3D-printing skin and bone so astronauts might heal themselves on missions

3D bioprinting for space

3D printing human tissue could help keep astronauts healthy all the way to Mars. An ESA project has produced its first bioprinted skin and bone samples.

These state-of-the-art samples were prepared by scientists from the University Hospital of Dresden Technical University (TUD), part of the project consortium together with OHB System AG as the prime contractor, and life sciences specialist Blue Horizon.

“Skin cells can be bioprinted using human blood plasma as a nutrient-rich ‘bio-ink’ – which would be easily accessible from the mission crewmembers,” comments Nieves Cubo from TUD.

“However, plasma has a highly fluid consistency, making it difficult to work with in altered gravitational conditions. We therefore developed a modified recipe by adding methylcellullose and alginate to increase the viscosity of the substrate. Astronauts could obtain these substances from plants and algae respectively, a feasible solution for a self-contained space expedition.

“Producing the bone sample involved printing human stem cells with a similar bio-ink composition, with the addition of a calcium phosphate bone cement as a structure-supporting material, which is subsequently absorbed during the growth phase.”

To prove that the bioprinting technique was transferable to space, printing of both the skin and bone samples took place upside down. With prolonged access to weightlessness impractical, the challenge of such ‘minus 1 G’ testing represented the next best option.

The samples represent the first steps in an ambitious end-to-end roadmap to make 3D bioprinting practical for space. The project is looking into the kind of onboard facilities that would be required, in terms of equipment, surgical rooms and sterile environments, as well as the ability to create more complex tissues for transplants – culminating ultimately in the printing of entire internal organs.

“A journey to Mars or other interplanetary destinations will involve several years in space,” comments Tommaso Ghidini, head of ESA’s Structures, Mechanisms and Materials Division, overseeing the project.

“The crew will run many risks, and returning home early will not be possible. Carrying enough medical supplies for all possible eventualities would be impossible in the limited space and mass of a spacecraft.

“Instead, a 3D bioprinting capability will let them respond to medical emergencies as they arise. In the case of burns, for instance, brand new skin could be bioprinted instead of being grafted from elsewhere on the astronaut’s body, doing secondary damage that may not heal easily in the orbital environment.

“Or in the case of bone fractures – rendered more likely by the weightlessness of space, coupled with the partial 0.38 Earth gravity of Mars – replacement bone could be inserted into injured areas. In all cases the bioprinted material would originate with the astronaut themselves, so there would be no issue with transplant rejection.”

With 3D bioprinting progressing steadily on Earth, this project is the first to adopt it off the planet, explains Tommaso: “It’s a typical pattern we see when promising terrestrial technologies are first harnessed for space, ranging from cameras to microprocessors. More needs to be done with less, to make things work in the challenging space environment, so various elements of the technology get optimised and miniaturised.

“Similarly, we hope that the work we do with 3D bioprinting will help accelerate its progress on Earth as well, hastening its widespread availability, bringing it to people even sooner.”

Learn and see more: Upside down 3D-printed skin and bone for humans to Mars

 

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Advancing the 3D bioprinting of complex tissues and structures

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A team of Brigham and Women’s Hospital researchers have developed a way to bioprint tubular structures that better mimic native vessels and ducts in the body.

The 3-D bioprinting technique allows fine-tuning of the printed tissues’ properties, such as number of layers and ability to transport nutrients. These more complex tissues offer potentially viable replacements for damaged tissue. The team describes its new approach and results in a paper published on Aug. 23 in Advanced Materials.

“The vessels in the body are not uniform,” said Yu Shrike Zhang, PhD, senior author on the study and an associate bioengineer in BWH’s Department of Medicine. “This bioprinting method generates complex tubular structures that mimic those in the human system with higher fidelity than previous techniques.”

Many disorders damage tubular tissues: arteritis, atherosclerosis and thrombosis damage blood vessels, while urothelial tissue can suffer inflammatory lesions and deleterious congenital anomalies.

To make the 3D bioprinter’s “ink,” the researchers mixed the human cells with a hydrogel, a flexible structure composed of hydrophilic polymers. They optimized the chemistry of the hydrogel to allow the human cells to proliferate, or “seed,” throughout the mixture.

