Objectives

Provide accurate, quantitative physical metrology tools that can quickly determine time-dependent force-displacement response of single cells for medical researchers.  Our tools are bio-MEMS devices that are the size of single cells or small groups of cells and have sensors in the appropriate force range, 10 – 10,000 nN and dependent on cell type.  These devices incorporate the ability to image subcellular structures of interest in concert with mechanical measurements.

Background

The isolation and measurement of single cells is one of the premier topics in medical research, and has been for a few years. The NIH roadmap directly addresses the need for cross disciplinary research with those in the physical sciences. The importance of mechanotransduction and mechanoregulation of cellular processes is acknowledged as significant in the areas of cardiovascular and cancer research, among others. The cost of hypertensive disease alone in the U.S. is currently $63.5 billion per year and the NIH estimates the costs of cancer to be $209.9 billion per year. Current techniques for mechanical measurements of single cells include micropipette aspiration, optical trapping, glass microplate, and bio-MEMS. Our technique is simpler to use, has more design flexibility, and can measure more mechanical properties in a single test than any other method. The sensitivity of our measurement method allows for differentiation of cell type and can detect changes in a cell due to biochemical environment or growth state.

Approach

Using our in-house MEMS facility, we have developed a simple platform for applying displacements to single cells and measuring the resulting load as an early feasibility demonstration. The current device is mounted in a temperature-controlled bioreactor filled with the nutritive fluid to keep the cell alive. The bioreactor is then mounted on a mechanical stage in a probe station. The device consists of a split platen with a pull rod attached to one side. The pull rod ends in a ring where a probe is inserted to apply displacements. The other half-platen is attached to serpentine springs whose displacement has been calibrated with applied force. The platen is coated with a protein (fibronectin, for instance) so that the cell will adhere. We have statically applied displacements and measured the resulting force on the structure of the cell. We are proposing here to build on this initial success in the following ways to ultimately develop standard tools for cell biologists.

Electron micrograph of the NIST “cell puller,” which measures the mechanical properties of a living cell. After the cell spreads and adheres to the center of the 200-micrometer-wide circular platform, half of the platform is pulled slowly away, while a sensor connected to the other half measures the force on the cell.

Recent Results

The heart of the device is a circular cell platform 200 micrometers wide. The two halves of the circle can be pulled as far as 100 micrometers apart under computer control, while the force needed to separate them is measured by sensors. In a demonstration using a connective tissue cell, the cell is placed on the center of the platform, allowed to spread and adhere for several hours, and then pulled slowly apart until it detaches. In experiments, the cells de-adhere from the substrate at a force of about 1500 nN.

Typical viscoelastic data from a single-cell test.

Recent Output

D.B. Serrell, T. Oreskovic, A.J. Slifka, R.L. Mahajan and D.S. Finch. A uniaxial bioMEMS device for quantitative force-displacement measurements. Biomedical Microdevices. Available online.

D.B. Serrell or A.J. Slifka

Materials Reliability Division

NIST Materials Science and Engineering Laboratory

The National Institute of Standards and Technology
is an agency of the U.S. Department of Commerce's
Technology Administration

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