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

Towards retrieving force feedback in robotic-assisted surgery: a supervised neuro-recurrent-vision approach

Robotic-assisted minimally invasive surgeries have gained a lot of popularity over conventional procedures as they offer many benefits to both surgeons and patients. Nonetheless, they still suffer from some limitations that affect their outcome. One of them is the lack of force feedback which restricts the surgeon's sense of touch and might reduce precision during a procedure. To overcome this limitation, we propose a novel force estimation approach that combines a vision based solution with supervised learning to estimate the applied force and provide the surgeon with a suitable representation of it. The proposed solution starts with extracting the geometry of motion of the heart's surface by minimizing an energy functional to recover its 3D deformable structure. A deep network, based on a LSTM-RNN architecture, is then used to learn the relationship between the extracted visual-geometric information and the applied force, and to find accurate mapping between the two. Our proposed force estimation solution avoids the drawbacks usually associated with force sensing devices, such as biocompatibility and integration issues. We evaluate our approach on phantom and realistic tissues in which we report an average root-mean square error of 0.02 N.Peer ReviewedPostprint (author's final draft

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

A Review on Pressure Ulcer: Aetiology, Cost, Detection and Prevention Systems

Pressure ulcer (also known as pressure sore, bedsore, ischemia, decubitus ulcer) is a global challenge for today’s healthcare society. Found in several locations in the human body such as the sacrum, heel, back of the head, shoulder, knee caps, it occurs when soft tissues are under continuous loading and a subject’s mobility is restricted (bedbound/chair bound). Blood flow in soft tissues becomes insufficient leading to tissue necrosis (cell death) and pressure ulcer. The subject’s physiological parameters (age, body mass index) and types of body support surface materials (mattress) are also factors in the formation of pressure ulcer. The economic impacts of these are huge, and the subject’s quality of life is reduced in many ways. There are several methods of detecting and preventing ulceration in human body. Detection depends on assessing local pressure on tissue and prevention on scales of risk used to assess a subject prior to admission. There are also various types of mattresses (air cushioned/liquid filled/foam) available to prevent ulceration. But, despite this work, pressure ulcers remain common.This article reviews the aetiology, cost, detection and prevention of these ulcers

Classification of analytics, sensorics, and bioanalytics with polyelectrolyte multilayer capsules

Polyelectrolyte multilayer (PEM) capsules, constructed by LbL (layer-by-layer)-adsorbing polymers on sacrificial templates, have become important carriers due to multifunctionality of materials adsorbed on their surface or encapsulated into their interior. They have been also been used broadly used as analytical tools. Chronologically and traditionally, chemical analytics has been developed first, which has long been synonymous with all analytics. But it is not the only development. To the best of our knowledge, a summary of all advances including their classification is not available to date. Here, we classify analytics, sensorics, and biosensorics functionalities implemented with polyelectrolyte multilayer capsules and coated particles according to the respective stimuli and application areas. In this classification, three distinct categories are identified: (I) chemical analytics (pH; K+, Na+, and Pb2+ ion; oxygen; and hydrogen peroxide sensors and chemical sensing with surface-enhanced Raman scattering (SERS)); (II) physical sensorics (temperature, mechanical properties and forces, and osmotic pressure); and (III) biosensorics and bioanalytics (fluorescence, glucose, urea, and protease biosensing and theranostics). In addition to this classification, we discuss also principles of detection using the above-mentioned stimuli. These application areas are expected to grow further, but the classification provided here should help (a) to realize the wealth of already available analytical and bioanalytical tools developed with capsules using inputs of chemical, physical, and biological stimuli and (b) to position future developments in their respective fields according to employed stimuli and application areas

The Interplay between Chemistry and Mechanics in the Transduction of a Mechanical Signal into a Biochemical Function

There are many processes in biology in which mechanical forces are generated. Force-bearing networks can transduce locally developed mechanical signals very extensively over different parts of the cell or tissues. In this article we conduct an overview of this kind of mechanical transduction, focusing in particular on the multiple layers of complexity displayed by the mechanisms that control and trigger the conversion of a mechanical signal into a biochemical function. Single molecule methodologies, through their capability to introduce the force in studies of biological processes in which mechanical stresses are developed, are unveiling subtle intertwining mechanisms between chemistry and mechanics and in particular are revealing how chemistry can control mechanics. The possibility that chemistry interplays with mechanics should be always considered in biochemical studies.Comment: 50 pages, 18 figure

