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Scientists develop a device that differentiates, in a single step and without markers, tumour cells from healthy cells

A CSIC team has designed a method and a device that differentiates, in a single analysis, different cells or particles present in a fluid. The prototype has been tested, and the results have been published and featured on the cover of ACS Sensors. The system has been patented and now the scientific team is looking for companies interested in a license agreement for its commercial exploitation.

Artistic representation of the device, with the transparent capillary and the laser beam.The technology is a mechano-optical system that allows differentiating particles, both organic or inorganic, by the simultaneous determination of their buoyant mass and their reflectivity with a single laser. This development has been led by Montserrat Calleja and Daniel Ramos, scientists at the Bionanomechanics Laboratory of the Institute of Micro and Nanotechnology (IMN) of the CSIC. The system has been patented and now the scientific team is looking for companies interested in a license agreement for commercial exploitation of this technology.

It is an ingenious and promising system, which has advantages over current methods, as it does not need any previous treatment of the sample. Besides, results are obtained with a single test where other methods need several tests.

The method can be applied to many areas, whenever is required to identify particles in a fluid, no matter what they are. It can identify cells in a biological sample, contaminants or pathogens in water, or polymer particles in a fluid of industrial interest.

The core of the device is a transparent and small capillary, which has a constant vibration frequency. The particles flow through this capillary, one at a time. A laser beam illuminates the transparent capillary. When a particle passes, it displaces part of the fluid in the capillary, which changes the capillary vibration (or the capillary resonance frequency). Depending on the particle mass, the change will be smaller or bigger. The difference between the mass of the displaced liquid and the mass of the particle is the buoyant mass.

The laser responds also differently depending on the particle optical properties (in this case, the method measures the reflectivity). A photodetector reads, through the changes of the laser read-out, both the reflectivity and the variation of the capillary resonance frequency. From the latter, it can be inferred the mass of the particles.

Montserrat Calleja, who leads the Bionanomechanichs Laboratory and the Project LIQUIDMASS of the European Research Council (ERC), explains: “the simultaneous measurement of the optical and mechanical properties of tumour cells will allow us to better understand the mechanisms that transform these cells and make them invasive”.

“It is a very small device”, explains Daniel Ramos, scientist at the IMN-CSIC who has led this work. “The capillary of the prototype has an inner diameter of 30 micrometers and an external diameter of 50 micrometers. The laser beam has a diameter of 20 micrometers. These sizes can be changed to adjust the device to the particles to be analysed. The capillary diameter should be similar to that of the particles to be detected, in order for the particles to enter the capillary one at a time.

In the article, the scientists have carried out a first assay with silica microparticles sized between 6 and 8 micrometers, and polymer microparticles of 12,4 micrometers. This first assay, where the scientists knew exactly what they had in the sample, was aimed at calibrating the device. Afterwards, the team carried out a second assay with breast cancer cells (MCF-7) and breast healthy cells (NCF-10A), both from the same type of epithelial tissue.

The device has been used to differentiate succesfully breast cancer cells (MCF-7) from breast healthy cells (NCF-10A), both from the same type of epithelial tissue.

This second test has proved that the device is efficient differentiating healthy cells from tumour cells from the same type of tissue. The device can analyze 300 cells per minute, which comparable to flow cytometry throughput, but it avoids preparing the sample and labelling the cells with monoclonal antibodies and fluorescent markers. The device could be quite easily coupled to the current flow cytometers.

The work featured on the ACS sensors cover. The new device has also advantages over current techniques based on hollow microchannel resonators. Although hollow resonators are very sensitive, they cannot differentiate similar particles that have similar buoyant mass. In this situation, usually are necessary several tests, changing every time the density of the fluid. However, this increases the complexity and the cost of the assay. Another drawback is that tests with different liquids are possible with inorganic particles, but they are not always possible with biological or environmental samples.

Prospects and possibilities

The device has been produced in the Clean Room of the IMN-CSIC. The scientists have been working in its design and manufacturing, as well as the design and assembly of the measuring unit, for three years. This work is part of the doctoral thesis of the young scientist Alberto Martín.

Among the next goals, the team has the goal of creating a database with the masses of the possible targets to be analysed (cells, microparticles of different materials, etc), to make possible their identification by the mass.

Now, the prototype has been applied to differentiate two cell lines, but the final goal is to improve the equipment to differentiate every single particle in a fluid sample. “It does not matter what is the fluid is, as far as it is transparent”, say the scientists. On the other hand, the combination of capillaries of different size would allow the selection of the particles that enter each capillary (i.e., the size of bacteria is 5 micrometers but a cell is about 20 micrometers).

The range of possibilities seems countless. Among them, scientists are considering bacteria and pathogen detection, medical diagnosis or pollutants detection. For instance, a device such as this one in a hospital would enable a fast detection, in just a few minutes, of pathogens present in a sample, says Daniel Ramos.

Mechano-Optical Analysis of Single Cells with Transparent Microcapillary Resonators, Alberto Martín-Pérez, Daniel Ramos, Eduardo Gil-Santos, Sergio García-López, Marina L. Yubero Priscila M. Kosaka Álvaro San Paulo Javier Tamayo Montserrat Calleja

Mercè Fernández Via / Delegación CSIC Catalunya

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