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3D printing

3D Printing a Human Heart Valve

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It is now possible to pull up the design of a guitar on a computer screen and print out its parts on a 3D printer equipped with special metal or plastic “inks.” The same technological ingenuity is also now being applied with bioinks—printable gels containing supportive biomaterials and/or cells—to print out tissue, bone, blood vessels, and, even perhaps one day, viable organs.

While there’s a long way to go until then, a team of researchers has reached an important milestone in bioprinting collagen and other extracellular matrix proteins that undergird every tissue and organ in the body. The researchers have become so adept at it that they now can print biomaterials that mimic the structural, mechanical, and biological properties of real human tissues.

Take a look at the video. It shows a life-size human heart valve that’s been printed with their improved collagen bioink. As fluid passes through the aortic valve in a lab test, its three leaf-like flaps open and close like the real thing. All the while, the soft, flexible valve withstands the intense fluid pressure, which mimics that of blood flowing in and out of a beating heart.

The researchers, led by NIH grantee Adam Feinberg, Carnegie Mellon University, Pittsburgh, PA, did it with their latest version of a 3D bioprinting technique featured on the blog a few years ago. It’s called: Freeform Reversible Embedding of Suspended Hydrogels v.2.0. Or, just FRESH v2.0.

The FRESH system uses a bioink that consists of collagen (or other soft biomaterials) embedded in a thick slurry of gelatin microparticles and water. While a number of technical improvements have been made to FRESH v. 2.0, the big one was getting better at bioprinting collagen.

The secret is to dissolve the collagen bioink in an acid solution. When extruded into a neutral support bath, the change in pH drives the rapid assembly of collagen. The ability to extrude miniscule amounts and move the needle anywhere in 3D space enables them to produce amazingly complex, high-resolution structures, layer by layer. The porous microstructure of the printed collagen also helps for incorporating human cells. When printing is complete, the support bath easily melts away by heating to body temperature.

As described in Science, in addition to the working heart valve, the researchers have printed a small model of a heart ventricle. By combining collagen with cardiac muscle cells, they found they could actually control the organization of muscle tissue within the model heart chamber. The 3D-printed ventricles also showed synchronized muscle contractions, just like you’d expect in a living, beating human heart!

That’s not all. Using MRI images of an adult human heart as a template, the researchers created a complete organ structure including internal valves, large veins, and arteries. Based on the vessels they could see in the MRI, they printed even tinier microvessels and showed that the structure could support blood-like fluid flow.

While the researchers have focused the potential of FRESH v.2.0 printing on a human heart, in principle the technology could be used for many other organ systems. But there are still many challenges to overcome. A major one is the need to generate and incorporate billions of human cells, as would be needed to produce a transplantable human heart or other organ.

Feinberg reports more immediate applications of the technology on the horizon, however. His team is working to apply FRESH v.2.0 for producing child-sized replacement tracheas and precisely printed scaffolds for healing wounded muscle tissue.

Meanwhile, the Feinberg lab generously shares its designs with the scientific community via the NIH 3D Print Exchange. This innovative program is helping to bring more 3D scientific models online and advance the field of bioprinting. So we can expect to read about many more exciting milestones like this one from the Feinberg lab.

Reference:

[1] 3D bioprinting of collagen to rebuild components of the human heart. Lee A, Hudson AR, Shiwarski DJ, Tashman JW, Hinton TJ, Yerneni S, Bliley JM, Campbell PG, Feinberg AW. Science. 2019 Aug 2;365(6452):482-487.

Links:

Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)

Regenerative Biomaterials and Therapeutics Group (Carnegie Mellon University, Pittsburgh, PA)

FluidForm (Acton, MA)

3D Bioprinting Open Source Workshops (Carnegie Mellon)

Video: Adam Feinberg on Tissue Engineering to Treat Human Disease (YouTube)

NIH 3D Print Exchange

NIH Support: National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Common Fund


Progress Toward 3D Printed Human Organs

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There’s considerable excitement that 3D printing technology might one day allow scientists to produce fully functional replacement organs from one’s own cells. While there’s still a lot to learn, this video shows just some of the amazing progress that’s now being made.