Mechanics and applications of stretchable serpentine structures

Stretchable structures have been developed for various applications, including expandable coronary stents, deployable sensor networks and stretchable bio-mimetic and bio-integrated electronics. High-performance, stretchable electronics have to utilize high-quality and long-lasting inorganic electronic materials such as silicon, oxide dielectrics and metals, which are intrinsically stiff and often brittle. It is therefore an interdisciplinary challenge to make inorganic electronics stretchable while retaining their electronic functionality. Patterning stiff materials into serpentine-shaped wavy ribbons has become a popular strategy for fabricating stretchable inorganic electronics. However due to a lack of mechanics understanding, design of serpentine structures is still largely empirical, whether for freestanding or substrate supported serpentines. This dissertation systematically investigates the mechanics of serpentine structures with emphasis on the effects of serpentine geometry and substrate stiffness, which involves theoretical analysis, numerical simulation, and experimental validation. Our theory has successfully predicted the stretchability and stiffness of various serpentine shapes and has been applied to the optimization of serpentine designs under practical constraints. We are also the first to point out that not all geometric effects are monotonic and serpentines are not always more stretchable than linear ribbons. To manufacture high quality serpentine ribbons with high throughput and low cost, we have invented a “cut-and-paste” method to fabricate both metallic and ceramic serpentines. As a demonstration of our method, a noninvasive, tattoo-like multifunctional epidermal sensor system has been built for the measurement of electrophysiological signals, skin temperature, skin hydration, and respiratory rate. Engineering of epidermal stretchable antenna for wireless communication is also detailed and rationalized.Mechanical Engineerin

Development of experimental setups for the characterization of the mechanoelectrical coupling of cells in vitro

The field of mechanobiology emerged from the many evidences that mechanical forces acting on cells have a central role in their development and physiology. Cells, in fact, convert such forces into biochemical activities and gene expression in a process referred as mechanotransduction. In vitro models that mimic cell environment also from the mechanical point of view represent therefore a key tool for modelling cell behaviour and would find many applications, e.g. in drug development and tissue engineering. In this work I introduce novel tools for the study of mechanotransduction. In particular, I present a system for the evaluation of the complex response of electrically active cells, such as neurons and cardiomyocytes. This system integrates atomic force microscopy, extracellular electrophysiological recording, and optical microscopy in order to investigate cell activity in response to mechanical stimuli. I also present cell scaffolds for the in vitro study of cancer. Obtained results, although preliminary, show the potential of the proposed systems and methods to develop accurate in vitro models for mechanobiology studies

Magnetic Hybrid-Materials

Externally tunable properties allow for new applications of suspensions of micro- and nanoparticles in sensors and actuators in technical and medical applications. By means of easy to generate and control magnetic fields, fluids inside of matrices are studied. This monnograph delivers the latest insigths into multi-scale modelling, manufacturing and application of those magnetic hybrid materials

The Effect of Biomechanical and Biochemical Factors on Endothelial Cells: Relevance to Atherosclerosis

Microscale technologies create great opportunities for biologists to unveil cellular or molecular mechanisms of complex biological processes. Advanced measuring techniques, like atomic force microscope (AFM), allow detecting and controlling biological samples at high spatial and temporal resolution. Further integration with microsystems, such as microfluidic platforms, gives the ability to get detailed insight into basic biological phenomena. Highly integrated microdevices show great promise for biomedical research and potential clinical applications. It is hypothesized that biomechanical factors play a significant role in the development of vascular diseases like atherosclerosis. To explore effects of biomechanical and biochemical stimuli on endothelial cells (ECs), AFM, which allows measurements of living cells, was utilized. Due to the heterogeneity of cells, standard characterization methods for mechanical properties of cells are still lacking. Therefore, a new quantitative method was developed for evaluation of cell elasticity correlating with cell morphology in this study. Moreover, cells are intrinsically viscoelastic materials revealed by stress relaxation measurements. A mechanically distinct bilayer model was proposed to discover the mechanical behaviour of cell components. Based on the elasticity characterization method and the stress relaxation model, the effect of cholesterol content on the mechanical response of ECs was examined, focusing on the behaviour of plasma membrane. To mimic physiological conditions more closely for in vitro settings, a mask-free, highly integrated, low cost and time effective method was developed to rapidly fabricate a prototype of microfluidic cell culture system (MCCS). To better understand cell-cell interaction in circulatory systems like MCCS, a theoretical study of evaluating intercellular forces was also performed. Based on MCCS and microvalve technique, a novel bio-inspired and cell-based system was developed to simulate the formation of atherosclerosis plaque. Biomechanical properties of ECs, hemodynamic effects, cell rolling and adhesion events were investigated under this pathological model. The devices can be leveraged for potential applicability to biological research and clinical tests such as drug screening. This research project has led to a better understanding of the underlying mechanisms of atherosclerosis and mechanical behaviours of ECs, as well as the development of AFM-based models that will be useful in determining cellular mechanical properties