A Stepwise Compression-Relaxation Testing Method for Tissue Characterization and Tumor Detection Via a Two-Dimensional Tactile Sensor

This dissertation presents a stepwise compression-relaxation (SCR) testing method built upon a two-dimensional (2D) tactile sensor for mechanical characterization of soft tissues and tumor detection. The core of the 2D sensor entails one whole polydimethylsiloxane (PDMS) microstructure embedded with a 3×3 sensing-plate/transducer array. A soft sample was compressed by the 2D sensor with a step incremental depth at a ramp speed, and then relaxed for certain hold time. When a soft sample was compressed by the 2D sensor, the sensing-plates translated the sample response at different tissue sites to the sensor deflections, which were registered as resistance changes by the transducer array. Instant elasticity (Einstant) and loss factor (tan δ) extracted from the measured data were used to quantify the sample elasticity and viscoelasticity, respectively. First, a three-way ANOVA analysis was conducted on the data of soft materials (PDMS/silicone rubbers) to evaluate the influence of testing parameters (incremental depth, hold time, and ramp speed) on the measured results. The results revealed that both Einstant and tan δ were significantly dependent on testing parameters. Next, the measured results on the soft tissues showed different elasticity and viscoelasticity between muscle tissues and fat/skin tissues. The measured results on the tumor tissues indicated different elasticity and viscoelasticity among the five breast tumor (BT) tissues, and between the two pancreatic tumor (PT) tissues before and after treatment. Due to the larger sample size of the BT tissues, the elasticity distribution among the measure BT tissue sites was used to determine the location, shape and size of the tumor in a BT tissue. The correlation of stress drop (Δσ) (obtained from the difference between the instant and relaxed sensor deflections at each step incremental depth) with the applied strain (ε) was used for tumor detection. Pearson correlation analysis was conducted to quantitatively analyze the measured Δσ-ε relation as slope of stress drop versus applied strain (m=Δσ/ε) and coefficient of determination (R2) as a measure of the goodness of fit of the linear regression for distinguishing tumor tissue from normal tissue. The measured results on soft materials showed that m was significantly dependent on testing parameters, but R2 showed no significant dependency on testing parameters. The measured results on the tumor tissues indicated R2 was significantly varied among the center, edge and outside sites of the BT tissues. However, no difference was found between the BT outside sites and the normal tissues. R2 also revealed significant difference between before and after treatment of the PT tissues, while no difference between the PT tissues after treatment and the normal tissues. R2 of the PT tissues before treatment was significantly different from that of the BT center sites, but m failed to capture their difference. Furthermore, dummy tumors made of silicone rubbers were found to behave differently from the native tumors. In summary, the feasibility of the SCR testing method for tissue characterization and tumor detection was experimentally validated on the measured soft samples, including PDMS, silicone rubbers, porcine and bovine normal tissues, mouse BT and PT tissues. Future work will investigate the feasibility of the SCR testing method for differentiation between benign tumors and malignant tumors

Cavitation in soft matter

Cavitation is the sudden, unstable expansion of a void or bubble within a liquid or solid subjected to a negative hydrostatic stress. Cavitation rheology is a field emerging from the development of a suite of materials characterization, damage quantification, and therapeutic techniques that exploit the physical principles of cavitation. Cavitation rheology is inherently complex and broad in scope with wide-ranging applications in the biology, chemistry, materials, and mechanics communities. This perspective aims to drive collaboration among these communities and guide discussion by defining a common core of high-priority goals while highlighting emerging opportunities in the field of cavitation rheology. A brief overview of the mechanics and dynamics of cavitation in soft matter is presented. This overview is followed by a discussion of the overarching goals of cavitation rheology and an overview of common experimental techniques. The larger unmet needs and challenges of cavitation in soft matter are then presented alongside specific opportunities for researchers from different disciplines to contribute to the field

Characterizing anisotropy in fibrous soft materials by MR elastography of slow and fast shear waves

