Bioengineers Are Closer Than Ever To Lab-Grown Lungs

By Robbie Gonzalez

The lungs in Joan Nichols’ lab have been keeping her up at night. Like children, they’re delicate, developing, and in constant need of attention, which is why she and her team at the University of Texas Medical Branch at Galveston’s Lung Lab have spent the last several years taking turns driving to the lab at 1:00 am to check that the bioreactors housing their experimental organs are not leaking, that the nutrient-rich soup supporting the lungs is still flowing, or that the budding sacs of tissues and veins have not succumbed to contamination. That last risk was a persistent source of anxiety: Building a lung requires suspending the thing for weeks on end in warm, wet, fungus friendly conditions—to say nothing of the subtropical climate of Galveston itself. “In this city, mold will grow on people if they sit still long enough,” Nichols says.

But their vigilance has paid off. In 2014, Nichols’ team became the first to bioengineer a human lung. A year later, the researchers implanted a single lab-built lung into a pig—another first. They’ve grown three more pig lungs since, using cells from their intended recipients, and transplanted each of them successfully without the use of immunosuppressive drugs. Taken together, the four porcine procedures, which the researchers describe in this week’s issue of Science Translational Medicine, are a major step toward growing human organs that are built to-order, using a transplant recipient’s own cells.

Bioengineering a lung is a bit like modeling with clay: Like a sculptor uses a wire armature to lend his creation form, Nichols’ team grew the tissues and blood vessels of their lab-grown lungs atop a framework of tough, flexible proteins. The researchers got that scaffolding secondhand, harvesting whole organs from dead pigs and bathing them in a concoction of sugar and detergent to strip them of the cells and blood of their previous owners like a coat of varnish from an old table.

Nichols calls the milky mass that remains the organ’s skeleton: It’s made mostly of collagen, which lends the lung strength, and elastin, which makes it flexible. Each scaffold goes into a bioreactor—one of the containers Nichols and her team built from scratch to house each of the proteinous blobs. The earliest models were little more than spruced-up fish tanks; the latest iterations still incorporate parts purchased from Home Depot.

Its humble origins notwithstanding, each bioreactor plays a vital role. “It lets you provide the organ with growth factors, media, mechanical stimulation,” says pediatric anesthesiologist Joaquin Cortiella, who co-leads the Lung Lab with Nichols. Its job is similar to that of a placenta, allowing the lung to develop in a warm, cozy, nutrient-rich environment for 30 days before it moves to the thoracic cavity of a living, breathing pig, nestled neatly beside the animal’s original lung.

Growing a lung in a bioreactor for a month is a significant accomplishment, says bioengineer Gordana Vunjak-Novakovic, director of the Laboratory for Stem Cells and Tissue Engineering at Columbia University, who was unaffiliated with the study. In an email to WIRED, she said that previous lab-grown lungs have spent a lot less time in culture before being transplanted. The extra time allowed Nichols’ and Cortiella’s bioengineered lungs to grow more blood vessels, the underdevelopment of which “is a major current limitation of lung survival,” said Vunjak-Novakovic. In past studies involving smaller animals, transplant recipients have died within a matter of hours due to fluid accumulation in the lungs. By contrast, the vasculature in Nichols’ and Cortiella’s organs allowed the pigs who received them to survive as long as two months post-transplant without any observable complications.

It’s unclear how the pigs would have fared beyond two months. The four animals in this study were euthanized 10 hours, two weeks, one month, and two months post-surgery, so the researchers could examine how each bioengineered lung had developed inside its recipient following transplantation. All signs pointed to the lungs integrating seamlessly—they continued to develop blood vessels and lung tissues and were colonized by the microbes specific to each animal’s native lung microbiome, all without respiratory symptoms or rejection by the recipient’s immune system.

A big lingering question is how well the bioengineered lungs deliver oxygen. Though each of the pigs had normal amounts of the stuff pumping through their bodies, that could have been the work of the animal’s original lung. The researchers worried the implanted organs were too underdeveloped to risk stopping each research animal from breathing on its original lung, to test the lab-grown one in isolation. That’ll have to wait for future experiments, which Cortiella and Nichols say will involve pigs living for a year or more on their transplanted organs.

Such studies will also require more animals. “It will be interesting to see how robust this technology is, as the number of animals was very low,” said Vunjak-Novakovic. Still, the results are promising. With sufficient funding, Nichols and Cortiella think they could be transplanting bioengineered lungs into humans within the decade.

