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.