Next, they filled the cartridge of a 3D bioprinter with this bio-ink. They fitted the bioprinter with a custom nozzle that would allow them to continuously print tubular structures with up to three layers. Once the tubes were printed, the researchers demonstrated their ability to transport nutrients by perfusing fluids.

The researchers found that they could print tissues mimicking both vascular tissue and urothelial tissue. They mixed human urothelial and bladder smooth muscle cells with the hydrogel to form the urothelial tissue. To print the vascular tissue, they used a mixture of human endothelial cells, smooth muscle cells and the hydrogel.

The printed tubes had varying sizes, thicknesses and properties. According to Zhang, structural complexity of bioprinted tissue is critical to its viability as a replacement for native tissue. That’s because natural tissues are complex. For instance, blood vessels are comprised of multiple layers, which in turn are made up of various cell types.

The team plans to continue preclinical studies to optimize the bio-ink composition and 3D-printing parameters before testing for safety and effectiveness.

“We’re currently optimizing the parameters and biomaterial even further,” said Zhang. “Our goal is to create tubular structures with enough mechanical stability to sustain themselves in the body.”

Learn more: One Step Closer to Bioengineered Replacements for Vessels and Ducts

 

 

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One step closer to 3-D printing transplantable tissues and organs with functioning capiliaries

Researchers from Rice University and Baylor College of Medicine have shown they initiate a process called tubulogenesis that is crucial to the formation of blood-transporting capillaries. In microscopic images taken a different times during a weeklong experiment, researchers tracked the changes in cells (green) and cell nuclei (orange) using fluorescent markers. (Photo by Jeff Fitlow/Rice University)

Rice, Baylor College of Medicine make necessary step on road to 3-D bioprinting

In their work toward 3-D printing transplantable tissues and organs, bioengineers and scientists from Rice University and Baylor College of Medicine have demonstrated a key step on the path to generate implantable tissues with functioning capillaries.

In a paper published online in the journal Biomaterials Science, a team from the laboratories of Rice bioengineer Jordan Miller and Baylor College of Medicine biophysicist Mary Dickinson showed how to use a combination of human endothelial cells and mesenchymal stem cells to initiate a process called tubulogenesis that is crucial to the formation of blood-transporting capillaries.

The work is an important step with fragile endothelial cells (ECs) made from “induced pluripotent stem cells,” or iPSCs, a type of cell that can potentially be made from the cells of any human patient. Because iPSCs can be patient-specific, researchers hope to find ways of using them to generate tissues and replacement organs that can be transplanted without risk of rejection by a patient’s immune system. But the fragility of endothelial cells during laboratory growth has limited the utilization of this critical cell type, which is found in all vasculature.

“Our work has important therapeutic implications because we demonstrate utilization of human cells and the ability to live-monitor their tubulogenesis potential as they form primitive vessel networks,” said study lead author Gisele Calderon, a graduate student in Miller’s Physiologic Systems Engineering and Advanced Materials Laboratory.

“We’ve confirmed that these cells have the capacity to form capillary-like structures, both in a natural material called fibrin and in a semisynthetic material called gelatin methacrylate, or GelMA,” Calderon said. “The GelMA finding is particularly interesting because it is something we can readily 3-D print for future tissue-engineering applications.”

Tissue engineering, also known as regenerative medicine, is a field aimed at integrating advances in stem cell biology and materials science to grow transplantable replacement tissues and organs. While tissue engineers have found dozens of ways to coax stems cells into forming specific kinds of cells and tissues, they still cannot grow tissues with vasculature — capillaries and the larger blood vessels that can supply the tissues with life-giving blood. Without vascularization, tissues more than a few millimeters in thickness will die due to lack of nutrients, so finding a way to grow tissues with blood vessels is one of the most sought-after advances in the field.

Miller, who earned his Ph.D. at Rice in 2008, has studied vascularization in tissue engineering for more than 14 years. During his postdoctoral studies at the University of Pennsylvania, he also became heavily involved in the open-source 3-D printing movement, and his work at Rice combines both.

“Ultimately, we’d like to 3-D print with living cells, a process known as 3-D bioprinting, to create fully vascularized tissues for therapeutic applications,” said Miller, assistant professor of bioengineering. “To get there, we have to better understand the mechanical and physiological aspects of new blood-vessel formation and the ways that bioprinting impacts those processes. We are using 3-D bioprinting to build tissues with large vessels that we can connect to pumps, and are integrating that strategy with these iPS-ECs to help us form the smallest capillaries to better nourish the new tissue.”

