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tissue engineering

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


Moving Closer to a Stem Cell-Based Treatment for AMD

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In recent years, researchers have figured out how to take a person’s skin or blood cells and turn them into induced pluripotent stem cells (iPSCs) that offer tremendous potential for regenerative medicine. Still, it’s been a challenge to devise safe and effective ways to move this discovery from the lab into the clinic. That’s why I’m pleased to highlight progress toward using iPSC technology to treat a major cause of vision loss: age-related macular degeneration (AMD).

In the new work, researchers from NIH’s National Eye Institute developed iPSCs from blood-forming stem cells isolated from blood donated by people with advanced AMD [1]. Next, these iPSCs were exposed to a variety of growth factors and placed on supportive scaffold that encouraged them to develop into healthy retinal pigment epithelium (RPE) tissue, which nurtures the light-sensing cells in the eye’s retina. The researchers went on to show that their lab-grown RPE patch could be transplanted safely into animal models of AMD, preventing blindness in the animals.

This preclinical work will now serve as the foundation for a safety trial of iPSC-derived RPE transplants in 12 human volunteers who have already suffered vision loss due to the more common “dry” form of AMD, for which there is currently no approved treatment. If all goes well, the NIH-led trial may begin enrolling patients as soon as this year.

Risk factors for AMD include a combination of genetic and environmental factors, including age and smoking. Currently, more than 2 million Americans have vision-threatening AMD, with millions more having early signs of the disease [2].

AMD involves progressive damage to the macula, an area of the retina about the size of a pinhead, made up of millions of light-sensing cells that generate our sharp, central vision. Though the exact causes of AMD are unknown, RPE cells early on become inflamed and lose their ability to clear away debris from the retina. This leads to more inflammation and progressive cell death.

As RPE cells are lost during the “dry” phase of the disease, light-sensing cells in the macula also start to die and reduce central vision. In some people, abnormal, leaky blood vessels will form near the macula, called “wet” AMD, spilling fluid and blood under the retina and causing significant vision loss. “Wet” AMD has approved treatments. “Dry” AMD does not.

But, advances in iPSC technology have brought hope that it might one day be possible to shore up degenerating RPE in those with dry AMD, halting the death of light-sensing cells and vision loss. In fact, preliminary studies conducted in Japan explored ways to deliver replacement RPE to the retina [3]. Though progress was made, those studies highlighted the need for more reliable ways to produce replacement RPE from a patient’s own cells. The Japanese program also raised concerns that iPSCs derived from people with AMD might be prone to cancer-causing genomic changes.

With these challenges in mind, the NEI team led by Kapil Bharti and Ruchi Sharma have designed a more robust process to produce RPE tissue suitable for testing in people. As described in Science Translational Medicine, they’ve come up with a three-step process.

Rather than using fibroblast cells from skin as others had done, Bharti and Sharma’s team started with blood-forming stem cells from three AMD patients. They reprogrammed those cells into “banks” of iPSCs containing multiple different clones, carefully screening them to ensure that they were free of potentially cancer-causing changes.

Next, those iPSCs were exposed to a special blend of growth factors to transform them into RPE tissue. That recipe has been pursued by other groups for a while, but needed to be particularly precise for this human application. In order for the tissue to function properly in the retina, the cells must assemble into a uniform sheet, just one-cell thick, and align facing in the same direction.

So, the researchers developed a specially designed scaffold made of biodegradable polymer nanofibers. That scaffold helps to ensure that the cells orient themselves correctly, while also lending strength for surgical transplantation. By spreading a single layer of iPSC-derived RPE progenitors onto their scaffolds and treating it with just the right growth factors, the researchers showed they could produce an RPE patch ready for the clinic in about 10 weeks.

To test the viability of the RPE patch, the researchers first transplanted a tiny version (containing about 2,500 RPE cells) into the eyes of a rat with a compromised immune system, which enables human cells to survive. By 10 weeks after surgery, the human replacement tissue had integrated into the animals’ retinas with no signs of toxicity.

