Engineering focusing on cancer.

While cancer research and care have benefited from revolutionary advances in the ability to manipulate and study living systems, the field is limited by a lack of synergy to leverage the power of engineering approaches. Cancer engineering is an emerging subfield of biomedical engineering that unifies engineering and cancer biology to better understand, diagnose, and treat cancer. We highlight cancer engineering's unique challenges, the importance of creating dedicated centers and departments that enable translational collaboration, and educational approaches to arm a new generation of scientists with engineering expertise and a fundamental understanding of cancer biology to transform clinical cancer care.

Improved total sensitivity estimation for multiple receive coils in MRI using ratios of first-order statistics.

OBJECT: Spatial variation in the sensitivity profiles of receive coils in MRI leads to spatially dependent scaling of the signal amplitude across an image. In practice, total sensitivity of the coil array is either calibrated or corrected directly by comparison to a uniform sensitivity image, fitting of coil profiles, or indirectly by constraining the reconstructed image or coil profiles. In the absence of these corrections, popular coil summation strategies are often designed to maximize the signal-to-noise ratio or optimize under-sampled encoding but not necessarily estimate the value of the signal unscaled by the coil spatial sensitivity. MATERIALS AND METHODS: We use ratios of first-order statistics to approach the unscaled value of the signal at any position. Motivated by the assumption that the coil array is a sample from much larger number of possible coils, we present two approaches to scale the mean signal in all coils: (1) an argument for use of the mode of the normalized signals, and (2) using a one-dimensional analog derive an approximate expression for scaling with the ratio of the square-of-the-mean to the mean-of-the-squares. We test these approaches with simulation where idealized coil elements are arrayed around an object, and on directly acquired data with an 8-channel coil array on a uniform 13C phantom, and on Hyperpolarized 13C pyruvate brain MRI. RESULTS: We show improved image uniformity using the ratios of first order statistics compared to a simple homomorphic filter, noting that these approaches are more sensitive to noise. DISCUSSION: We present simple methods for correcting the spatial variation in sensitivity profiles in the context of a coil array. These methods can be used as an initial or adjunct step in data post-processing.

Label-free viability assay using in-line holographic video microscopy.

Total holographic characterization (THC) is presented here as an efficient, automated, label-free method of accurately identifying cell viability. THC is a single-particle characterization technology that determines the size and index of refraction of individual particles using the Lorenz-Mie theory of light scattering. Although assessment of cell viability is a challenge in many applications, including biologics manufacturing, traditional approaches often include unreliable labeling with dyes and/or time consuming methods of manually counting cells. In this work we measured the viability of Saccharomyces cerevisiae yeast in the presence of various concentrations of isopropanol as a function of time. All THC measurements were performed in the native environment of the sample with no dilution or addition of labels. Holographic measurements were made with an in-line holographic microscope using a 40[Formula: see text] objective lens with plane wave illumination. We compared our results with THC to manual counting of living and dead cells as distinguished with trypan blue dye. Our findings demonstrate that THC can effectively distinguish living and dead yeast cells by the index of refraction of individual cells.

Vinculin and the mechanical response of adherent fibroblasts to matrix deformation.

Cells respond to the mechanics of their environment. Mechanical cues include extracellular matrix (ECM) stiffness and deformation, which are primarily sensed through integrin-mediated adhesions. We investigated the impact of ECM deformation on cellular forces, measuring the time-evolution of traction forces of isolated mouse fibroblasts in response to stretch and release. Stretch triggered a marked increase of traction stresses and apparent stiffness. Expression of the focal adhesion protein vinculin not only increased baseline traction forces, but also increased dissipation of mechanical energy, which was correlated with the cells' failure to recover baseline traction forces after release of stretch.

Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients.

Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response.Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg Cancer Res; 78(14); 3755-60. ©2018 AACR.

Direct measurement of strain-dependent solid surface stress.

Surface stress, also known as surface tension, is a fundamental material property of any interface. However, measurements of solid surface stress in traditional engineering materials, such as metals and oxides, have proven to be very challenging. Consequently, our understanding relies heavily on untested theories, especially regarding the strain dependence of this property. Here, we take advantage of the high compliance and large elastic deformability of a soft polymer gel to directly measure solid surface stress as a function of strain. As anticipated by theoretical work for metals, we find that the surface stress depends on the strain via a surface modulus. Remarkably, the surface modulus of our soft gels is many times larger than the zero-strain surface tension. This suggests that surface stresses can play a dominant role in solid mechanics at larger length scales than previously anticipated.Solid surface stress is a fundamental property of solid interfaces. Here authors measure the solid surface stress of a gel, and show its dependence on surface strain through a surface modulus.

Tracking particles with large displacements using energy minimization.

We describe a method to track particles undergoing large displacements. Starting with a list of particle positions sampled at different time points, we assign particle identities by minimizing the sum across all particles of the trace of the square of the strain tensor. This method of tracking corresponds to minimizing the stored energy in an elastic solid or the dissipated energy in a viscous fluid. Our energy-minimizing approach extends the advantages of particle tracking to situations where particle imaging velocimetry and digital imaging correlation are typically required. This approach is much more reliable than the standard squared-displacement minimizing approach for spatially-correlated displacements that are larger than the typical interparticle spacing. Thus, it is suitable for particles embedded in a material undergoing large deformations. On the other hand, squared-displacement minimization is more effective for particles undergoing uncorrelated random motion. In the ESI, we include a flexible MATLAB particle tracker that implements either approach with a robust optimal assignment algorithm. This implementation returns an estimation of the strain tensor for each particle, in addition to its identification.

Highly stiff yet elastic microcapsules incorporating cellulose nanofibrils.