But first come more experiments—and better, more reliable research facilities. High on Nichols’ wish list is a clean room for the bioreactors, accessible only to researchers clad head-to-toe in bunny suits. She’d like more automated equipment too, which would translate to less manual labor and fewer opportunities for error. And of course, she’s looking forward to the day when she and her colleagues can monitor their lungs remotely via a livestream. Babysitting bioengineered lungs may always be a 24-hour job, but at least with a video monitor the members of the Lung Lab could work remotely.

Jerry Cahill’s CF Podcast: The Pre-Transplant Process with Dr. Emily DiMango

The latest video in The Path Forward with Cystic Fibrosis series, Dr. Emily DiMango, Director of the Gunnar Esiason Adult CF Program at Columbia University Medical Center, discusses the lung transplant process through the lens of a CF doctor.

First, she reviews the importance of CF patients participating in drug trials in order to start life-changing medications sooner. She then answers the following questions:

· What does pre-transplant management look like for a CF patient?
· When is the right time to be referred to the list?
· What is the referral process like?

Finally, she reiterates the importance of well-rounded treatment that includes physical health, nutritional health, and emotional health.

This video was originally posted on JerryCahill.com

You have a new set of lungs! What should you expect next?

Cystic Fibrosis Podcast 183:
The Path Forward with Cystic Fibrosis
By Jerry Cahill
In the latest edition of The Path Forward with Cystic Fibrosis, Dr. Arcasoy from Columbia University Medical Center is back to explain what happens after a patient has a double lung transplant. He discusses pain management and the post-transplant care team in detail.
Here’s what to expect immediately pre and post-surgery:
  • Post-surgical care including pain management
  • Medical care that includes antibiotics, antirejection medication, and anti-infection medication
  • Psycho-social recovery assistance
Dr. Arcasoy also explains who your post-transplant care team is and what they do… it’s a lot, so here’s a cheat sheet:
WHO: Medical Transplant Pulmonologist and the Coordinator
WHAT:
Patients will meet with their Post-transplant team once a week for three months, then every 3-4 weeks for a year. At every meeting, the following occurs:
  • Chest x-ray
  • Lab work
  • Pulmonary function test
  • Physical exam
  • Conversation to review medications and overall health & wellness
  • Follow up lab review and medication changes
The schedule for bronchoscopies vary depending on the center, and additional testing can be added at any time deemed necessary.
Remember – every patient’s experience is completely unique! Do not get discouraged; and work with your care team to prepare both mentally and physically for the bumps along the way.

This video podcast was made possible through an unrestricted educational grant from Columbia University Medical Center and the Lung Transplant Project.

NIH Awards $8.6 Million for Bold Bid to Transform Lung Transplantation

http://www.newswise.com/articles/view/677465/?sc=mwhn

Researchers at the University of Virginia School of Medicine have received more than $8.6 million in federal grants to support efforts that could dramatically increase the number of lungs available for transplant – and then Continue reading NIH Awards $8.6 Million for Bold Bid to Transform Lung Transplantation

Subject: CF MiniCon: Transplant – May 21 Virtual Event for Adults With CF

This year the Cystic Fibrosis Foundation will be supporting three virtual events created by and for adults with CF to connect and share their experiences. In 2016, a group of adults with CF created BreatheCon, a two-day event that had a powerful effect in connecting community members. This year, in addition to BreatheCon, we are also introducing two CF MiniCons, which are one-day, topic-specific virtual events.

While last year’s BreatheCon was a pilot program, with 188 attendees and limited mostly to word of mouth promotion, this year we encourage you to spread the word about these virtual events to all adults with CF. Please note these events are open only to adults with CF (not to Care Center staff).

CF MiniCon: Transplant – May 21

On Sunday, May 21 from 6:00 – 9:30 p.m. Eastern Time, members of the CF community will be hosting CF MiniCon: Transplant, where adults with CF can have an honest and open dialogue about the transplant process.

This virtual event will include presentations, group chats, and small group video breakouts on a variety of aspects of transplantation that are unique to people living with CF. Discussion will focus on lifestyle, not on medical topics.

All adults with CF age 18 and over are welcome to attend CF MiniCon: Transplant. Registration is open now through May 18 at www.cff.org/minicon. For questions or more information, email  breathecon@cff.org.

