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Figure A is a scanning electron microscopy image of a cluster of biocontainer cubes.
Figures B through D show some of the stages in the cube-manufacturing process. Each cube is created as a flat pattern of six squares (B), which are then joined by a soldering process. The solder forms hinges (C), which are folded to make a three-dimensional cube (D).
Researchers at The Johns Hopkins University (Baltimore) have developed microcontainers as a new platform for drug delivery, cell encapsulation, and gene therapy. Using the devices, doctors would be able to treat an illness by implanting the containers at a diseased or injured site. Doctors could also track these very small boxes using magnetic resonance imaging (MRI). If researchers integrate electronics into the technology, the cubes could be remotely controlled and used as biosensors in the body.
The team's immediate medical goals are to use the technology for cell-encapsulated therapy and remote-controlled chemical release. According to David Gracias, PhD, current cell encapsulation methods involve hydrogel- or sponge-based plastic devices. The metal containers that Gracias's team is using are more mechanically and chemically stable. “In this application, you don't want a plastic that biodegrades or else the encapsulated cells will be exposed to the outside environment directly,” says Gracias, an assistant professor in the Johns Hopkins department of chemical and bio-molecular engineering. The therapy could be used for a range of conditions, such as Parkinson's disease, or to release dopamine.
The metallic composition of the microcontainers is one of their most beneficial features. Metals, because of their electrical properties, can interact with electromagnetic fields. Using such fields, Gracias hopes to remotely control the containers and release their contents.
The researchers made the self-assembling boxes by using thin-film deposition, photolithography, and electrodeposition techniques to create a flat pattern of six squares. Metallic solder forms the hinges on the edges of the squares. Then the flat part is heated, causing the hinges to melt. The surface tension in the solder joins the pairs of squares together. As the containers cool, they retain the shape of a cube.
“The process is compatible with microelectronic fabrication, so it's possible to envision adding electronics to it,” says Gracias. The method also enables the containers to be made in large numbers and in a relatively inexpensive way.
Doctoral student Timothy Leong and project leader David Gracias make the self-assembling microcontainers in a cleanroom.
The boxes are constructed of nickel, copper, and gold, which allows them to be tracked using MRI technology. The box frame can be made of any of the three metals. Once constructed, the biocontainer is completely plated with gold. It's possible that the other metals could produce a toxic response inside the body, says Gracias.
The pore size of the containers can be adjusted to control the diffusion of chemicals flowing in and out of the container, as well as the body's immune response to the container. However, the pore size is currently at the microscale, so researchers are working on shrinking it down to the nanometer scale. “One of the big challenges is to make a container that has extremely small pores and does not leak,” says Gracias. “The Holy Grail would be to have a hole so small that the cytokines and the immune cells could not enter the container.” If the researchers achieved this goal, only therapeutic molecules, and nutrients like oxygen and water, would flow between the box and the outside environment.
The National Institutes of Health funded the research. More information about it can be found in the December issue of the journal Biomedical Microdevices.