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Abstract:
A multidisciplinary team of investigators from Case Western Reserve University, Duke University and University of Massachusetts, Amherst, created an environment where magnetic particles suspended within a specialized liquid solution acted like molecular sheep dogs by nudging free-floating human cells to form chains in response to external magnetic fields.

Magnetic Nano-‘shepHErds’ Organize Cells

Cleveland, OH | Posted on April 1st, 2009

The power of magnetism could be an enabling technology to address a major problem facing bioengineers as they try to create new tissue—getting human cells to not only form structures, but to stimulate the growth of blood vessels to nourish their growth.

A multidisciplinary team of investigators from Case Western Reserve University, Duke University and University of Massachusetts, Amherst, created an environment where magnetic particles suspended within a specialized liquid solution acted like molecular sheep dogs by nudging free-floating human cells to form chains in response to external magnetic fields. These chains, the researchers said, could potentially be integrated into approaches for creating human tissues and organs.

These cells not only naturally adhere to each other upon contact, the researchers said, but the aligned cellular configurations formed may promote or accelerate the creation and growth of tiny blood vessels.

"The cells have receptors on their surfaces that have an affinity for other cells," said Melissa Krebs, third-year biomedical engineering graduate student at Case Western Reserve University Biomedical Engineering and first co-author of the "Formation of Ordered Cellular Structures in Suspension via Label-Free Negative Magnetophoresis," appearing online in advance of the May publication of Nano Letters, a journal published by the American Chemical Society. "They become sticky and attach to each other. When endothelial cells get together in a linear fashion, as they did in our experiments, it may help them to organize into tiny tubules."

Randall Erb, fourth-year graduate student in the laboratory of Benjamin Yellen, assistant professor of Mechanical Engineering and Materials Science, at Duke University's Pratt School of Engineering and Krebs' brother was co-first author of the study.

"We have developed an exciting way of using magnetism to manipulate human cells floating freely in a solution containing magnetic nanoparticles" said Erb. "This new cell assembly process holds much promise for tissue engineering research and offers a novel way to organize cells in an inexpensive, easily accessible way."

The iron-containing nanoparticles used by the researchers are suspended within a liquid known as a ferrofluid. One of the unique properties of these ferrofluids is that they become highly magnetized in the presence of external magnetism, which allows researchers to readily manipulate the chain formation by altering the strength of the magnetic field.

At the end of the process, the nanoparticles are simply washed away, leaving a linear chain of cells. That the cells remain alive, healthy, and relatively unaltered without any harmful effects from the process is one of the major advances of the new approach over other strategies using magnetism.

"Others have tried using magnetic particles either within or on the surface of the cells," Erb explained. "However, the iron in the nanoparticles can be toxic to cells. Also, the process of removing the nanoparticles afterward can be harmful to the cells and their function."

The key ingredient for these studies was the synthesis of non-toxic ferrofluids by colleagues Bappaditya Samanta and Vincent Rotello at the University of Massachusetts, who developed a method for coating the magnetic nanoparticles with bovine serum albumin (BSA), a protein derived from cow blood. BSA is a stable protein used in many experiments because it is biochemically inert. In these experiments, the BSA shielded the cells from the toxic iron.

"The other main benefit of our approach is that we are creating three-dimensional cell chains without any sophisticated techniques or equipment," Krebs said. "Any type of tissue we'd ultimately want to engineer will have to be three-dimensional."

For their experiments, the researchers used human umbilical vein endothelial cells. Others types of cells have also been used, and it appears to the researchers that this new approach can work with any type of cell.

"While still in the early stages, we have shown that we can form oriented cellular structures," said Eben Alsberg, assistant professor of Biomedical Engineering and Orthopaedic Surgery at Case Western Reserve and senior author of the paper. "The next step is to see if the spatial arrangement of these cells in three dimensions will promote vascular formation. A major current hurdle in tissue engineering is vascularization, and we hope that this technology may help to address the problem."

The research was supported by the National Institutes of Health, the National Science Foundation and Case Western Reserve University.

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About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and 15th largest among the nation’s medical schools for research funding from the National Institutes of Health. Eleven Nobel Laureates have been affiliated with the school.

The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching and in 2002, became the third medical school in history to receive a pre-eminent review from the national body responsible for accrediting the nation’s academic medical institutions. The School’s innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century.

Annually, the School of Medicine trains more than 600 M.D. and M.D./Ph.D. students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News and World Report Guide to Graduate Education. The School of Medicine’s primary clinical affiliate is University Hospitals and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic Foundation, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002.

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