Next, the researchers tested a larger RPE patch (containing 70,000 cells) in pigs with an AMD-like condition. This patch is the same size the researchers ultimately would expect to use in people. Ten weeks after surgery, the RPE patch had integrated into the animals’ eyes, where it protected the light-sensing cells that are so critical for vision, preventing blindness.

These results provide encouraging evidence that the iPSC approach to treating dry AMD should be both safe and effective. But only a well-designed human clinical trial, with all the appropriate prior oversights to be sure the benefits justify the risks, will prove whether or not this bold approach might be the solution to blindness faced by millions of people in the future.

As the U.S. population ages, the number of people with advanced AMD is expected to rise. With continued progress in treatment and prevention, including iPSC technology and many other promising approaches, the hope is that more people with AMD will retain healthy vision for a lifetime.

References:

[1] Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sharma R, Khristov V, Rising A, Jha BS, Dejene R, Hotaling N, Li Y, Stoddard J, Stankewicz C, Wan Q, Zhang C, Campos MM, Miyagishima KJ, McGaughey D, Villasmil R, Mattapallil M, Stanzel B, Qian H, Wong W, Chase L, Charles S, McGill T, Miller S, Maminishkis A, Amaral J, Bharti K. Sci Transl Med. 2019 Jan 16;11(475).

[2] Age-Related Macular Degeneration, National Eye Institute.

[3] Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Takasu N, Ogawa S, Yamanaka S, Takahashi M, et al. N Engl J Med. 2017 Mar 16;376(11):1038-1046.

Links:

Facts About Age-Related Macular Degeneration (National Eye Institute/NIH)

Stem Cell-Based Treatment Used to Prevent Blindness in Animal Models of Retinal Degeneration (National Eye Institute/NIH)

Kapil Bharti (NEI)

NIH Support: National Eye Institute; Common Fund


Putting Bone Metastasis in the Spotlight

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When cancers spread, or metastasize, from one part of the body to another, bone is a frequent and potentially devastating destination. Now, as you can see in this video, an NIH-funded research team has developed a new system that hopefully will provide us with a better understanding of what goes on when cancer cells invade bone.

In this 3D cross-section, you see the nuclei (green) and cytoplasm (red) of human prostate cancer cells growing inside a bioengineered construct of mouse bone (blue-green) that’s been placed in a mouse. The new system features an imaging window positioned next to the new bone, which enabled the researchers to produce the first series of direct, real-time micrographs of cancer cells eroding the interior of bone.


The Science of Saliva

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Artificial salivary glands

Credit: Swati Pradhan-Bhatt, Christiana Care Health System, Newark, DE

Whether it’s salmon sizzling on the grill or pizza fresh from the oven, you probably have a favorite food that makes your mouth water. But what if your mouth couldn’t water—couldn’t make enough saliva? When salivary glands stop working and the mouth becomes dry, either from disease or as a side effect of medical treatment, the once-routine act of eating can become a major challenge.

To help such people, researchers are now trying to engineer replacement salivary glands. While the research is still in the early stages, this image captures a crucial first step in the process: generating 3D structures of saliva-secreting cells (yellow). When grown on a scaffold of biocompatible polymers infused with factors to encourage development, these cells cluster into spherical structures similar to those seen in salivary glands. And they don’t just look like salivary cells, they act like them, producing the distinctive enzyme in saliva, alpha amylase (blue).


Snapshots of Life: Healing Spinal Cord Injuries

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Nerve cell on a nanofiber gel

Credit: Mark McClendon, Zaida Alvarez Pinto, Samuel I. Stupp, Northwestern University, Evanston, IL

When someone suffers a fully severed spinal cord, it’s considered highly unlikely the injury will heal on its own. That’s because the spinal cord’s neural tissue is notorious for its inability to bridge large gaps and reconnect in ways that restore vital functions. But the image above is a hopeful sight that one day that could change.

Here, a mouse neural stem cell  (blue and green) sits in a lab dish, atop a special gel containing a mat of synthetic nanofibers (purple). The cell is growing and sending out spindly appendages, called axons (green), in an attempt to re-establish connections with other nearby nerve cells.


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