The video comes from a bioengineering team at Rice University, Houston, that has learned to bioprint the small air sacs in the lungs. When hooked up to a machine that pulsed air in and out of the air sacs, the rhythmic movement helped to mix red blood cells traveling through an associated blood vessel network. Those red cells also took up oxygen in much the way that blood vessels do when surrounding the hundreds of millions of air sacs in our lungs.

As mentioned in the video, one of the biggest technical hurdles in growing fully functional replacement tissues and organs is to find a way to feed the growing tissues with a blood supply and to remove waste products. In this study recently published in Science [1], the NIH-supported team cleared this hurdle by creating an open-source bioprinting technology they call SLATE, which is short for “stereo-lithography apparatus for tissue engineering.”

The SLATE system “grows” soft hydrogel scaffolds one layer at a time. Each layer is printed using a liquid pre-hydrogel solution that solidifies when exposed to blue light. By also projecting light into the hydrogel as a pixelated 3D shape, it’s possible to print complex 3D structures within minutes.

When the researchers first started, their printouts lacked the high resolution, submillimeter-scale channels needed to generate intricate vascular networks. In other manufacturing arenas, light-absorbing chemicals have helped control the conversion from liquid to solid in a very fine polymer layer. But these industrial light-absorbing chemicals are highly toxic and therefore unsuitable for scaffolds that grow living tissues and organs.

The researchers, including Bagrat Grigoryan, Jordan Miller, and Kelly Stevens, wondered whether they could swap out those noxious ingredients with synthetic and natural food dyes widely used in the food industry. These dyes include curcumin, anthocyanin, and tartrazine (yellow dye #5). Their studies showed that those fully biocompatible dyes worked as effective light absorbers, allowing the scientists to recreate the complex architectures of human vasculature. Importantly, the living cells survived within the soft scaffold!

These models are already yielding intriguing new insights into the vascular structures found within our organs and how those architectures may influence function in ways that hadn’t been well understood. In the near term, tissues and organs grown on such scaffolds might also find use as sophisticated, 3D tissue “chips,” with potential for use in studies to predict whether drugs will be safe in humans.

In the long term, this technology may allow production of replacement organs from those needing them. More than 100,000 men, women, and children are on the national transplant waiting list in the United States alone and 20 people die each day waiting for a transplant [2]. Ultimately, with the aid of bioprinting advances like this one, perhaps one day we’ll have a ready supply of perfectly matched and fully functional organs.

References:

[1] Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Grigoryan B, Paulsen SJ, Corbett DC, Sazer DW, Fortin CL, Zaita AJ, Greenfield PT, Calafat NJ, Gounley JP, Ta AH, Johansson F, Randles A, Rosenkrantz JE, Louis-Rosenberg JD, Galie PA, Stevens KR, Miller JS. Science. 2019 May 3;364(6439):458-464.

[2] Organ Donor Statistics, Health Resources & Services Administration, October 2018.

Links:

Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Miller Lab (Rice University, Houston)

NIH Support: National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of General Medical Sciences; Common Fund


Putting 3D Printing to Work to Heal Spinal Cord Injury

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3D printed scaffold for spinal repair
Credit: Jacob Koffler and Wei Zhu, University of California, San Diego

For people whose spinal cords are injured in traffic accidents, sports mishaps, or other traumatic events, cell-based treatments have emerged as a potential avenue for encouraging healing. Now, taking advantage of advances in 3D printing technology, researchers have created customized implants that may boost the power of cell-based therapies for repairing injured spinal cords.

Made of soft hydrogels that mimic spinal cord tissue, the implant pictured here measures just 2 millimeters across and is about as thick as a penny. It was specially designed to encourage healing in rats with spinal cord injuries. The tiny, open channels that surround the solid “H”-shaped core are designed to guide the growth of new neural extensions, keeping them aligned properly with the spinal cord.

When left on their own, neural cells have a tendency to grow haphazardly. But the 3D-printed implant is engineered to act as a scaffold, keeping new cells directed toward the goal of patching up the injured part of the spinal cord.

