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Stanford-developed collagen patch speeds repair of damaged heart tissue in mice

STANFORD, Calif. -- You can't resurrect a dead cell anymore than you can breathe life into a brick, regardless of what you may have gleaned from zombie movies and Dr. Frankenstein. So when heart cells die from lack of blood flow during a heart attack, replacing those dead cells is vital to the heart muscle's recovery.

But muscle tissue in the adult human heart has a limited capacity to heal, which has spurred researchers to try to give the healing process a boost. Various methods of transplanting healthy cells into a damaged heart have been tried, but have yet to yield consistent success in promoting healing.

Now, researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital have developed a patch composed of structurally modified collagen that can be grafted onto damaged heart tissue. Their studies in mice have demonstrated that the patch not only speeds generation of new cells and blood vessels in the damaged area, it also limits the degree of tissue damage resulting from the original trauma.

The key, according to Pilar Ruiz-Lozano, PhD, associate professor of pediatrics, is that the patch doesn't seek to replace the dead heart-muscle cells. Instead, it replaces the epicardium, the outer layer of heart tissue, which is not muscle tissue, but which protects and supports the heart muscle, or myocardium.

"This synthetic tissue has the mechanical properties of the embryonic epicardium," said Ruiz-Lozano, who is the senior author of a study that describes the researchers' findings. The study will be published online Aug. 29 in Biomaterials. Vahid Serpooshan, PhD, a postdoctoral scholar in cardiology, is the lead author.

Embryonic epicardium is significantly more flexible than adult epicardium, but more rigid and structured than existing materials, making it more conducive to growth of new tissue. "We paid tremendous attention to the physical properties of the materials and how their elasticity could modify the function of the heart," Ruiz-Lozano said.

The epicardium - or its artificial replacement - has to allow the cell migration and proliferation needed to rebuild damaged tissue, as well as be sufficiently permeable to allow nutrients and cellular waste to pass through the network of blood vessels that weaves through it. The mesh-like structure of collagen fibers in the patch has those attributes, serving to support and guide new growth. Like sugar snap pea vines climbing a garden trellis, blood vessels spread through the interlacing fibers of the patch, blossoming new muscle cells like peapods as they proliferate.

Collagen is a fibrous protein found in connective tissue, including skin, bone, cartilage and tendons, as well as in the epicardium. Because the patch is made of acellular collagen, meaning it contains no cells, recipient animals do not need to be immunosuppressed to avoid rejection. With time, the collagen gets absorbed into the organ.

Compared with control mice that received no patch, mice that were given the patch promptly after experiencing a surgically induced heart attack showed significant improvement in overall cardiac function in echocardiograms two weeks later. The patched hearts showed more migration of cells to the site of the injury four weeks after patch implantation. The new cells were present both in the patch and in the adjacent damaged heart tissue.

The patched hearts also had greater development of new blood vessels, which appeared to have improved delivery of oxygen and nutrients to the tissue, thus reducing the number of cells that perished compared to unpatched hearts.

In addition to helping heart tissue regenerate, the patch could be used as a delivery system for getting medications or stem cells into a patient, Ruiz- Lozano said.

Daniel Bernstein, MD, professor of pediatric cardiology and a co-author of the paper, said the potential of the patch as a delivery system could make it useful in treating children with heart problems.

"For pediatric patients with congenital heart disease, or who have heart damage from a viral infection or other heart injury, we could use this to introduce growth factors directly to the heart in a way that would persist for a long period of time," he said.

Ruiz-Lozano and her colleagues are already at work on studies to explore the use of the patch as a delivery system, along with conducting studies of how the patch will perform in larger animals.

Other Stanford authors of the study are staff scientist Mingming Zhao; postdoctoral scholars Scott Metzler, PhD, Andrew Wang, PhD, and Andrey Malkovskiy, PhD; Ke Wei, a research assistant in pulmonary and critical care medicine; Parisha Shah, manager of Ruiz-Lozano's laboratory; visiting scholar Morteza Mahmoudi; Jayakumar Rajadas, PhD, director of the Biomaterials and Advanced Drug Delivery Laboratory; and Manish Butte, MD, PhD, assistant professor of pediatrics.
The study was funded by the National Institutes of Health (grants HL65484, HL086879, HL061535 and K08 AI079268), the California Institute for Regenerative Medicine, the Oak Foundation, Stanford's Bio-X program and the National Science Foundation.

Authors

About Stanford Children’s Health and Lucile Packard Children’s Hospital Stanford
Stanford Children’s Health, with Lucile Packard Children’s Hospital Stanford at its core, is an internationally recognized leader in world-class, nurturing care and extraordinary outcomes in every pediatric and obstetric specialty from the routine to rare, for every child and pregnant woman. Together with our Stanford Medicine physicians, nurses, and staff, we deliver this innovative care and research through partnerships, collaborations, outreach, specialty clinics and primary care practices at more than 100 locations in the U.S. western region. As a non-profit, we are committed to supporting our community – from caring for uninsured or underinsured kids, homeless teens and pregnant moms, to helping re-establish school nurse positions in local schools. Learn more about our full range of preeminent programs and network of care at stanfordchildrens.org, and on our Healthier, Happy Lives blog. Join us on Facebook, Twitter, LinkedIn, and YouTube.

Lucile Packard Children’s Hospital Stanford is the heart of Stanford Children’s Health, and is one of the nation’s top hospitals for the care of children and expectant mothers. For a decade, we have received the highest specialty rankings of any Northern California children’s hospital, according to U.S. News & World Report’s 2014-15 Best Children’s Hospitals survey, and are the only hospital in Northern California to receive the national 2013 Leapfrog Group Top Children’s Hospital award for quality and patient care safety. Discover more at stanfordchildrens.org.

About Stanford University School of Medicine
The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.