Scientists at the University of California, Berkeley, have made a significant development in miniaturised microscopes and envision a future where doctors can view the DNA of tumour cells inside a patient as drugs are delivered.
Luke P. Lee, assistant professor of bioengineering at UC Berkeley, and his doctoral student Sunghoon Kwon have captured an image of a plant cell with a microlens, which is said to be smaller than the tip of a ballpoint pen.
In testing the accuracy of the microlens and scanner, Kwon placed a cell sample taken from a flowering lily, Convallaria majalis, onto the platform of a conventional confocal microscope.
Without moving the sample, they reportedly captured a cross-sectional image of the cell wall, first with the traditional microscope, then with the microlens scanner. They found that the two images matched, showing for the first time that his microscopic lens could perform as well as a conventional one.
The microlens and scanner are part of a device Lee is developing called the micro confocal imaging array, or micro-CIA. The micro-CIA belongs to a group of devices known as Bio-Polymer-Opto-Electro-Mechanical-Systems, or BioPOEMS. Invented by Lee, BioPOEMS combine the world of optics to that of microelectromechanical systems (MEMS), for use in biological applications.
Lee is particularly excited by the potential for advancements in medicine possible with a miniaturised microscope. ‘You could put this device on the tip of an endoscope that could be guided inside a cancer patient,’ said Lee. ‘Doctors could then see how tumour cells behave in vivo. It would also be feasible to deliver drugs directly to the tumour cell, and then view how the cell responds to the drugs.’
High-end confocal microscopes, which house several lasers, take up to a meter of desk space, can cost more than $1 million and typically require highly-trained operators to run them, said Lee. The high cost of owning and running confocal microscopes limits the amount of research that can be done with them, he said.
Unlike scanning electron microscopes, which construct 3-D topological images of dead cells, confocal microscopes can reportedly capture images of nanoscale activity inside living cells. Confocal microscopes also allow researchers to focus on specific components inside the cell, such as DNA strands, or mitochondria.
Cell parts marked with a fluorescent dye are ‘excited’ by the laser and emit light back at specific wavelengths. Mitochondria, for instance, emit a fluorescent red colour while nucleic acids emit a fluorescent blue, depending upon the molecular labelling of each component in the cell. To form 3-D images, 2-D slices are stacked together in a way similar to how an MRI image is formed.
Equipped with a microlens about 300 microns in diameter, the microscopic scanner Lee tested is a square of about 1 millimetre on each side and can move a distance of 50 to 100 microns. Lee is also testing a nanolens as small as 500 nanometers in diameter, or 200 times thinner than a strand of human hair, and smaller than the average red blood cell.
Lee’s design of the micro-CIA will include three scanners stacked vertically above the staging platform where samples are studied. The scanners will measure each of the three axes – X, Y and Z – in three-dimensional space.
To make the scanner and lens, Lee employed technology similar to that used to manufacture microchips. The lens is made of a tiny drop of polymer shaped by surface tension and hardened by exposure to ultraviolet light. To focus the lens, Lee and Kwon adjusted the distance between the lens and sample. While it is also possible to focus by changing the shape of the lens, Lee said doing so would likely increase the cost and complexity of production, something he wants to avoid.
Comb-drives on each side of the microlens act as microactuators, tiny engines powered by electrostatic forces that move the microlens back and forth 4,500 times per second. Sensors then pick up fluorescent signals and feed the data back to a computer where the image is displayed in real time.