Additional 2017 Events
Please be on the lookout for additional details on CF MiniCon: Young Adult Transition (July 22) and BreatheCon 2017 (September 8-9) in the weeks leading up to the events. If you would like to recommend someone from your community who has CF and is age 18 or over to help plan these events, or if you have any questions, please email Danielle Lowe Cipriani at dcipriani@cff.org.

We look forward to working with you to support virtual connections for people living with CF.

Thank you,
Drucy Borowitz, M.D.

Vice President of Community Partnerships

Exploring the Cause of Chronic Lung Transplant Rejection

Exploring the Cause of Chronic Lung Transplant Rejection, in a Quest to Stop It

http://www.newswise.com/articles/view/670346/?sc=mwhn

For patients affected by lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and others, cures for their diseases are incredibly rare, if not nonexistent. Continue reading Exploring the Cause of Chronic Lung Transplant Rejection

Scripps study could impact future treatment of organ transplant patients

http://www.cbs8.com/story/31476725/scripps-study-could-impact-future-treatment-of-organ-transplant-patients

Posted: Mar 15, 2016 3:59 PM EDT Updated: Mar 15, 2016 3:59 PM EDT

LA JOLLA (CNS) – A study released Tuesday by scientists at The Scripps Research Institute in La Jolla could lead to major changes in the way patients with transplanted organs are treated in the future to prevent rejection.

In the study published in the American Journal of Transplantation, the researchers analyzed 234 kidney transplant biopsies and discovered that around 80 percent of the genes expressed in cases of early, acute rejection were also present in instances of chronic, much later rejections.

Acute and chronic rejections were thought to be separate conditions, but now appear to be difference stages along the same arc, the scientists say. About half of kidney transplants are rejected within 10 years, forcing patients onto dialysis, according to TSRI.

“For our transplant population, this is a major new understanding of the molecular basis of immune rejection that challenges the field to reconsider its current paradigms and has multiple immediate and actionable therapy implications for patients,”said Dr. Daniel Salomon, director of the Laboratory for Functional Genomics at TSRI. “The insights here most likely apply to liver, heart and lung transplants, too.”

He said the research shows that almost all transplant organ failure is due to inadequate suppression of the immune system, so that post-transplant patients can potentially be treated with the same therapies in order to prevent rejection.

“The new view that emerges from this research is that almost all transplant organ failure is due to inadequate immunosuppression, and with that understanding comes a potential for a major change in the practice of post- transplant drug therapy,”said Salomon, who is also medical program director of the Scripps Center for Organ Transplantation.

The researchers said more frequent biopsies could catch the body’s rejection of transplanted kidneys earlier than they are now.

Their study found a kind of kidney damage and scarring called interstitial fibrosis and tubular atrophy that could be a clue of approaching kidney rejection. Previous studies found that the presence of IFTA and inflammation — as seen under a light microscope — correlated with an increased risk of rejection. But IFTA on its own has been seen as evidence of a past injury, not active rejection, and is rarely treated.

“There was injury and inflammation there, just like in acute rejection patients — we just weren’t able to see it with the light microscope,”said Brian Modena, the first author of the study. “If you catch that early, you might potentially prevent chronic rejection. That would be a hugely positive benefit for our patients.”

TSRI reported that genetic expression profiling also proved to be a good tool for detecting subclinical acute rejection, which is active in about 20 percent of transplant patients in their first year, but impossible to suspect or diagnose until progression to clinical rejection.

Numerous other researchers took part in the study, including representatives of the Mayo Clinic, Northwestern Comprehensive Transplant Center in Chicago, and the University of Michigan. The study was funded by the National Institutes of Health.

Continue reading Scripps study could impact future treatment of organ transplant patients

Ex-vivo Lung Perfusion Technology Opens New Possibilities In One Of The Most Problematic Areas Of Lung Transplant Surgery

http://cysticfibrosisnewstoday.com/2015/10/13/trial-shows-ex-vivo-lung-filtering-technique-cuts-transplant-rejection/

Originally published in Cystic Fibrosis News Today
By Charles Moore

Exciting new research, partly funded by the U.K. Cystic Fibrosis Trust and the Robert Luff Foundation and announced at the Trust’s U.K. CF Conference last week, shows promising results in reconditioning poorly functioning donor lungs Continue reading Ex-vivo Lung Perfusion Technology Opens New Possibilities In One Of The Most Problematic Areas Of Lung Transplant Surgery