Each of the trillions of living cells in the human body are constantly supplied with oxygen and nutrients by tiny blood vessels known as capillaries. Measuring just a few thousandths of a millimeter in diameter, some capillaries are so narrow that individual blood cells must squeeze through them in single-file. Capillaries are made entirely from networks of endothelial cells, the type of cell that lines the inner surface of every blood vessel in the human body.

In the process of tubulogenesis — the first step to making capillaries — endothelial cells undergo a series of changes. First, they form small, empty chambers called vacuoles, and then they connect with neighboring cells, linking the vacuoles together to form endothelial-lined tubes that can eventually become capillaries.

“We expect our findings will benefit biological studies of vasculogenesis and will have applications in tissue engineering to prevascularize tissue constructs that are fabricated with advanced photo-patterning and three-dimensional printing,” said Dickinson, the Kyle and Josephine Morrow Chair in Molecular Physiology and Biophysics at Baylor College of Medicine and adjunct professor of bioengineering at Rice.

In the study, Calderon, Rice undergraduate Patricia Thai and colleagues investigated whether commercially available endothelial cells grown from iPSCs had tubulogenic potential. The test examined this potential in two types of semisolid gels — fibrin and GelMA. Finally, the researchers also investigated whether a second type of stem cell, human mesenchymal stem cells, could improve the likelihood of tubulogenesis.

Calderon said fibrin was chosen for the experiment because it’s a natural material that’s known to induce tubulogenesis for wound healing. As such, the researchers expected endothelial cells would be induced to form tubules in fibrin.

Calderon said the first step in the experiments was to develop a third-generation lentivirus reporter to genetically modify the cells to produce two types of fluorescent protein, one located only in the nucleus and another throughout the cell. This permanent genetic modification allowed the team to noninvasively observe the cell morphology and also identify the action of each individual cell for later quantitative measurements. Next, the cells were mixed with fibrin and incubated for a week. Several times per day, Calderon and Thai used microscopes to photograph the growing samples. Thanks to the two fluorescent markers, time-lapse images revealed how the cells were progressing on their tubulogenic odyssey.

Calderon conducted advanced confocal microscopy at the Optical Imaging and Vital Microscopy Core facility at Baylor College of Medicine. Calderon and Thai then used an open-source software called FARSIGHT to quantitatively analyze the 3-D growth patterns and development character of the tubulogenenic networks in each sample. In fibrin, the team found robust tubule formation, as expected. They also found that endothelial cells had a more difficult time forming viable tubules in GelMA, a mix of denatured collagen that was chemically modified with methacrylates to allow rapid photopolymerization.

Over several months and dozens of experiments the team developed a workflow to produce robust tubulogenesis in GelMA, Calderon said. This involved adding mesenchymal stem cells, another type of adult human stem cell that had previously been shown to stabilize the formation of tubules.

Miller said that while clinical applications of 3-D bioprinting are expected to advance rapidly over the next few decades, even small tissue samples with working capillary networks could find use much more quickly for laboratory applications like drug testing.

“You could foresee using these three-dimensional, printed tissues to provide a more accurate representation of how our bodies will respond to a drug,” Miller said. “Preclinical human testing of new drugs today is done with flat two-dimensional human tissue cultures. But it is well-known that cells often behave differently in three-dimensional tissues than they do in two-dimensional cultures. There’s hope that testing drugs in more realistic three-dimensional cultures will lower overall drug development costs. And the potential to build tissue constructs made from a particular patient represents the ultimate test bed for personalized medicine. We could screen dozens of potential drug cocktails on this type of generated tissue sample to identify candidates that will work best for that patient.”

Learn more: Houston team one step closer to growing capillaries

 

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Researchers hack off-the-shelf 3-D printer for 3-D bioprinting

This is a coronary artery structure being 3-D bioprinted. CREDIT Carnegie Mellon University College of Engineering

This is a coronary artery structure being 3-D bioprinted.
CREDIT
Carnegie Mellon University College of Engineering

Models of hearts, arteries, bones and brains are 3-D printed out of biological materials

As of this month, over 4,000 Americans are on the waiting list to receive a heart transplant. With failing hearts, these patients have no other options; heart tissue, unlike other parts of the body, is unable to heal itself once it is damaged. Fortunately, recent work by a group at Carnegie Mellon could one day lead to a world in which transplants are no longer necessary to repair damaged organs.