For the new work, an NIH-funded research team, led by Jacob Koffler, Wei Zhu, Shaochen Chen, and Mark Tuszynski of the University of California, San Diego (UCSD), used an innovative 3D printing technology called microscale continuous projection printing. This technology relies on a computer projection system and precisely controlled mirrors, which direct light into a solution containing photo-sensitive polymers and cells to produce the final product. Using this approach, the researchers fabricated finely detailed, rodent-sized implants in less than 2 seconds. That’s about 1,000 times faster than a traditional 3D printer!

In a study published recently in Nature Medicine, the researchers placed their custom-made implants, loaded with rat embryonic neural stem cells, into the injured spinal cords of 11 rats. Other rats with similar injuries received empty implants or stem cells without the implant. Within 5 months, rats with the cell-loaded implants had new neural cells bridging the injured area, along with spontaneous regrowth of blood vessels to feed the new neural tissue. Most importantly, they had regained use of their hind limbs. Animals receiving empty implants or cell-based therapy without an implant didn’t show that kind of recovery.

The new findings offer proof-of-principle that 3D printing technology can be used to create implants tailored to the precise shape and size of an injury. In fact, the researchers have already scaled up the process to produce 4-centimeter-sized implants to match several different, complex spinal cord injuries in humans. These implants were printed in a mere 10 minutes.

The UCSD team continues to work on further improvements, including the addition of growth factors or other ingredients that may further encourage neuron growth and functional recovery. If all goes well, the team hopes to launch human clinical trials of their cell-based treatments for spinal cord injury within a few years. And that should provide hope for the hundreds of thousands of people around the world who suffer serious spinal cord injuries each year.

Reference:

[1] Biomimetic 3D-printed scaffolds for spinal cord injury repair. Koffler J, Zhu W, Qu X, Platoshyn O, Dulin JN, Brock J, Graham L, Lu P, Sakamoto J, Marsala M, Chen S, Tuszynski MH. Nat Med. 2019 Feb;25(2):263-269.

Links:

Spinal Cord Injury Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Stem Cell Information (NIH)

Koffler Lab (University of California, San Diego)

Shaochen Chen (UCSD)

Tuszynski Lab (UCSD)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Child Health and Human Development


Taking Microfluidics to New Lengths

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Fiber Microfluidics

Caption: Microfluidic fiber sorting a solution containing either live or dead cells. The type of cell being imaged and the real time voltage (30v) is displayed at bottom. It is easy to imagine how this could be used to sort a mixture of live and dead cells. Credit: Yuan et al., PNAS

Microfluidics—the manipulation of fluids on a microscopic scale— has made it possible to produce “lab-on-a-chip” devices that detect, for instance, the presence of Ebola virus in a single drop of blood. Now, researchers hope to apply the precision of microfluidics to a much broader range of biomedical problems. Their secret? Move the microlab from chips to fibers.

To do this, an NIH-funded team builds microscopic channels into individual synthetic polymer fibers reaching 525 feet, or nearly two football fields long! As shown in this video, the team has already used such fibers to sort live cells from dead ones about 100 times faster than current methods, relying only on natural differences in the cells’ electrical properties. With further design and development, the new, fiber-based systems hold great promise for, among other things, improving kidney dialysis and detecting metastatic cancer cells in a patient’s bloodstream.


Wearable Scanner Tracks Brain Activity While Body Moves

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Credit: Wellcome Centre for Human Neuroimaging, University College London.

In recent years, researchers fueled by the BRAIN Initiative and many other NIH-supported efforts have made remarkable progress in mapping the human brain in all its amazing complexity. Now, a powerful new imaging technology promises to further transform our understanding [1]. This wearable scanner, for the first time, enables researchers to track neural activity in people in real-time as they do ordinary things—be it drinking tea, typing on a keyboard, talking to a friend, or even playing paddle ball.

This new so-called magnetoencephalography (MEG) brain scanner, which looks like a futuristic cross between a helmet and a hockey mask, is equipped with specialized “quantum” sensors. When placed directly on the scalp surface, these new MEG scanners can detect weak magnetic fields generated by electrical activity in the brain. While current brain scanners weigh in at nearly 1,000 pounds and require people to come to a special facility and remain absolutely still, the new system weighs less than 2 pounds and is capable of generating 3D images even when a person is making motions.


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