview of the potential impact of nanotechnology in improving existing products as well as generating new solutions for the grand challenges that medicine is facing.

There are more details in the news item and at the Italian Embassy in Sweden’s Office of the Scientific Attaché in Sweden, Norway and Iceland workshop page.