Iterative Control Approach to High-Speed Force-Distance Curve Measurement Using AFM for Biological Applications

Atomic force microscopy (AFM) has been used in a wide variety of biological studies, from the topography imaging to the interactions of both sub-cell molecular (i.e., DNA and protein) and cell membranes. Particularly, the force-curve measurement using AFM has become a powerful tool to study the biophysical and/or biochemical properties of single bimolecular and single cell, at unprecedented spatial and force resolution. However, currently the temporal resolution of AFM force curve measurement is limited by its low operation speed, in studies such as the time-dependence of the unfolding force of a titin domain, or the unbinding force of a single DNA strand. Large temporal distortions also occur during the force-volume imaging of a live cell when mapping the force-curve distribution across the cell membrane, because of the large time lapse between the force-curve acquired at the first and the last sample point. In this article, a novel inversion-based iterative control technique is proposed to dramatically increase the speed of force-curve measurements. The experimental results presented show that by using the proposed control technique, the speed of force-curve measurements can be significantly increased (over 60 times)—with no loss of spatial resolution. This control technique, demonstrated on a commercial AFM platform with a conventional cantilever, can be easily automated with guaranteed performance. The proposed technique is further illustrated by applying it to quantitatively study the time-dependent elastic modulus of poly(dimethylsiloxane) (PDMS), a whose surface stiffness is similar to many soft biological samples. The elastic modulus of PDMS were measured by using force-curves captured at push-in (load) rates spanning two-order differences, which clearly show the transition of the PDMS viscoelastic responses from rubbery (soft) towards glassy (stiff).