Matthew Davidson, a Research Associate with the University of Colorado demonstrates a 3D printed biomaterials for use inside the body including bandages that could be put on a beating human heart in Jason Burdick’s lab. (Photo by Casey A. Cass/University of Colorado)
Soft, strong, and flexible, that’s what you need if you’re going to apply a bandage to a heart and according to an August 1, 2024 news item on phys.org, researchers have developed a promising new material,
In the quest to develop life-like materials to replace and repair human body parts, scientists face a formidable challenge: Real tissues are often both strong and stretchable and vary in shape and size.
A CU [Colorado University] Boulder-led team, in collaboration with researchers at the University of Pennsylvania, has taken a critical step toward cracking that code. They’ve developed a new way to 3D print material that is at once elastic enough to withstand a heart’s persistent beating, tough enough to endure the crushing load placed on joints, and easily shapable to fit a patient’s unique defects.
Better yet, it sticks easily to wet tissue.
Their breakthrough, described in the Aug. 2 [2024] edition of the journal Science, helps pave the way toward a new generation of biomaterials, from internal bandages that deliver drugs directly to the heart to cartilage patches and needle-free sutures.
“Cardiac and cartilage tissues are similar in that they have very limited capacity to repair themselves. When they’re damaged, there is no turning back,” said senior author Jason Burdick, a professor of chemical and biological engineering at CU Boulder’s BioFrontiers Institute. “By developing new, more resilient materials to enhance that repair process, we can have a big impact on patients.”
Worm ‘blobs’ as inspiration
Historically, biomedical devices have been created via molding or casting, techniques which work well for mass production of identical implants but aren’t practical when it comes to personalizing those implants for specific patients. In recent years, 3D printing has opened a world of new possibilities for medical applications by allowing researchers to make materials in many shapes and structures.
Unlike typical printers, which simply place ink on paper, 3D printers deposit layer after layer of plastics, metals or even living cells to create multidimensional objects.
One specific material, known as a hydrogel (the stuff that contact lenses are made of), has been a favorite prospect for fabricating artificial tissues, organs and implants.
But getting these from the lab to the clinic has been tough because traditional 3D-printed hydrogels tend to either break when stretched, crack under pressure or are too stiff to mold around tissues.
“Imagine if you had a rigid plastic adhered to your heart. It wouldn’t deform as your heart beats,” said Burdick. “It would just fracture.”
To achieve both strength and elasticity within 3D printed hydrogels, Burdick and his colleagues took a cue from worms, which repeatedly tangle and untangle themselves around one another in three-dimensional “worm blobs” that have both solid and liquid-like properties. Previous research has shown that incorporating similarly intertwined chains of molecules, known as “entanglements,” can make them tougher.
Their new printing method, known as CLEAR (for Continuous-curing after Light Exposure Aided by Redox initiation), follows a series of steps to entangle long molecules inside 3D-printed materials much like those intertwined worms.
When the team stretched and weight-loaded those materials in the lab (one researcher even ran over a sample with her bike) they found them to be exponentially tougher than materials printed with a standard method of 3D printing known as Digital Light Processing (DLP). Better yet: They also conformed and stuck to animal tissues and organs.
“We can now 3D print adhesive materials that are strong enough to mechanically support tissue,” said co-first author Matt Davidson, a research associate in the Burdick Lab. “We have never been able to do that before.”
Revolutionizing care
Burdick imagines a day when such 3D-printed materials could be used to repair defects in hearts, deliver tissue-regenerating drugs directly to organs or cartilage, restrain bulging discs or even stitch people up in the operating room without inflicting tissue damage like a needle and suture can.
His lab has filed for a provisional patent and plans to launch more studies soon to better understand how tissues react to the presence of such materials.
But the team stresses that their new method could have impacts far beyond medicine—in research and manufacturing too. For instance, their method eliminates the need for additional energy to cure, or harden, parts, making the 3D printing process more environmentally friendly.
“This is a simple 3D processing method that people could ultimately use in their own academic labs as well as in industry to improve the mechanical properties of materials for a wide variety of applications,” said first author Abhishek Dhand, a researcher in the Burdick Lab and doctoral candidate in the Department of Bioengineering at the University of Pennsylvania. “It solves a big problem for 3D printing.”
Here’s a link to and a citation for the paper,
Additive manufacturing of highly entangled polymer networks by Abhishek P. Dhand, Matthew D. Davidson, Hannah M. Zlotnick, Thomas J. Kolibaba, Jason P. Killgore, and Jason A. Burdick. Science 1 Aug 2024 Vol 385, Issue 6708 pp. 566-572 DOI: 10.1126/science.adn692
I have two stories about lungs and they are entirely different with the older one being a bioengineering story from the US and the more recent one being an artificial tissue story from the University of Toronto and the University of Ottawa (both in Canada).
