Swedish Bioengineer Under Investigation

Paolo Macchiarini, a thoracic surgeon at the Karolinska Institute in Stockholm, Sweden, which is one of the most prestigious medical universities in Europe, is a pioneer in the field of bioengineering. Macchiarini led the laboratory and surgical teams that reconstructed the tracheas of patients with bioengineered tracheas. Now the Karolinska Institute has launched two investigations to address discrepancies between the published reports and internal findings of other physicians associated with these transplantations.

Since 2008, Macchiarini has replaced parts of airways damaged by injury, cancer or other disorders in 17 patients. In earlier cases, Macchiarini and his surgical team used tracheas isolated from cadavers as the source of transplantations. However, in later cases, he transplanted synthetic tracheas. In both procedures, tracheas were treated with stem cells taken from the patient’s bone marrow before transplantation in order for the transplants to act like biological tissue.

Several bioengineering researchers have lauded Macchiarini for his innovations. When you consider the function of a trachea (or windpipe), it is more than just tube that leads to the lungs. It also must defend against the constant assault of inhaled bacteria and to form a seal with adjoining airway tissue. David Mooney, a bioengineer from Harvard University in Cambridge, Massachusetts said that Macchiarini research represented a “bright spot” for the field of bioengineering.

The first of these investigations being conducted by the Karolinska Institute relies upon an external expert. This expert is due to report their findings on 15 January, 2015. This investigation examines the three procedures that Macchiarini used at the Karolinska Institute, all of which transplanted artificial tracheas, and was prompted by a report filed in August by four thoracic doctors at the affiliated Karolinska Hospital. These physicians, Matthias Corbascio, Thomas Fux, Karl-Henrik Grinnemo and Oscar Simonson, helped to treat the three patients.

These four physicians compared results in a paper Macchiarini published in a prestigious journal known as The Lancet (Lancet 378, 1997–2004; 2011) with the medical records of the patients. The Lancet paper describes the first use of a synthetic trachea that had been seeded with the patient’s own stem cells. According to these doctors, there are discrepancies between the results reports in the paper and the patient’s medical records.

For example, the Lancet paper says that the synthetic trachea was “partly covered by nearly healthy epithelium”, indicating the growth of a protective cell layer, whereas the doctors say they could find no evidence in biopsy reports for healthy growth. The paper also states that the implanted trachea showed signs of tight connection with the adjacent tissue and that it was acting like “an almost normal airway”, whereas bronchoscopy reports noted gaps between the trachea and the bronchus, the tube that leads from the trachea to the lungs, and the need for stents to stabilize the airway.

“The problems alluded to are irreconcilable with the published reports,” says a US-based thoracic surgeon who reviewed the report but requested that his or her name not be released.

Dr. Macchiarini has elected to not reply to specific questions about alleged discrepancies between his publications and the medical records at this time because the allegations against him “now have to be investigated by an external expert, which is the normal process following cases of accusations of scientific misconduct”. He adds: “I certainly do welcome that investigation.” He is confident that “there is nothing suspect, unethical, inflated or misleading about anything I have done or reported”.

The Lancet says: “At this stage, we can’t comment on the allegations regarding Dr. Macchiarini’s procedures.”

In the formal complaint filed by the four doctors also claims that there were no informed-consent forms in the medical records for two of the three procedures carried out at the Karolinska Hospital. For example, one form on record was signed 17 days after the procedure.

To this Macchiarini replied, “Of course there was consent. We would never have proceeded with the transplants if there wasn’t.” He adds: “I do not know why the form is dated 17 days after the procedure and can only assume it is some kind of clerical issue.” The patient “signed it in my presence, prior to the operation”. He adds that “there was absolutely no ethical breach”.

The Karolinska Institute’s ethics council, meanwhile, is also in the midst of a second investigation. This internal investigation was launched in response to a report received in June from Pierre Delaere, a head and neck surgeon at the University Hospital, KU Leuven, Belgium. In this report, Delaere complains that published descriptions of the transplants minimize complications faced by patients, such as the need for stents.

Macchiarini sent a 15-page response to the Karolinska in August, in which he acknowledged that he had “shortened” the discussion of complications because “of the editor’s requirements during the review process.”  Macchiarini maintains that “all aspects of the patients’ outcomes are discussed in detail.” In an accompanying letter, Macchiarini says that he has “thoroughly reviewed” Delaere’s allegations and believes that they are “unfounded.”

The ethics council plans to interview the concerned parties during January, and to give recommendations to the vice-chancellor of the Karolinska Institute, Anders Hamsten, by the end of February at the earliest. Hamsten will then decide how to proceed. According to Hamsten, the institute has initiated investigations into Macchiarini’s publications twice in the past, following allegations of scientific misconduct from other complainants. However, both investigations concluded in July 2013 and in September 2014 that there was no evidence of scientific misconduct.

Currently, Macchiarini is currently spending part of his time at the Kuban State Medical University in Krasnodar, Russia. He intends to conduct research on the use of synthetic trachea transplants, but his own clinical trial there had to be put on hold when a transplant patient died on September 20, 2014. This patient had a synthetic transplant in June 2012 and, when that one began to fail, was given a second transplant in August 2013.