The general objective of this work was to develop experimental methods based on magnetic resonance elastography (MRE) to characterize fibrous soft materials. Mathematical models of tissue biomechanics capable of predicting injury, such as traumatic brain injury (TBI), are of great interest and potential. However, the accuracy of predictions from such models depends on accuracy of the underlying material parameters. This dissertation describes work toward three aims. First, experimental methods were designed to characterize fibrous materials based on a transversely isotropic material model. Second, these methods are applied to characterize the anisotropic properties of white matter brain tissue ex vivo. Third, a theoretical investigation of the potential application of MRE to probe nonlinear mechanical behavior of soft tissue was performed. These studies provide new methods to characterize anisotropic and nonlinear soft materials as well as contributing significantly to our understanding of the behavior of specific biological soft tissues

Evaluation of the laser-induced thermotherapy treatment effect of breast cancer based on tissue viscoelastic properties

Photothermal therapy (PTT) has been emerging as an effective, minimally invasive approach to treat cancers. However, a method to quantitatively evaluate the treatment effect after laser-induced thermotherapy (LITT) is needed. In this study, we used 808 nm laser radiation with three different power densities to treat the breast cancer tissue from 4T1 cell lines in a mouse model. The viscoelastic properties of the treated cancer tissues were characterized by a two-term Prony series using a ramp-hold indentation method. We observed that instantaneous shear modulus G0 was significantly higher for the treated cancer tissues than that of the untreated tissue when treated with a power density of 1.5 W/cm2, but significantly lower with a power density of 2.5 W/cm2. The long-term shear modulus G∞ was also significantly higher for the cancer tissue at 1.5 W/cm2, compared to the untreated tissue. The treatment effects were verified by estimating the cell apoptosis rate using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Our results indicate that the viscoelastic properties of the tissue could potentially be used as biomarkers for evaluating the LITT treatment effect. In addition, we also observed a strain-independent behavior of the treated cancer tissue, which provided useful information for applying in vivo imaging method such as magnetic resonance elastography (MRE) for treatment evaluation based on biomechanical properties

Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Bayesian changepoint analysis for atomic force microscopy and soft material indentation

Material indentation studies, in which a probe is brought into controlled physical contact with an experimental sample, have long been a primary means by which scientists characterize the mechanical properties of materials. More recently, the advent of atomic force microscopy, which operates on the same fundamental principle, has in turn revolutionized the nanoscale analysis of soft biomaterials such as cells and tissues. This paper addresses the inferential problems associated with material indentation and atomic force microscopy, through a framework for the changepoint analysis of pre- and post-contact data that is applicable to experiments across a variety of physical scales. A hierarchical Bayesian model is proposed to account for experimentally observed changepoint smoothness constraints and measurement error variability, with efficient Monte Carlo methods developed and employed to realize inference via posterior sampling for parameters such as Young's modulus, a key quantifier of material stiffness. These results are the first to provide the materials science community with rigorous inference procedures and uncertainty quantification, via optimized and fully automated high-throughput algorithms, implemented as the publicly available software package BayesCP. To demonstrate the consistent accuracy and wide applicability of this approach, results are shown for a variety of data sets from both macro- and micro-materials experiments--including silicone, neurons, and red blood cells--conducted by the authors and others.Comment: 20 pages, 6 figures; submitted for publicatio

Noncontact elastic wave imaging optical coherence elastography for evaluating changes in corneal elasticity due to crosslinking

The mechanical properties of tissues can provide valuable information about tissue integrity and health and can assist in detecting and monitoring the progression of diseases such as keratoconus. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess localized mechanical contrast in tissues with micrometer spatial resolution. In this work we present a noncontact method of optical coherence elastography to evaluate the changes in the mechanical properties of the cornea after UV-induced collagen cross-linking. A focused air-pulse induced a low amplitude (μm scale) elastic wave, which then propagated radially and was imaged in three dimensions by a phase-stabilized swept source optical coherence tomography (PhSSSOCT) system. The elastic wave velocity was translated to Young’s modulus in agar phantoms of various concentrations. Additionally, the speed of the elastic wave significantly changed in porcine cornea before and after UV-induced corneal collagen cross-linking (CXL). Moreover, different layers of the cornea, such as the anterior stroma, posterior stroma, and inner region, could be discerned from the phase velocities of the elastic wave. Therefore, because of noncontact excitation and imaging, this method may be useful for in vivo detection of ocular diseases such as keratoconus and evaluation of therapeutic interventions such as CXL