Lab grown lungs
The Canadian Broadcasting Corporation’s Quirks and Quarks radio programme posted a December 29, 2018 news item (with embedded radio files) about bioengineered lunjgs,
There are two major components to building an organ: the structure and the right cells on that structure. A team led by Dr. Joan Nichols, a Professor of Internal Medicine, Microbiology and Immunology at the University of Texas Medical Branch in Galveston, were able to tackle both parts of the problem
In their experiment they used a donor organ for the structure. They took a lung from an unrelated pig, and stripped it of its cells, leaving a scaffold of collagen, a tough, flexible protein. This provided a pre-made appropriate structure, though in future they think it may be possible to use 3-D printing technology to get the same result.
They then added cultured cells from the animal who would be receiving the transplant – so the lung was made of the animal’s own cells. Cultured lung and blood vessel cells were placed on the scaffold and it was placed in a tank for 30 days with a cocktail of nutrients to help the cells stick to the scaffold and proliferate. The result was a kind of baby lung.
They then transplanted the bio-engineered, though immature, lung into the recipient animal where they hoped it would continue to develop and mature – growing to become a healthy, functioning organ.
The recipients of the bio-engineered lungs were four pigs adult pigs, which appeared to tolerate the transplants well. In order to study the development of the bio-engineered lungs, they euthanized the animals at different times: 10 hours, two weeks, one month and two months after transplantation.
They found that as early as two weeks, the bio-engineered lung had integrated into the recipient animals’ body, building a strong network of blood vessels essential for the lung to survive. There was no evidence of pulmonary edema, the build of fluid in the lungs, which is usually a sign of the blood vessels not working efficiently. There was no sign of rejection of the transplanted organs, and the pigs were healthy up to the point where they were euthanized.
One lingering concern is how well the bio-engineered lungs delivered oxygen. The four pigs who received the trasplant [sic] had one original functioning lung, so they didn’t depend on their new bio-engineered lung for breathing. The scientists were not sure that the bio-engineered lung was mature enough to handle the full load of oxygen on its own.
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You can hear Bob McDonald’s (host of Quirks & Quarks, a Canadian Broadcasting Corporation science radio programme) interview lead scientist, Dr. Joan Nichols if you go to here. (Note: I find he overmodulates his voice but some may find he has a ‘friendly’ voice.)
This is an image of the lung scaffold produced by the team,
Lung scaffold in the bioreactor chamber on Day 1 of the experiment, before the cells from the study pig were added. (Credit: Joan Nichols) [downloaded from https://www.cbc.ca/radio/quirks/dec-29-2018-water-on-mars-lab-grown-lungs-and-more-the-biggest-science-stories-of-2018-1.4940811/lab-grown-lungs-are-transplanted-in-pigs-today-they-may-help-humans-tomorrow-1.4940822]
In 2014, Joan Nichols and Joaquin Cortiella from The University of Texas Medical Branch at Galveston were the first research team to successfully bioengineer human lungs in a lab. In a paper now available in Science Translational Medicine, they provide details of how their work has progressed from 2014 to the point no complications have occurred in the pigs as part of standard preclinical testing.
“The number of people who have developed severe lung injuries has increased worldwide, while the number of available transplantable organs have decreased,” said Cortiella, professor of pediatric anesthesia. “Our ultimate goal is to eventually provide new options for the many people awaiting a transplant,” said Nichols, professor of internal medicine and associate director of the Galveston National Laboratory at UTMB.
To produce a bioengineered lung, a support scaffold is needed that meets the structural needs of a lung. A support scaffold was created using a lung from an unrelated animal that was treated using a special mixture of sugar and detergent to eliminate all cells and blood in the lung, leaving only the scaffolding proteins or skeleton of the lung behind. This is a lung-shaped scaffold made totally from lung proteins.
The cells used to produce each bioengineered lung came from a single lung removed from each of the study animals. This was the source of the cells used to produce a tissue-matched bioengineered lung for each animal in the study. The lung scaffold was placed into a tank filled with a carefully blended cocktail of nutrients and the animals’ own cells were added to the scaffold following a carefully designed protocol or recipe. The bioengineered lungs were grown in a bioreactor for 30 days prior to transplantation. Animal recipients were survived for 10 hours, two weeks, one month and two months after transplantation, allowing the research team to examine development of the lung tissue following transplantation and how the bioengineered lung would integrate with the body.
All of the pigs that received a bioengineered lung stayed healthy. As early as two weeks post-transplant, the bioengineered lung had established the strong network of blood vessels needed for the lung to survive.
“We saw no signs of pulmonary edema, which is usually a sign of the vasculature not being mature enough,” said Nichols and Cortiella. “The bioengineered lungs continued to develop post-transplant without any infusions of growth factors, the body provided all of the building blocks that the new lungs needed.”
Nichols said that the focus of the study was to learn how well the bioengineered lung adapted and continued to mature within a large, living body. They didn’t evaluate how much the bioengineered lung provided oxygenation to the animal.