According to Macchiarini, the patient’s doctor has now reported the cause of death as “bilateral acute pneumonia with heart–lung insufficiency”, which he says is unrelated to the trachea transplant. He says that she was “breathing normally and asymptomatic” two weeks before her death. “We will be considering the restarting of the clinical trial now that this cause has been ascertained.”

The most recent of Macchiarini’s total of eight synthetic trachea-transplant patients, who was operated on in June, “is doing very well, is asymptomatic”, he says.

Six have died, with their post-transplant life-spans ranging from 3 to 31 months. Macchiarini says that one died because of complications following an accident, another from drinking too much alcohol, and another from “respiratory failure and subsequent multi-system organ failure.”  In none of these cases has the death been linked to the transplant, although the surgery probably weakened an already very weak patient.

The remaining patient has been in intensive care ever since her procedure, more than two years ago. However, Macchiarini maintains that her condition is not as result of the trachea transplant since this patient’s medical situation was rather dire when she came to Karolinska.  According to Macchiarini, “Her doctors gave her a life expectancy of 3 to 6 months.”  He also says that during the surgery, it became clear that her airways had far more damage than had been revealed by examinations and tests prior to the operation.   Macchiarini added that this level of damage could not have been diagnosed before the surgery.

Nine other patients have received tracheas from cadavers. According to a paper by Macchiarini this year, four of those patients have died, either from recurrence of tumors or from gastrointestinal bleeding. Of the five still living, the paper reports that four are dependent on stents, and one has no need for stents (P. Jungebluth and P. Macchiarini Thorac. Surg. Clin. 24, 97–106; 2014).

Trachea-Bronchus Stent
Trachea-Bronchus Stent

Macchiarini emphasizes that the procedure is experimental. “Given the nature of this work, we are not in a position to guarantee them long-term survival and they are all abundantly aware of that going in,” he says. “We at least give them a chance, a chance at a longer life, and the hope of being the patient who survives long-term.”

These accusations against Macchiarini are rather grave. If these accusations turn out to be true, it could put a potentially productive bioengineering project on the shelf. However, Macchiarini tends to operate on patients who are gravely ill to begin with. Therefore it is no surprise that many of them died after the surgery. However, failing to acquire patient consent is a very serious charge, as is misrepresenting data. Hopefully, the investigations will get to the bottom of this.

Baby from Ohio Saved With An Airway Splint Made by A 3-D Printer

A baby boy from Ohio, Kaiba (KEYE’-buh) Gionfriddo, was born with a trachea (windpipe) that was fragile and kept collapsing. Without precious oxygen, he choked and passed out. Even though the physicians attending him thought about using an airway splint to open his airway, they had yet to implant it. Kaiba was not getting any better, and without a way to get him the oxygen that his little body desperately needed, he did not have much time. All he could do was lie in a hospital bed on a breathing machine.

Kaiba Gionfriddo

To solve this problem, the doctors used plastic particles and a 3-D laser printer to generate an airway splint to deliver oxygen to his lungs. This is a technological first and is the latest advance in the quickly advancing field of regenerative medicine that tries to make human body parts in the lab.

The even more stupendous aspect of this feat is that the production of the tracheal tube only too k one day. Yes, in a single day they “printed out” 100 tiny tubes by employing computer-guided lasers to stack and fuse thin layers of plastic to form various shapes and sizes. The next day, with special permission from the US Food and Drug Administration, they implanted one of these tubes in Kaiba. Needless to say, this is the first time such a treatment has even been done.

Suddenly, Kaiba, whom doctors said would probably never leave the hospital alive, could breathe normally for the first time. Kaiba was 3 months old when the operation was done last year and is nearly 19 months old now. He is about to have his tracheotomy tube removed since it was placed in his throat when he was a couple of months old. He no longer needs a breathing machine and has had not had a single breathing crisis since coming home a year ago.

“He’s a pretty healthy kid right now,” says Dr. Glenn Green, a pediatric ear, nose and throat specialist at C.S. Mott Children’s Hospital of the University of Michigan in Ann Arbor, where the operation was done. This remarkable feat of tissue engineering is described in the New England Journal of Medicine.

Independent experts have highly praised this and the potential 3-D printing provides for creating and quickly manufacturing body parts to solve unmet medical needs.

“It’s the wave of the future,” says Dr. Robert Weatherly, a pediatric specialist at the University of Missouri in Kansas City. “I’m impressed by what they were able to accomplish.”

So far, only a few adults have had trachea, or windpipe transplants, and these are usually used to replace windpipes destroyed by cancer. The windpipes came from dead donors or were lab-made, sometimes using stem cells. Last month, a 2-year-old girl born without a windpipe received one grown from her own stem cells on a plastic scaffold at a hospital in Peoria, Ill.

