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Insight & Intelligence™ : Oct 10, 2012

Tissue Engineering No Easy Cell

A new paradigm of medicine is taking hold with regenerative medicine at the forefront, but challenges still remain.
  • Alex Philippidis

Nina Tandon, Ph.D., dazzled attendees at the TEDx conference this summer by crystallizing years of recent research into an encouraging vision of a new paradigm of medicine she calls Body 3.0.

“There is a shift philosophically from the idea of, ‘Okay let’s build a hip,’ to, ‘Let’s build an environment like a fancy fish tank, so to speak’—we call them bioreactors—‘that allow cells to build a piece of bone themselves,’” said Dr. Tandon, senior fellow at Columbia University’s Lab for Stem Cells and Tissue Engineering.

While simple human tissue has been successfully grown and implanted into patients, researchers will need years to achieve similar successes with more complex tissues, especially the heart and liver: “Cardiac is probably much further down the line. It’s probably more like 15 to 20 years.”

Bioprinting

Dr. Tandon, an electrical and biochemical engineer whose research focuses on directing cell growth and differentiation through electrical signals, spoke with GEN about the challenges behind creating a heart from 3D bioprinted tissue. Researchers at Cornell University, for example, have printed cartilaginous meniscus and bone implants, and are working to print spinal disks and heart valves. And in 2010, Organovo introduced the first 3D bioprinter. Organovo does not yet sell its NovoGen MMX bioprinters but shares them with partners, corporate (Pfizer and United Therapeutics) and academic (Harvard Medical School and the Sanford Consortium for Regenerative Medicine).

A normal 3D printer, she noted, works by extruding hot ink a few microliters at a time, with the amount of material dictating the resolution for printing. That material cools off upon contact with whatever it is printing on, then hardens.

“You can’t burn cells. So you need to have materials that are soft at a temperature that’s okay with cells, and that’s hard at room temperature. Or you need hydrogels. Another thing that could be considered is using cold material in the extruder device” capable of gellating at room temperature, Dr. Tandon said. “What ends up being really tough is figuring out which hydrogels are appropriate for the cells, and that are also adaptable to that particular technology.”

“Just Like Growing a City”

Researchers agree engineered tissue could cut the cost of developing new drugs by giving researchers an alternative to animal tests, and that bone and cartilage engineering offer likely near-term success. They are simpler to construct, without the vasculature or metabolic demand required of more complex organs.

“It’s just like growing a city. You have to have the supply lines coming in and the supply lines coming out. So if you have a city of organisms that only need to eat every two weeks, as compared to a city of human beings, it’s going to be a lot easier to build that city,” Tracy Grikscheit, M.D., a pediatric surgeon and scientist focused on regenerative medicine and tissue engineering at The Saban Research Institute at Children’s Hospital Los Angeles, told GEN.

Dr. Grikscheit leads a research team focused on growing rat, mouse, and pig intestinal tissue in laboratory animals. After success growing intestinal tissue using donor cells, the lab is now studying how to develop in human patients the technique for seeding of scaffolds with cells.

Healthy intestines are removed from the animals, cut, and treated with enzymes and other compounds to form clusters of mixed cells, including cells in the connective tissue and stem cells in the intestine’s absorptive lining. The clusters are placed on a biodegradable polymer scaffold, orienting the lining to grow inward and supporting connective tissue including muscle and nerve, on the outside.

She said growing cells in a body versus a bioincubator offers the advantage of not having to recreate in vitro the body’s complicated signaling webs regulating growth factor release.

“If you want to get LGR5 intestinal stem cells to grow well, you have to buy a couple of thousand dollars of factors. You have to replace notch, noggin, and other growth factors that you have to put into the dish with the cells, and then you need to put them in at the exact right amounts to mimic what would happen physiologically,” Dr. Grikscheit said.

Challenges

Challenges range from accounting for blood supply, to ensuring volumes of available donor cells, to fostering cell growth without overdoing it. Dealing with human cells adds the complications of dealing with regulators.

“There are some technical and technological considerations in there. Once you’re able to address that, there are still going to be some regulatory issues, in terms of getting past the FDA with how much of this is a biologic, and how exactly do you address this for use in the patient?” Warren L. Grayson, Ph.D., an assistant professor in the department of biomechanical engineering at Johns Hopkins University (JHU), told GEN.

Dr. Grayson, who works at JHU’s Translational Tissue Engineering Center and Institute for NanoBioTechnology, was part of a team that published promising results last year in PLOS ONE on creating an in vitro model of vascularized bone by co-culturing human umbilical vein endothelial cells and human mesenchymal stem cells. In 2010, while at Columbia, he was part of a team that successfully engineered half-centimeter-long bones for the back of the jaw in vitro using human adipose-derived stem cells, decellularized bone scaffolds, and perfusion bioreactors. Details were published in Tissue Engineering Part A, a journal owned by GEN publisher Mary Ann Liebert, Inc.

Both groups were led by Gordana Vunjak-Novakovic, Ph.D, director of Columbia’s tissue engineering lab.

More recently, researchers led by Patrick Byrne, director of Johns Hopkins Medicine’s Center for Facial Plastic and Reconstructive Surgery, used cartilage from a 42-year-old woman’s ribs to craft an ear, around which was grown skin from her forearm, which was expanded using a saline-filled balloon. That ear was reattached to the woman’s head in January.

“Even with the obstacles of a) introducing vasculature, and b) using the cell types that are more abundant and available, we are actually much closer to that stage than we were a couple of years ago,” Dr. Grayson said.

Before widespread use of stem cells can be expected, researchers will need to address variability and scale, Susan L. Solomon, CEO and co-founder of The New York Stem Cell Foundation, told GEN. The foundation is building the NYSCF Global Stem Cell Array, a bank of 2,500 stem cell lines representing the genetic diversity of the United States and the world.

“When we’re talking about really getting into wide-scale use of stem cells for both creating new drugs and also cell therapy, that requires that we have large quantities and that they be uniform,” Solomon said.

Among those watching tissue engineering developments closely are pharma giants interested in successful in vitro models for tissue engineering, but hesitant to embrace models lacking broad support from researchers and regulators.

As Dr. Tandon correctly observes, this is an opportunity for academic and industry leaders to partner to address technical hurdles, much as the IEEE has long set tech standards: “What we’re talking about here is a transition of biology into information technology, using manufacturing technology. So it makes sense that we should look to information technology and how protocols were established between industry partners back then.”

For creating new tissue for humans, those protocols will need to cover cell supply and uniformity, the growing of cell tissue through bioprinting or scaffolding, and the implantation of tissue to maximize safety and efficacy. While there may be no getting around FDA, consensus academic-industry standards should save time and trouble that regulators might otherwise spend on rules that may unnecessarily hinder a technology with so much potential to save, or heal, so many lives.