“We do know that the animals had 100 percent oxygen saturation, as they had one normal functioning lung,” said Cortiella. “Even after two months, the bioengineered lung was not yet mature enough for us to stop the animal from breathing on the normal lung and switch to just the bioengineered lung.”
For this reason, future studies will look at long-term survival and maturation of the tissues as well as gas exchange capability.
The researchers said that with enough funding, they could grow lungs to transplant into people in compassionate use circumstances within five to 10 years.
“It has taken a lot of heart and 15 years of research to get us this far, our team has done something incredible with a ridiculously small budget and an amazingly dedicated group of people,” Nichols and Cortiella said.
Here’s a citation and another link for the paper,
Production and transplantation of bioengineered lung into a large-animal model by Joan E. Nichols, Saverio La Francesca, Jean A. Niles, Stephanie P. Vega, Lissenya B. Argueta, Luba Frank, David C. Christiani, Richard B. Pyles, Blanca E. Himes, Ruyang Zhang, Su Li, Jason Sakamoto, Jessica Rhudy, Greg Hendricks, Filippo Begarani, Xuewu Liu, Igor Patrikeev, Rahul Pal, Emiliya Usheva, Grace Vargas, Aaron Miller, Lee Woodson, Adam Wacher, Maria Grimaldo, Daniil Weaver, Ron Mlcak, and Joaquin Cortiella. Science Translational Medicine 01 Aug 2018: Vol. 10, Issue 452, eaao3926 DOI: 10.1126/scitranslmed.aao3926
This paper is behind a paywall.
Artificial lung cancer tissue
The research teams at the University of Toronto and the University of Ottawa worked on creating artificial lung tissue but other applications are possible too. First, there’s the announcement in a February 25, 2019 news item on phys.org,
A 3-D hydrogel created by researchers in U of T Engineering Professor Molly Shoichet’s lab is helping University of Ottawa researchers to quickly screen hundreds of potential drugs for their ability to fight highly invasive cancers.
Cell invasion is a critical hallmark of metastatic cancers, such as certain types of lung and brain cancer. Fighting these cancers requires therapies that can both kill cancer cells as well as prevent cell invasion of healthy tissue. Today, most cancer drugs are only screened for their ability to kill cancer cells.
“In highly invasive diseases, there is a crucial need to screen for both of these functions,” says Shoichet. “We now have a way to do this.”
In their latest research, the team used hydrogels to mimic the environment of lung cancer, selectively allowing cancer cells, and not healthy cells, to invade. In their latest research, the team used hydrogels to mimic the environment of lung cancer, selectively allowing cancer cells, and not healthy cells, to invade. This emulated environment enabled their collaborators in Professor Bill Stanford’s lab at University of Ottawa to screen for both cancer-cell growth and invasion. The study, led by Roger Y. Tam, a research associate in Shochet’s lab, was recently published in Advanced Materials.
“We can conduct this in a 384-well plate, which is no bigger than your hand. And with image-analysis software, we can automate this method to enable quick, targeted screenings for hundreds of potential cancer treatments,” says Shoichet.
One example is the researchers’ drug screening for lymphangioleiomyomatosis (LAM), a rare lung disease affecting women. Shoichet and her team were inspired by the work of Green Eggs and LAM, a Toronto-based organization raising awareness of the disease.
Using their hydrogels, they were able to automate and screen more than 800 drugs, thereby uncovering treatments that could target disease growth and invasion.
In the ongoing collaboration, the researchers plan to next screen multiple drugs at different doses to gain greater insight into new treatment methods for LAM. The strategies and insights they gain could also help identify new drugs for other invasive cancers.
Shoichet, who was recently named a Distinguished Woman in Chemistry or Chemical Engineering, also plans to patent the hydrogel technology.
“This has, and continues to be, a great collaboration that is advancing knowledge at the intersection of engineering and biology,” says Shoichet.
I note that Shoichet (pronounced ShoyKet) is getting ready to patent this work. I do have a question about this and it’s not up to Shoichet to answer as she didn’t create the system. Will the taxpayers who funded her work receive any financial benefits should the hydrogel prove to be successful or will we be paying double, both supporting her research and paying for the hydrogel through our healthcare costs?
Getting back to the research, here’s a link to and a citation for the paper,
Rationally Designed 3D Hydrogels Model Invasive Lung Diseases Enabling High‐Content Drug Screening by Roger Y. Tam, Julien Yockell‐Lelièvre, Laura J. Smith, Lisa M. Julian, Alexander E. G. Baker, Chandarong Choey, Mohamed S. Hasim, Jim Dimitroulakos, William L. Stanford, Molly S. Shoichet. Advanced Materials Volume 31, Issue 7 February 15, 2019 1806214 First published online: 27 December 2018 DOI: https://doi.org/10.1002/adma.201806214