Kaiba, however, had a different problem; namely an incompletely formed bronchus. The bronchi are the tubes that branch from the windpipe to the lungs. Approximately 2,000 babies are born with such defects each year in the United States and most outgrow them by age 2 or 3, as they grow and mature and their respiratory tract replaces the lost tissues.

In severe cases, parents learn of the defect when the child suddenly stops breathing and dies. That almost happened when Kaiba was 6 weeks old at a restaurant with his parents, April and Bryan Gionfriddo, who live in Youngstown, in northeast Ohio. “He turned blue and stopped breathing on us,” and his father did CPR to revive him, April Gionfriddo says.

More episodes followed, and Kaiba had to go on a breathing machine when he was 2 months old. Doctors told the couple his condition was grave. “Quite a few of them says he had a good chance of not leaving the hospital alive. It was pretty scary,” his mother says. “We pretty much prayed every night, hoping that he would pull through.”

Fortunately a physician at Akron Children’s Hospital named Dr. Marc Nelson suggested the experimental work in Michigan in which researchers were testing airway splints made from biodegradable polyester that are sometimes used to repair bone and cartilage.

Kaiba had the operation on Feb. 9, 2012. The splint was placed around his defective bronchus, which was stitched to the splint to keep it from collapsing. The splint has a slit along its length so it can expand and grow as the child does — something a permanent, artificial implant could not do.

The plastic from which the splint is made is designed to degrade and gradually be absorbed by the body over three years, as healthy tissue forms to replace it, according to the biomedical engineer who led the work, Scott Hollister.

Green and Scott Hollister have a patent pending on the device and Hollister has a financial interest in a company that makes scaffolds for implants.

Dr. John Bent, a pediatric specialist at New York’s Albert Einstein College of Medicine, says only time will tell if this proves to be a permanent solution, but he praised the researchers for persevering to develop it.

“I can think of a handful of children I have seen in the last two decades who suffered greatly … that likely would have benefited from this technology,” Bent says.

Bioengineered Trachea Implanted into a Child

Hannah Genevieve Warren was born in 2010 in Seoul, South Korea with tracheal agenesis, which is to say that she was born without a trachea. Hannah had a tube inserted through her esophagus to her lungs that allowed her to breathe. Children with tracheal agenesis usually die in early childhood, 100% of the time. No child with this condition has ever lived past six years of life. Hannah spent the first two years of her life at the Seoul National Hospital before she was transported to Illinois for an unusual surgery.

While at the Children’s Hospital of Illinois, on April 9, 2013, Hannah had a bioengineered trachea transplanted into her body. This trachea was the result of a remarkable feat of technology called the InBreath tracheal scaffold and bioreactor system that was designed and manufactured by Harvard Bioscience, Inc. Harvard Bioscience, or HBIO, is a global developer, manufacturer and marketer of a broad range of specialized products, primarily apparatus and scientific instruments, used to advance life science research and regenerative medicine.

InBreath tracheal scaffold
InBreath tracheal scaffold

Hannah’s tracheal transplant was the first regenerated trachea transplant surgery that used a biomaterial scaffold that manufactured by the Harvard Apparatus Regenerative Technology (HART) Inc., a wholly owned subsidiary of Harvard Bioscience. HART ensured that the scaffold and bioreactor were custom-made to Hannah’s dimensions. Then the scaffold was seeded with bone marrow cells taken from Hannah’s bone marrow, and the cells were incubated in the bioreactor for two days prior to implantation. Because Hannah’s own cells were used, her body accepted the transplant without the need for immunosuppressive (anti-rejection) drugs.

InBreath Bioreactor
InBreath Bioreactor

The surgeons who participated in this landmark transplant were led by Dr. Paolo Macchiarini of Karolinska University Hospital and Karolinska Institutet in Huddinge, Stockholm and Drs. Mark J. Holterman and Richard Pearl both of Children’s Hospital of Illinois. This surgery was approved by the FDA under an Investigational New Drug (IND) application submitted by Dr. Holterman.

Dr. Mark Holterman, Professor of Surgery and Pediatrics at University of Illinois College of Medicine at Peoria, commented: “The success of this pediatric tracheal implantation would have been impossible without the Harvard Bioscience contribution. Their team of engineers applied their talent and experience to solve the difficult technical challenge of applying regenerative medicine principles in a small child.”

David Green, President of Harvard Bioscience, said: “We would like to congratulate Dr. Macchiarini, Dr. Holterman, Dr. Pearl and their colleagues for accomplishing the world’s first transplant of a regenerated trachea in a child using a synthetic scaffold and giving Hannah a chance at a normal life. We also wish Hannah a full recovery and extend our best wishes to her family.”

Hannah’s surgery is the seventh successful implant of a regenerated trachea in a human using HART technology. Prior successes included the first ever successful regenerated trachea transplant in 2008, the first successful regenerated trachea transplant using a synthetic scaffold in 2011, and the commencement of the first clinical trial of regenerated tracheas in 2012. HART has plans to commence discussions with the FDA and EU regulatory authorities in the near future regarding the clinical pathway necessary to bring this new therapeutic approach to a wider range of patients who are in need of a trachea transplant.