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Date: 20 April 2014
Researchers develop a new "nanobiotechnology" that enables magnetic control of events at the cellular level  

Topic Name: Researchers develop a new "nanobiotechnology" that enables magnetic control of events at the cellular level
Category: Nanobiotechnology
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Research persons: Don Ingber, MD, PhD, Robert Mannix, PhD

Location: Children's Hospital Boston, United States


Researchers develop a new

Researchers at Children's Hospital Boston have developed a new "nanobiotechnology" that enables magnetic control of events at the cellular level. They describe the technology, which could lead to finely-tuned but noninvasive treatments for disease, in the January issue of Nature
(published online January 3).

Don Ingber, MD, PhD
, and Robert Mannix, PhD, of Children's program in Vascular Biology, in collaboration with Mara Prentiss, PhD, a physicist at
Harvard University, devised a way to get tiny beads--30 nanometers (billionths of a meter) in diameter--to bind to receptor molecules on the cell surface. When exposed to a magnetic field, the beads themselves become magnets, and pull together through magnetic attraction. This pull drags the cell's receptors into large clusters, mimicking what happens when drugs or other molecules bind to them. This clustering, in turn, activates the receptors, triggering a cascade of biochemical signals that influence different cell functions.
The technology could lead to non-invasive ways of controlling drug release or physiologic processes such as heart rhythms and muscle contractions, says Ingber, the study's senior investigator. More importantly, it represents the first time magnetism has been used to harness specific cellular signaling systems normally used by hormones or other natural molecules.
"This technology allows us to control the behavior of living cells through magnetic forces rather than chemicals or hormones," says Ingber. "It may provide a new way to interface with machines or computers in the future, opening up entirely new ways of controlling drug delivery, or making detectors that have living cells as component parts. We've harnessed a biological control system, but we can control it at will, using magnetic forces." 
In a demonstration involving mast cells (a kind of cell in the immune
), Ingber and Mannix showed that the beads, when bound to cell receptors and exposed to a magnetic field, were able to stimulate an influx of calcium into the cells. (Calcium influx is a fundamental signal used by nerve cells to initiate nerve conduction, by heart and muscle cells to stimulate contractions and by other cells for secretion.) Magnetic fields alone, without the beads, had no effect.
The beads--30-nm size (with an inner 5-nm particle) provides the optimal crystal geometry to make them "superparamagnetic"--able to be magnetized and demagnetized over and over, notes Mannix, who shares first authorship of the paper with Sanjay Kumar, MD, PhD of Children's. (Kumar is now a faculty member in Bioengineering at the University of California at Berkeley.) To give a sense of scale, one nanometer is to a meter (about a yard) as one blueberry is to the diameter of the Earth.
The beads were made to attach to the mast-cell receptors by pre-coating them with antigens; these antigens then bound to antibodies that coated the receptors, similar to the way antibodies bind to antigens in the immune system. "Our goal was to have one antigen coating each bead, so that each bead would bind to just one receptor," Mannix says.
As an accompanying News & Views article notes, "scaling down the interactions to single receptors demonstrates unprecedented control at the individual protein level."
Electrical stimuli have been used to influence the activity of nerve cells, but isn't effective in cells that aren't electrically excitable by nature, the researchers note. The advantage of a "nanomagnetic" control system is that it can be used in a broad range of cell types and provides a near-instantaneous on-off switch, unlike hormones and chemicals that can take minutes to hours to act and then may linger in the body. In addition, magnets can be portable and have low power requirements, allowing their use in the military and other mobile situations. 
Ingber envisions a kind of pacemaker that would involve an injection of nanoparticles into the heart that could then be controlled magnetically. "You could make those cells responsive to magnetic forces that work through the skin, rather than having to do surgical implants or place wires," he speculates.
"You could also have a pacemaker for muscles in different parts of your body, or a pacemaker for producing hormones or insulin," Ingber adds. "If you're a diabetic, you could have cells that produce insulin put under your skin, and then inject nanoparticles that go to those cells. Then, when you have a meal and need more insulin, you could just use a magnet to cause the cells to produce more. So you wouldn't have to keep buying the drug and injecting it."
The nanomagnetic system could also interface with external instruments and computer controls that take in information from the body or the surrounding environment and activate the magnet as needed, Ingber adds. 
A diabetic, for example, could have a transdermal glucose sensor that controls the magnet, which then controls the insulin production by itself. In the neonatal intensive care unit, sick newborns could have their heart and breathing rates monitored and their cells rigged to respond through magnetic stimulation, without a tangle of wires and probes. Or, on the battlefield, the magnet could trigger production of an antidote when a toxin or infectious agent is sensed in the environment.
But these examples are just theoretical. "The applications are hard to define because we're opening up a whole new area of control that never existed before," Ingber says.
Note for Nanobiotechnology
Nanobiotechnology is the branch of nanotechnology with biological and biochemical applications or uses. Nanobiotechnology often studies existing elements of nature in order to fabricate new devices. The term bionanotechnology is often used interchangeably with nanobiotechnology, though a distinction is sometimes drawn between the two. If the two are distinguished, nanobiotechnology usually refers to the use of nanotechnology to further the goals of biotechnology, while bionanotechnology might refer to any overlap between biology and nanotechnology, including the use of biomolecules as part of or as an inspiration for nanotechnological devices.
Note for Superparamagnetism
Superparamagnetism is a phenomenon by which magnetic materials may exhibit a behavior similar to paramagnetism even when at temperatures below the Curie or the Néel temperature. This is a small length-scale phenomenon, where the energy required to change the direction of the magnetic moment of a particle is comparable to the ambient thermal energy. At this point, the rate at which the particles will randomly reverse direction becomes significant.
Superparamagnetism occurs when the material is composed of very small crystallites (1–10 nm). In this case even when the temperature is below the Curie or Neel temperature (and hence the thermal energy is not sufficient to overcome the coupling forces between neighboring atoms), the thermal energy is sufficient to change the direction of magnetization of the entire crystallite. The resulting fluctuations in the direction of magnetization cause the magnetic field to average to zero. Thus the material behaves in a manner similar to paramagnetism, except that instead of each individual atom being independently influenced by an external magnetic field, the magnetic moment of the entire crystallite tends to align with the magnetic field.
Note for Nanoparticle
A nanoparticle (or nanopowder or nanocluster or nanocrystal) is a small particle with at least one dimension less than 100 nm. Nanoparticle research is currently an area of intense scientific research, due to a wide variety of potential applications in biomedical, optical, and electronic fields. The National Nanotechnology Initiative of the United States government has driven huge amounts of state funding exclusively for nanoparticle research.
Nanoparticles are of great scientific interest as they are effectively a bridge between bulk materials and atomic or molecular structures. A bulk material should have constant physical properties regardless of its size, but at the nano-scale this is often not the case. Size-dependent properties are observed such as quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials.
The study was supported by a Defense Advanced Research Projects Agency (DARPA) grant from the
Department of Defense and an
NIH postdoctoral fellowship.
In figure 1, At left, cells were pre-coated with tiny magnetic beads, each binding to a cell receptor (see arrows). When a magnetic field is applied (at right), the beads become magnets and cluster together, pulling the receptors with them. This clustering mimics what happens when drugs or other molecules bind to the receptors, triggering the same biochemical responses in the cell.

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