Bioengineering with New Materials

Heart attacks, stroke, and other medical conditions kill heart tissue. Researchers want to patch those dead areas with heart tissue regenerated outside the body. That would ordinarily involve open heart surgery. A new technology might let them do it with minimally invasive injections.

“We can build beautiful tissues in the lab,” said Milica Radisic, whose Functional Tissue Engineering Lab developed the technology. “But no one will use them if they cannot deliver them that way.”

Radisic and surgeons at Toronto’s Hospital for Sick Children have shown that the patches improved rat heart function after heart attacks. They also showed that they could apply patches to the heart, aorta, and liver of pigs.

First, they squeeze the 10-mm x 10-mm bandage-shaped patch into a tapered needle. Surgeons insert the needle into the chest through a small incision called a keyhole. As soon as the patch exits the needle’s 1-mm-diameter opening, it deploys to full size.

Radisic originally planned to suture the patch onto the heart, but the keyhole was too small. “It was not a super user-friendly procedure,” she said. Instead, her team coats the heart with glue derived from fibrin, a blood-clotting protein and the patch with thrombin, an enzyme that promotes clotting. When the two meet, they cross-link to form a strong bond.

Everything depends on the patch material. It must be biocompatible and biodegradable, so it disappears as the cells regenerate heart muscle. It must also have enough elasticity to deform with a beating heart. A polymer Radisic had previously developed, poly(octamethylene maleate (anhydride) citrate), meets those criteria.

Her team then built a polymer scaffold on which to grow cells. They created a tiny, intricate, three-dimensional structure by using semiconductor technology to fabricate those patterns on silicon, then using the wafer to mold the polymer.

Radisic wanted to squeeze the 100-square-millimeter scaffold through 1-mm-diameter needle opening and have it pop open. Shape memory polymers, whose chemistry causes them to shift shape when temperatures change, can do this, but they did not have the other properties she needed.

Instead, her team developed a way to do this physically. She built a diamond-shaped lattice that stores energy like a spring when compressed into the scaffold. Coating the cells with collagen, a protein found in connective tissue, enabled them to survive their journey through the needle.

Radisic’s approach to injectable scaffolds—shape memory properties without shape memory chemistry—could revolutionize how physicians deliver regenerated tissue for body repair. Her lab has applied for patents on the invention, and plans to test the patch on the liver and other organs.

The lab is also developing other technologies, including the AngioChip, a 3-D scaffold that includes blood vessels fabricated from a silicon mold. When seeded with heart cells, it organizes into a beating mini-heart that physicians can use to test new types of heart drugs. Radisic has founded a company, TARA Biosystems, to commercialize the technology.

Fantastic Voyage for Drugs

Joseph Wang, director of UC San Diego’s Laboratory for Nanobioelectronics, refers to the 1966 movie "Fantastic Voyage" in his presentations. While he cannot shrink a submarine to navigate the bloodstream, he has created micromotors that deliver medicine directly to the stomach lining.

Wang worked with UCSD’s Liangfang Zhang to develop the micromotors. Post-doctoral researcher Berta Esteban Fernandez de Avila then showed that micromotors could reduce infections by an ulcer-causing bacterium, Helicobacter pylori, in rats slightly better than conventional therapy.

Conventional drugs to treat H. pylori infections don’t work in the stomach’s acid environment. Doctors typically give patients proton pump inhibitors to reduce acidity, but they can cause headaches, diarrhea, fatigue, and even anxiety or depression.

The micromotors solve the problem by neutralizing stomach acid and delivering drugs directly to the bacteria that line the stomach, Esteban said.

The micromotors start as magnesium particles on a glass tray. Esteban uses atomic layer deposition to coat millions of particles at a time with titanium dioxide. About 20 percent of the particle’s surface facing the tray remains uncoated. She then chemically coats the particles with an antibiotic mixed with chitosan, a natural sugar. The final micromotor is half as wide as a strand of human hair.

When a micromotor enters the stomach, the exposed magnesium reacts with gastric acid to release hydrogen. This propels it around the stomach while the reaction neutralizes the acid. As acidity falls, the stomach lining becomes more negatively charged. This attracts the positively-charged chitosan, which binds to the stomach wall to deliver its medicine.

While atomic layer deposition is relatively expensive, it produces many doses at a time. Esteban’s next steps are to optimize the system and compare it against standard ulcer therapies. She also plans to test drug combinations that treat several diseases at once in both the stomach and intestinal tract.

Meanwhile, the lab is developing diagnostic micromotors that work in the body and detect poisons on marshy ground. It has also developed ultrasound-activated motors that can break up blood clots.