Regenerative Medicine Takes Giant Leaps

Regenerative medicine - implanting tissues and synthetic organs to replace their diseased and damaged natural equivalents - is a technology ready to break out. But it is also one that continues to search for ways to move into larger tests and commercial products.

That was a key takeaway from the Tissue Engineering and Regenerative Medicine Society (TERMIS) Americas meeting held in Charlotte, NC, December 3-6.

The need for new regenerative applications and solutions is critical. More than 100,000 people have signed up for kidney and liver transplants, and the number keeps rising. Many will die before they receive transplants, especially since many donated organs fail to meet minimum standards and others do not arrive soon enough to remain viable. Those who receive viable transplants are condemned to taking large amounts of immunosuppressants to prevent their bodies from attacking the implant.

Yet clinicians are making progress, Jason Werthheim, the vice chair of surgical research at Northwestern University’s Feinberg School of Medicine, said in a session that brought together clinicians to discuss the promise of regenerative medicine.

Werthheim pointed to the recent birth of a child born to a mother who had received a uterus transplant. This was made possible by advances in transplantation and implant management. Yet it raises ethical questions about condemning a woman to a life of immunosuppressant therapy to keep the transplanted uterus in her body.

Clearly, the best way is to transplant substitutes, tissues and organs grown from a patient’s own cells, which would not raise immune system issues.

For that to happen, researchers need to work with the Food and Drug Administration to develop standards, as well as a working definition of these new tissues. This would gain the credibility of the physician community and make it easier to put together the transdisciplinary teams needed to move the clinical aspects of the technology forward.

Those physicians are certainly paying attention.

“No one would have ever have imagined that regenerative medicine would be so safe,” said Kenton Gregory, a cardiologist director of the Center for Regenerative Medicine at Oregon Health & Science University in Portland. “I can’t think of a safer debut of new medical technology.”

It took 12 years, 30,000 to 40,000 patients, and $1 billion to prove balloon pump therapy works for the heart, he said. Today, firms are moving ahead with new trials for immune therapy and mesenchymal stem cell therapy for stroke. “They have learned valuable lessons from negative trials,” he said. “For example, we learned that we cannot just inject stem cells, we need to do more with them first. But there is a lot of enthusiasm for the field.”

For Gregory, the key barriers have to do with numbers. Most clinical trials involve so few patients, they cannot truly show efficacy.

“My patients are also more complicated,” he said. “They may have several conditions, and they are on other drugs. It will take time and money to do enough trials to unravel it all. We are going to need big investments from government and commercial partners. But once we get to multicenter clinical trials, more physicians will start investing in these projects.”

Julie Allickson, director of translational research at Wake Forest School of Medicine’s Institute for Regenerative Medicine, noted that only 15 products have received approval under FDA’s special approval route for cell therapy and tissues. She expects the number to grow rapidly.

The challenge, she said, is scaling up and automating production of these products. In part, that will depend on developing ways to grow, preserve, ship, and deliver cell therapy products and tissues in the same bioreactor. She cited news stories citing the enormous price of gene therapy, but noted there is no proven reimbursement model that makes these products available for everyone.

Peter Rubin, the chair of plastic surgery at University of Pittsburgh Medical Center, emphasized the importance of creating products that fit into existing best practices.

“Whatever you develop, it has to fit into an existing schema of clinical delivery,” he said. “Surgeons are trained to do things in a certain way and feel comfortable within it.

“And you have to take into account resource allocation and cost,” he added. “A lot of people are working in a big health system, and gone are the days when we would spend 400 percent more on product to get a new therapy into the clinic. Costs are a big issue.”

While many at TERMIS had big picture concerns, the meeting also highlighted technologies that might address them.

Stan Wadsworth, chief science officer of Aspect Biosystems, showed a 3D tissue printer that uses a microfluidic chip, similar to those found on lab-on-a-chip systems. It switches between materials on the fly, combining them with a cell-loaded fiber that forms layer after layer of populated scaffold to create a 3D tissue structure.

“The system lets you switch between different cell types and matrix materials, while varying the pressure to define the dimensions of the scaffold,” Wadsworth said. “Embedding the cells in the fiber protects them from shear forces that could damage them.”

Riccardo Gottardi of University of Pittsburgh’s Center for Cell and Molecular Engineering showed a bioreactor that can grow bone and cartilage joint constructs in a single chamber, and that is small enough for high-throughput screening. It would enable researchers to grow and test joints in a single bioreactor.

Ordinarily, bone and cartilage require different growth factors and conditions to develop, and so they cannot be grown together. The new bioreactor could make it possible to grow arrays of samples and test them to understand how joints develop, how joint diseases like osteoarthritis progress, and which drugs might halt this progression without causing damage elsewhere in the joint.

Cortes Williams, a graduate student at University of Oklahoma, modeled scaffolds, printed the models, and then scanned and mechanically tested them. He found that CAD models do not accurately predict scaffold properties. Shear is usually greater than expected, and when combined with scaffold roughness, leads to a greater variation in forces on cells growing within the scaffold.

Williams has developed a probability density function to improve predictability, and is working on a better way to model 3D printed scaffolds so scientists will have more control over their tissues.

Another approach to controlling shear comes from Josephine Lembong, from the Center for Engineering Complex Tissues at University of Maryland. It places cylindrical pillars on the flat bottom of a fluidic bioreactor platform. By controlling the flow and amount of actin in the media, she can use the pillars to distribute cells more evenly within the bioreactor.

Other presentations focused on new technologies for bioreactors, 3D tissue printers, laser-based scaffold generation, cell inks, and more. Overall, TERMIS Americas showed a technology on the rise, grappling with ways to move from lab-scale to large clinical trial and commercial production.

Read more about Cell Therapy on AABME.org.