“We’ve been able to take MRI images of coronary arteries and 3-D images of embryonic hearts and 3-D bioprint them with unprecedented resolution and quality out of very soft materials like collagens, alginates and fibrins,” said Adam Feinberg, an associate professor of Materials Science and Engineering and Biomedical Engineering at Carnegie Mellon University. Feinberg leads the Regenerative Biomaterials and Therapeutics Group, and the group’s study was published in the October 23 issue of the journal Science Advances. A demonstration of the technology can be viewed online.

“As excellently demonstrated by Professor Feinberg’s work in bioprinting, our CMU researchers continue to develop novel solutions like this for problems that can have a transformational effect on society,” said Jim Garrett, Dean of Carnegie Mellon’s College of Engineering. “We should expect to see 3-D bioprinting continue to grow as an important tool for a large number of medical applications.”

Traditional 3-D printers build hard objects typically made of plastic or metal, and they work by depositing material onto a surface layer-by-layer to create the 3-D object. Printing each layer requires sturdy support from the layers below, so printing with soft materials like gels has been limited.

“3-D printing of various materials has been a common trend in tissue engineering in the last decade, but until now, no one had developed a method for assembling common tissue engineering gels like collagen or fibrin,” said TJ Hinton, a graduate student in biomedical engineering at Carnegie Mellon and lead author of the study.

“The challenge with soft materials — think about something like Jello that we eat — is that they collapse under their own weight when 3-D printed in air,” explained Feinberg. “So we developed a method of printing these soft materials inside a support bath material. Essentially, we print one gel inside of another gel, which allows us to accurately position the soft material as it’s being printed, layer-by-layer.”

One of the major advances of this technique, termed FRESH, or “Freeform Reversible Embedding of Suspended Hydrogels,” is that the support gel can be easily melted away and removed by heating to body temperature, which does not damage the delicate biological molecules or living cells that were bioprinted. As a next step, the group is working towards incorporating real heart cells into these 3-D printed tissue structures, providing a scaffold to help form contractile muscle.

Bioprinting is a growing field, but to date, most 3-D bioprinters have cost over $100,000 and/or require specialized expertise to operate, limiting wider-spread adoption. Feinberg’s group, however, has been able to implement their technique on a range of consumer-level 3-D printers, which cost less than $1,000 by utilizing open-source hardware and software.

Read more: Carnegie Mellon researchers hack off-the-shelf 3-D printer towards rebuilding the heart

 

 

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Exploring 3-D printing to make organs for transplants

A close-up of tiny bioink droplets used to print organs shows live cells inside. Credit: American Chemical Society

A close-up of tiny bioink droplets used to print organs shows live cells inside.
Credit: American Chemical Society

Printing whole new organs for transplants sounds like something out of a sci-fi movie, but the real-life budding technology could one day make actual kidneys, livers, hearts and other organs for patients who desperately need them.

In the ACS journal Langmuir, scientists are reporting new understanding about the dynamics of 3-D bioprinting that takes them a step closer to realizing their goal of making working tissues and organs on-demand.

Yong Huang and colleagues note that this idea of producing tissues and organs, or biofabricating, has the potential to address the shortage of organ donations. And biofabricated ones could even someday be made with a patient’s own cells, lowering the risk of rejection. Today, more than 120,000 people are on waiting lists for donated organs, with most needing kidney transplants. But between January and April of this year, just short of 10,000 people received the transplant they needed. There are a few different biofabricating methods, but inkjet printing has emerged as a frontrunner. It’s been used to print live cells, from hamster ovary cells to human fibroblasts, which are a common type of cell in the body. But no studies had been done to really understand how biological inks behave when they’re dispensed through printer nozzles. Huang’s team set out to fill that gap.

They tested bioinks with different concentrations of mouse fibroblasts plus a hydrogel made out of sodium alginate. They discovered, among other findings, that adding more cells in the material reduces both the droplet size and the rate at which it gets dispensed. The new results will help scientists move forward with this promising technology.

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