

Printed tissue could vastly improve drug testing




Living cells may literally die before the tissue gets off the printer table.



Liver tissue printed in a petri dish. (Image: Organovo)



The liver tissue model that Organovo plans to release next year is for research use only and will be used in the laboratory for medical studies and drug research. That's important in its own right: Developing a new drug costs, on average, $1.2 billion and takes 12 years.

Organovo has as yet not released any information on possible future implantable organs. Any such initiative would have to undergo rigorous government review before being approved for clinical purposes.

Still, the creation of a viable liver is a watershed moment for the bio-printing industry and medicine because it proves 3D printed tissue can be kept alive long enough to test the effects of drugs on it or implant it in a human body where it can further develop.

"It is too early to speculate on the breadth of applications that tissue engineering will ultimately deliver or on the efficacy that will be achieved," Renard said.

That question, Renard said, can only be answered through continued successful tissue development and the completion of clinical trials, followed by a review by the Food and Drug Administration (FDA) -- a process that can take three to 10 years.

To spur on the development of bio-printed organs, the Methuselah Foundation, a Springfield, Va.-based not-for-profit that supports regenerative medicine research, this month announced a $1 million prize for the first organization to print a fully functioning liver.

Currently, there are about 120,000 people on the organ waiting list in the U.S., and even those who receive a donated organ face the prospect of ongoing medical challenges because of organ rejection issues. However, if a patient's own stem cells could be used to regenerate a living organ, rejection would become moot.

Research into whole organ regeneration currently receives less than $500 million in funding a year in the U.S., compared to $5 billion for cancer research and $2.8 billion for HIV and AIDS, the Methuselah Foundation said in its contest announcement. "Regenerative medicine is the future of healthcare, but right now the field is falling through the cracks," said Methuselah CEO David Gobel.

Organs on a chip

While it may be a decade or more before human trials for organ transplants are approved by the FDA, the creation of organ tissue still holds the prospect of revolutionizing medicine.

Printing out sustainable organ tissue could allow pharmaceutical companies to develop and test drugs on human and not animal organs. Using human tissue yields more accurate results.

Researchers are now experimenting with laying down a thin layer of human tissue from any number of organs for pharmaceutical development. The process is known as creating an "organ on a chip" or a "human on a chip."

Scientists have for years been able manually grow thin skin tissue for temporary skin grafts that act as a type of bandage while the body heals itself. However, 3D printing has advanced that process.

Instead of the arduous task of manually laying down cells, 3D printing automates the process in an exact and repeatable way using a syringe on the end of a robotic mechanism guided by computer-aided design (CAD) software.

"Using 3D printing has given us the reproducibility and the automation needed to scale up," said Jordan Miller, assistant professor of bioengineering at Rice University. Miller recently helped open a microfabrication lab at Rice University after spending years in a similar lab at the University of Pennsylvania's department of bioengineering.

The key to creating viable, living tissue is first understanding how it works.

As much as scientists know about the human body, the way tissue is formed at the cellular and sub-cellular level is still in large part a mystery. There are about 40 different cell types that make up a human liver, including Kupffer cells for removing debris from the blood, stellate cells for regenerating tissue that has died or been injured, and sinusoidal endothelial cells, which make up the interior surface of blood vessels and lymphatic vessels.

3D printed breast tissue could someday help to reconstruct breasts in cancer survivors. (Image: TeVido BioDevices)

"It's a complicated challenge," Miller said. "We don't know all the structures in the body. We're still learning. So we don't know to what extent we need to reconstitute all those features. We have some evidence that we may not need to re-create all those functions."

Miller and others believe that if they reconstitute a portion of tissue, even if it's not complete, there's a good chance it will continue to grow into a fully functioning organ once implanted in the body.

"We've had some success in thin tissues, skin, corneas and bladder," Miller said. "It gets more complicated when you're talking about biochemical functions in the liver or kidney. Those are fragile cells that don't do well in labs. Some of the most interesting cells we want to print are hardest to keep alive."

Instead of printing cells 10 layers deep, as might be needed for a skin graft, researchers are attempting to print cells 5,000 or 10,000 layers deep, Miller said.

Just add sugar and water, and voila -- blood vessels

In order to print thick tissues, scientists must also be able to create the vascular system needed for sustainability.

One approach with 3D printing has been to print out a temporary "scaffolding" made of sugar glass (a sugar-and-water combination) that can act as a mold to support cells that eventually form blood vessels. It's similar to the way a bronze statue is created: First the mold is formed, then filled with metal. In this case, living cells are used instead of metal.

Miller and others have had some success re-creating those vascular structures through the use of sugar glass -- the same substance that's used to make easily breakable bottles and windows for stunts in movies.

"You start with a template, cast it and then melt [the sugar glass] out, leaving the vascular structure behind," Miller said. "Sugar is great because it's very rigid."

Using sugar glass as the scaffolding, Miller and his team of researchers have had some success in re-creating liver tissue. To date, the researchers have been able to create a piece of tissue the size of a thumbnail and keep it alive for two weeks.

Replacing ears and breasts

Earlier this year, researchers at Princeton University created a functional ear using a modified $1,000 ink-jet printer. They said the ear they created has the potential to hear radio frequencies far beyond the range of normal human capability because the tissue was combined with electronics as it grew in a petri dish.

Princeton University's "bionic ear" was initially printed into a petri dish using a modified ink-jet printer. (Image: Princeton University)

The researchers laid down 3D printed cells and structural nanoparticles to build the ear. A cell culture was used to combine a small coil antenna with cartilage, creating what the scientists called a "bionic ear."

Scott Collins, CTO and vice president of research and development at bio-printing company TeVido BioDevices, said his firm is in the early-stages of using 3D bio-printing of live cells to build custom implants and grafts for breast cancer survivors.

This year alone, about 300,000 women in the U.S. will be diagnosed with breast cancer and up to 60% of them will choose a lumpectomy. According to TeVido BioDevices, at least 25% of women who undergo lumpectomies are dissatisfied with their physical appearance after the operation.

TeVido is developing an implant from fat and skin cells as well as working to print nipples and the surrounding areola using the patient's own cells. That way, the tissue won't be rejected and will have natural shape and pigmentation.

"Today, we have ways of implanting the breast mound, but as far as rebuilding nipple and areola, it doesn't work well," Collins said. "The pigment is just tattooed on and fades over time."


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This story, "The first 3D printed organ -- a liver -- is expected in 2014" was originally published by Computerworld.

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