Photoacoustic Elastography and Next-generation Photoacoustic Tomography Techniques Towards Clinical Translation

Ultrasonically probing optical absorption, photoacoustic tomography (PAT) combines rich optical contrast with high ultrasonic resolution at depths beyond the optical diffusion limit. With consistent optical absorption contrast at different scales and highly scalable spatial resolution and penetration depth, PAT holds great promise as an important tool for both fundamental research and clinical application. Despite tremendous progress, PAT still encounters certain limitations that prevent it from becoming readily adopted in the clinical settings. This dissertation aims to advance both the technical development and application of PAT towards its clinical translation. The first part of this dissertation describes the development of photoacoustic elastography techniques, which complement PAT with the capability to image the elastic properties of biological tissue and detect pathological conditions associated with its alterations. First, I demonstrated vascular-elastic PAT (VE-PAT), capable of quantifying blood vessel compliance changes due to thrombosis and occlusions. Then, I developed photoacoustic elastography to noninvasively map the elasticity distribution in biological tissue. Third, I further enhanced its performance by combing conventional photoacoustic elastography with a stress sensor having known stress–strain behavior to achieve quantitative photoacoustic elastography (QPAE). QPAE can quantify the Young’s modulus of biological tissues on an absolute scale. The second part of this dissertation introduces technical improvements of photoacoustic microscopy (PAM). First, by employing near-infrared (NIR) light for illumination, a greater imaging depth and finer lateral resolution were achieved by near-infrared optical-resolution PAM (NIR-OR-PAM). In addition, NIR-OR-PAM was capable of imaging other tissue components, including lipid and melanin. Second, I upgraded a high-speed functional OR-PAM (HF-OR-PAM) system and applied it to image neurovascular coupling during epileptic seizure propagation in mouse brains in vivo with high spatio-temporal resolution. Last, I developed a single-cell metabolic PAM (SCM-PAM) system, which improves the current single-cell oxygen consumption rate (OCR) measurement throughput from ~30 cells over 15 minutes to ~3000 cells over 15 minutes. This throughput enhancement of two orders of magnitude achieves modeling of single-cell OCR distribution with a statistically meaningful cell count. SCM-PAM enables imaging of intratumoral metabolic heterogeneity with single-cell resolution. The third part of this dissertation introduces the application of linear-array-based PAT (LA-PAT) in label-free high-throughput imaging of melanoma circulating tumor cells (CTCs) in patients in vivo. Taking advantage of the strong optical absorption of melanin and the unique capability of PAT to image optical absorption, with 100% relative sensitivity, at depths with high ultrasonic spatial resolution, LA-PAT is inherently suitable for melanoma CTC imaging. First, with a center ultrasonic frequency of 21 MHz, the LA-PAT system was able to detect melanoma CTCs clusters and quantify their sizes based on the contrast-to-noise ratio (CNR). Second, I developed an LA-PAT system with a center ultrasonic frequency of 40 MHz and imaged melanoma CTCs in patients in vivo with a CNR greater than 12. We successfully imaged 16 melanoma patients and detected melanoma CTCs in 3 of them. Among the CTC-positive patients, 67% had disease progression despite systemic therapy. In contrast, only 23% of the CTC-negative patients showed disease progression. This study lays a solid foundation for translating CTC detection to bedside for clinical care and decision-making

Bone mechanical properties in healthy and diseased states

The mechanical properties of bone are fundamental to the ability of our skeletons to support movement and to provide protection to our vital organs. As such, deterioration in mechanical behavior with aging and/or diseases such as osteoporosis and diabetes can have profound consequences for individuals’ quality of life. This article reviews current knowledge of the basic mechanical behavior of bone at length scales ranging from hundreds of nanometers to tens of centimeters. We present the basic tenets of bone mechanics and connect them to some of the arcs of research that have brought the field to recent advances. We also discuss cortical bone, trabecular bone, and whole bones, as well as multiple aspects of material behavior, including elasticity, yield, fracture, fatigue, and damage. We describe the roles of bone quantity (e.g., density, porosity) and bone quality (e.g., cross-linking, protein composition), along with several avenues of future research.Author manuscrip