Nanogel Delivers Cellular Patches To Damaged Hearts

Researchers can improve the effectiveness of stem cell therapy in mice with injured hearts by injecting the cells in a nanogel that mimics the supportive matrix of proteins found in natural tissue (ACS Nano 2014, DOI: 10.1021/nn504617g).

Such engineered tissue could patch areas where muscle has died during a heart attack, preventing heart failure without the need for an organ transplant. Stem cells, whether sourced from embryos or made by inducing adult cells to revert to an embryonic state, are the best starting point for engineering therapeutic heart tissue, says Kiwon Ban of Emory University School of Medicine, who is an author of the new study. Researchers have coaxed stem cells to develop into heart cells called cardiomyocytes and then transplanted them into animals. However, these cells can’t make it alone. Half of them die right after injection, and the survival rate is as low as 10% after one week. A second ingredient is necessary—some kind of biological mortar to hold them in place and support their development and integration into the body.

Biomaterials engineers have tried making several such cellular mortars, starting with natural proteins found in connective tissue, such as collagen. In the new study, the Emory researchers, led by cardiologist Young-sup Yoon, collaborated with biomaterials engineer Ho-Wook Jun of the University of Alabama, Birmingham, who previously had developed a self-assembling nanogel made up of two peptides.

The peptides each have a hydrophobic and a hydrophilic part; this drives them to form a nanostructured gel when mixed in water. The gel mimics the structure and mechanical properties of the natural extracellular matrix. One peptide acts like a natural protein that adheres to cells and promotes cell survival. The second peptide is readily broken down by a protease. The team designed the gel so that when it is implanted, it begins to degrade a bit, allowing cells from the body to migrate in. Eventually the gel should disintegrate completely as the heart tissue builds its own extracellular matrix. This particular gel has already performed well as a support for other kinds of cells grown from stem cells, including pancreatic and muscle cells.

The Emory researchers mixed the gel with cardiomyocytes derived from embryonic stem cells and injected this mixture into the hearts of mice with injuries simulating the damage caused by a heart attack. They compared the health and survival of the cells transplanted naked with the health of cells transplanted in the nanogel. As a further control, they also monitored mice that had been injected with a salt solution. After two weeks, mice treated with cells, whether in the gel or not, had better heart function on an echocardiogram than untreated mice. Animals injected with the cells in the nanogel continued to have strong cardiac function through the end of the 12-week experiment. But the health of mice treated with cells alone began to deteriorate after three weeks. Examining the mice’s hearts under the microscope after 14 weeks, the researchers found new cells integrating into the heart tissue in animals treated with the nanogel. In mice treated with naked cardiomyocytes, all the therapeutic cells were gone.

The new study demonstrates that in some respects the chemical engineers are ahead of the biologists in tissue engineering, says Richard T. Lee, a cardiologist who leads the cardiovascular program at the Harvard Stem Cell Institute. The methods for delivering cells are getting better, he says, but scientists still don’t know the best types of cells to deliver. The next step, Lee says, is to work on the cell biology to figure out which stage of stem cell development is optimal for transplants.