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Multicellular cancer spheroids are an in vitro tissue model that mimics the three-dimensional microenvironment. As spheroids grow, they develop the gradients of oxygen, nutrients, and catabolites, affecting crucial tumor characteristics such as proliferation and treatment responses. The measurement of spheroid stiffness provides a quantitative measure to evaluate such structural changes over time. In this report, we measured the stiffness of size-matched day 5 and day 20 tumor spheroids using a custom-built microscale force sensor and conducted transmission electron microscopy (TEM) imaging to compare the internal structures. We found that older spheroids reduce interstitial spaces in the core region and became significantly stiffer. The measured elastic moduli were 260±100 and 680±150 Pa, for day 5 and day 20 spheroids, respectively. The day 20 spheroids showed an optically dark region in the center. Analyzing the high-resolution TEM images of spheroid middle sections across the diameter showed that the cells in the inner region of the day 20 spheroids are significantly larger and more closely packed than those in the outer regions. On the other hand, the day 5 spheroids did not show a significant difference between the inner and outer regions. The observed reduction of the interstitial space may be one factor that contributes to stiffer older spheroids. 

We report on the design and the modeling of a three-dimensional (3D) printed flexure-based actuation mechanism for robotic microtweezers, the main body of which is a single piece of nylon. Our design aims to fill a void in sample manipulation between two classes of widely used instruments: nano-scale and macro-scale robotic manipulators. The key component is a uniquely designed cam flexure system, which linearly translates the bending of a piezoelectric bimorph actuator into angular displacement. The 3D printing made it possible to realize the fabrication of the cam with a specifically calculated curve, which would otherwise be costly using conventional milling techniques. We first characterized 3D printed nylon by studying sets of simple cantilevers, which provided fundamental characteristics that could be used for further designs. The finite element method analysis based on the obtained material data matched well with the experimental data. The tweezers showed angular displacement from 0° to 10° linearly to the deflection of the piezo actuator (0–1.74 mm) with the linearity error of 0.1°. Resonant frequency of the system with/without working tweezer tips was discovered as 101 Hz and 127 Hz, respectively. Our design provides simple and low-cost construction of a versatile manipulator system for samples in the micro/meso-scale (0.1–1 mm).