Microcapsules with high mechanical stability and elasticity are desirable in a variety of contexts. We report a single-step method to fabricate such microcapsules by microfluidic interfacial complexation between high stiffness cellulose nanofibrils (CNF) and an oil-soluble cationic random copolymer. Single-capsule compression measurements reveal an elastic modulus of 53 MPa for the CNF-based capsule shell with complete recovery of deformation from strains as large as 19%. We demonstrate the ability to manipulate the shell modulus by the use of polyacrylic acid (PAA) as a binder material, and observe a direct relationship between the shell modulus and the PAA concentration, with moduli as large as 0.5 GPa attained. These results demonstrate that CNF incorporation provides a facile route for producing strong yet flexible microcapsule shells.

Wetting and phase separation in soft adhesion.

In the classic theory of solid adhesion, surface energy drives deformation to increase contact area whereas bulk elasticity opposes it. Recently, solid surface stress has been shown also to play an important role in opposing deformation of soft materials. This suggests that the contact line in soft adhesion should mimic that of a liquid droplet, with a contact angle determined by surface tensions. Consistent with this hypothesis, we observe a contact angle of a soft silicone substrate on rigid silica spheres that depends on the surface functionalization but not the sphere size. However, to satisfy this wetting condition without a divergent elastic stress, the gel phase separates from its solvent near the contact line. This creates a four-phase contact zone with two additional contact lines hidden below the surface of the substrate. Whereas the geometries of these contact lines are independent of the size of the sphere, the volume of the phase-separated region is not, but rather depends on the indentation volume. These results indicate that theories of adhesion of soft gels need to account for both the compressibility of the gel network and a nonzero surface stress between the gel and its solvent.

Soft microcapsules with highly plastic shells formed by interfacial polyelectrolyte-nanoparticle complexation.

Composite microcapsules have been aggressively pursued as designed chemical entities for biomedical and other applications. Common preparations rely on multi-step, time consuming processes. Here, we present a single-step approach to fabricate such microcapsules with shells composed of nanoparticle-polyelectrolyte and protein-polyelectrolyte complexes, and demonstrate control of the mechanical and release properties of these constructs. Interfacial polyelectrolyte-nanoparticle and polyelectrolyte-protein complexation across a water-oil droplet interface results in the formation of capsules with shell thicknesses of a few µm. Silica shell microcapsules exhibited a significant plastic response at small deformations, whereas lysozyme incorporated shells displayed a more elastic response. We exploit the plasticity of nanoparticle incorporated shells to produce microcapsules with high aspect ratio protrusions by micropipette aspiration.

Single-step microfluidic fabrication of soft monodisperse polyelectrolyte microcapsules by interfacial complexation.

Common methods for fabrication of polyelectrolyte microcapsules rely on a multi-step process. We propose a single-step approach to generate polyelectrolyte microcapsules with 1-2 µm shells based on polyelectrolyte complexation across a water/oil droplet interface and study the effect of parameters controlling the polyelectrolyte complexation on shell thickness.

Traction force microscopy in physics and biology.

Adherent cells, crawling slugs, peeling paint, sessile liquid drops, bearings and many other living and non-living systems apply forces to solid substrates. Traction force microscopy (TFM) provides spatially-resolved measurements of interfacial forces through the quantification and analysis of the deformation of an elastic substrate. Although originally developed for adherent cells, TFM has no inherent size or force scale, and can be applied to a much broader range of mechanical systems across physics and biology. In this paper, we showcase the wide range of applicability of TFM, describe the theory, and provide experimental details and code so that experimentalists can rapidly adopt this powerful technique.

Surface tension and contact with soft elastic solids.

The Johnson-Kendall-Roberts theory is the basis of modern contact mechanics. It describes how two deformable objects adhere together, driven by adhesion energy and opposed by elasticity. Here we characterize the indentation of glass particles into soft, silicone substrates using confocal microscopy. We show that, whereas the Johnson-Kendall-Roberts theory holds for particles larger than a critical, elastocapillary lengthscale, it fails for smaller particles. Instead, adhesion of small particles mimics the adsorption of particles at a fluid interface, with a size-independent contact angle between the undeformed surface and the particle given by a generalized version of the Young's law. A simple theory quantitatively captures this behaviour and explains how solid surface tension dominates elasticity for small-scale indentation of soft materials.

Universal deformation of soft substrates near a contact line and the direct measurement of solid surface stresses.

Droplets deform soft substrates near their contact lines. Using confocal microscopy, we measure the deformation of silicone gel substrates due to glycerol and fluorinated-oil droplets for a range of droplet radii and substrate thicknesses. For all droplets, the substrate deformation takes a universal shape close to the contact line that depends on liquid composition, but is independent of droplet size and substrate thickness. This shape is determined by a balance of interfacial tensions at the contact line and provides a novel method for direct determination of the surface stresses of soft substrates. Moreover, we measure the change in contact angle with droplet radius and show that Young's law fails for small droplets when their radii approach an elastocapillary length scale. For larger droplets the macroscopic contact angle is constant, consistent with Young's law.

Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration.

Little is known about how neutrophils and other cells establish a single zone of actin assembly during migration. A widespread assumption is that the leading edge prevents formation of additional fronts by generating long-range diffusible inhibitors or by sequestering essential polarity components. We use morphological perturbations, cell-severing experiments, and computational simulations to show that diffusion-based mechanisms are not sufficient for long-range inhibition by the pseudopod. Instead, plasma membrane tension could serve as a long-range inhibitor in neutrophils. We find that membrane tension doubles during leading-edge protrusion, and increasing tension is sufficient for long-range inhibition of actin assembly and Rac activation. Furthermore, reducing membrane tension causes uniform actin assembly. We suggest that tension, rather than diffusible molecules generated or sequestered at the leading edge, is the dominant source of long-range inhibition that constrains the spread of the existing front and prevents the formation of secondary fronts.