Scaffolding to help mend a broken heart
Although medical advances over recent years have seen the majority of people surviving heart attacks, the damage done to the heart muscle is irreversible. As a result, most patients eventually succumb to congestive heart failure, the most common cause of death in developed countries. Stem cells offer hope for achieving what the human body can’t do: mending broken hearts. Now researchers have built a scaffold that supports the growth and integration of stem cell-derived cardiac muscles cells. The scaffold supports the growth of cardiac cells in the lab and encourages blood vessel growth in living animals.
The tiny tubular porous scaffold, built by engineers and physicians at the University of Washington (UW), supports and stabilizes the fragile cardiac cells and can be injected into a damaged heart, where it will foster cell growth and eventually dissolve away. The new scaffold not only supports cardiac muscle growth, but also potentially accelerates the body's ability to supply oxygen and nutrients to the transplanted tissue. Eventually, the idea is that doctors would seed the scaffold with stem cells from either the patient or a donor, then implant it when the patient is treated for a heart attack, before scar tissue has formed.
The use of scaffolds to help guide the growth of cells and tissue inside the body is a hot area of research. MIT researchers have demonstrated the effectiveness of a two-layer scaffold that can simulate bone and cartilage growth, while researchers at Columbia University have devised a tooth-shaped scaffold that would allow teeth to be grown inside a patient’s mouth. There are also other heart scaffolds or tissue patches currently being developed that combine cardiac muscle cells and two other types of cells needed to kick-start the growth of blood vessels and connective tissue. Preparing each type of cells is an enormous amount of work, so a scaffold that requires just one type of cell, like this one, would be significantly cheaper and easier to use.
Scaffold no "pore" substitute
The scaffold is a flexible polymer with interconnected pores all of the same size and includes channels to accommodate cardiac cells' preference for fusing together in long chains. Researchers first verified the design using chicken embryonic heart cells, and confirmed that the scaffold could support heart tissue growth at concentrations similar to those in living heart tissue.
They then seeded the scaffold with cardiac muscle cells derived from human embryonic stem cells. These cells survived and collected in the channels. Over five days, the cardiac muscle cells multiplied faster in the scaffold environment than other cell types, and could survive up to 300 micrometers (about the diameter of four human hairs) from the scaffold edge – an important point if the scaffold is to integrate with the body.
The cells expressed two proteins associated with muscle contraction and could contract with sufficient force to deform the scaffold.
Researchers also implanted a bare scaffold into a living rat's heart to verify the scaffold's biocompatibility. Results showed that after four weeks the heart had accepted the foreign body, and new blood vessels had penetrated into the scaffold.
Switching macrophage playing a part?
The researchers don’t know why the blood vessels penetrate so well. One hypothesis involves the macrophage, a cell in the immune system, and the size of the pores, which seems to be critical. The macrophages first attack the foreign body as an invader and try to digest it. They enter the pores and are themselves entrapped. At this point the macrophage seems to switch from its attack mode to its healing mode. The team is now investigating the blood vessel formation.Heart tissues need a rich blood supply, and that's been one of the limiting factors to heart repair and vascular tissue engineering, said co-author Chuck Murry, professor of pathology and bioengineering.
"The first thing that transplanted heart cells have to do is survive. And when you transition them from a culture dish to the body, initially they don't have a blood supply. So we have to promote the host blood supply as fast as possible," Murry said. "We're very optimistic that this scaffold will help keep the muscle cells alive after implantation and will help transition them to working heart muscles.”
The scaffold is made from a jelly-like hydrogel material developed by UW bioengineering doctoral student Lauran Madden. A needle is used to implant the tiny (third of a millimeter wide by 4 millimeters long) scaffold rods into the heart muscle. But the scaffold can support growth of larger clumps of heart tissue, Madden said.
The next steps will involve adjusting the scaffold degradation time so that the scaffold degrades at the same rate that cardiac cells proliferate and that blood vessels and support fibers grow in, and then implant a cell-laden scaffold into a damaged heart.
"What we have now is a really good system going in the dish, and we're working to transition it to in the body," Madden said.
A description of the scaffold is published this week in the Proceedings of the National Academy of Sciences.
Beat BioTherapeutics, a Seattle startup co-founded by lead author of the study and UW professor of bioengineering, Buddy Ratner, Murry and co-author Michael Laflamme, a UW assistant professor of pathology, plans to license the technology to help bring it to patients.