Master of Science

thesisTraumatic brain injury (TBI) is a leading cause of death and disability in the U.S.A. In mild cases, common etiologies of TBI (i.e., hemorrhage or edema) are not readily apparent during medical examination. We propose that the pia-arachnoid complex (PAC) contributes to the brain's response in TBI. The PAC is the only layer of tissue between the brain and dura (a tough membrane tightly adhered to the skull), and acts as a mechanical tether between the brain and skull. If the fine structures of the PAC are damaged during TBI, they likely go undiagnosed due to their small size and difficulty to image. To better understand the mechanics of PAC injury, several experimental and computational studies were conducted. First, a novel application of optical coherence tomography (OCT) was utilized to acquire microscale images of the in-situ porcine PAC and measure the amount of arachnoid trabeculae (AT) present. Next, two parametric studies were conducted on a microscale model of the PAC which evaluated its sensitivity to variable substructure moduli and AT volume fraction (VF). Afterwards, the microscale PAC model was paired with a macroscale head model to determine the effect of a nonuniform AT VF on whole-head mechanics. Finally, an immature porcine model of mild TBI was used to investigate PAC damage following head rotation, and identify clinically relevant MRI biomarkers indicative of PAC damage. The OCT imaging of the PAC revealed high variability of VF within each head, but low variability between brain regions and between animals. The microscale parametric studies showed high sensitivity to changes in substructure moduli and VF. The macroscale model studies showed improvement of intracranial hemorrhage prediction when variable VF was introduced into the models. Clinically relevant biomarkers of PAC damage were not able to be confidently developed, but increased sample size and improved resolution may lead to innovative biomarkers for TBI. The work presented here addresses a significant lack of data on the PAC, and presents new insights into its anatomy and biomechanics. Many of the studies presented here are the first of their kind, opening up many new paths of TBI research opportunities

Neuromodulation by Mechanical Strain in C. elegans

Current computational models for traumatic brain injury are limited by a lack of understanding of the changes in neuronal function following repeated strain, highlighting the need for large datasets characterizing neuronal response to stretch. To provide a platform capable of gathering these datasets, an apparatus to strain embedded neuronal samples and monitor the subsequent neural response optogenetically was developed. The apparatus enables loading and immobilization of live Caenorhabditis elegans specimen, delivers stretch stimulus to the embedded animals, and provides sufficient image resolution to analyze neuronal calcium activity fluorescently both pre- and post-stretch

Shear-promoted drug encapsulation into red blood cells: a CFD model and μ-PIV analysis

The present work focuses on the main parameters that influence shear-promoted encapsulation of drugs into erythrocytes. A CFD model was built to investigate the fluid dynamics of a suspension of particles flowing in a commercial micro channel. Micro Particle Image Velocimetry (μ-PIV) allowed to take into account for the real properties of the red blood cell (RBC), thus having a deeper understanding of the process. Coupling these results with an analytical diffusion model, suitable working conditions were defined for different values of haematocrit

Development of novel micropneumatic grippers for biomanipulation

Microbjects with dimensions from 1 μm to 1 mm have been developed recently for different aspects and purposes. Consequently, the development of handling and manipulation tools to fulfil this need is urgently required. Micromanipulation techniques could be generally categorized according to their actuation method such as electrostatic, thermal, shape memory alloy, piezoelectric, magnetic, and fluidic actuation. Each of which has its advantage and disadvantage. The fluidic actuation has been overlooked in MEMS despite its satisfactory output in the micro-scale. This thesis presents different families of pneumatically driven, low cost, compatible with biological environment, scalable, and controllable microgrippers. The first family demonstrated a polymeric microgripper that was laser cut and actuated pneumatically. It was tested to manipulate microparticles down to 200 microns. To overcome the assembly challenges that arise in this family, the second family was proposed. The second family was a micro-cantilever based microgripper, where the device was assembled layer by layer to form a 3D structure. The microcantilevers were fabricated using photo-etching technique, and demonstrated the applicability to manipulate micro-particles down to 200 microns using automated pick-and-place procedure. In addition, this family was used as a tactile-detector as well. Due to the angular gripping scheme followed by the above mentioned families, gripping smaller objects becomes a challenging task. A third family following a parallel gripping scheme was proposed allowing the gripping of smaller objects to be visible. It comprises a compliant structure microgripper actuated pneumatically and fabricated using picosecond laser technology, and demonstrated the capability of gripping microobject as small as 100 μm microbeads. An FEA modelling was employed to validate the experimental and analytical results, and excellent matching was achieved

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

A Customer Programmable Microfluidic System

Microfluidics is both a science and a technology offering great and perhaps even revolutionary capabilities to impact the society in the future. However, due to the scaling effects there are unknown phenomena and technology barriers about fluidics in microchannel, material properties in microscale and interactions with fluids are still missing. A systematic investigation has been performed aiming to develop A Customer Programmable Microfluidic System . This innovative Polydimethylsiloxane (PDMS)-based microfluidic system provides a bio-compatible platform for bio-analysis systems such as Lab-on-a-chip, micro-total-analysis system and biosensors as well as the applications such as micromirrors. The system consists of an array of microfluidic devices and each device containing a multilayer microvalve. The microvalve uses a thermal pneumatic actuation method to switch and/or control the fluid flow in the integrated microchannels. It provides a means to isolate samples of interest and channel them from one location of the system to another based on needs of realizing the customers\u27 desired functions. Along with the fluid flow control properties, the system was developed and tested as an array of micromirrors. An aluminum layer is embedded into the PDMS membrane. The metal was patterned as a network to increase the reflectivity of the membrane, which inherits the deformation of the membrane as a mirror. The deformable mirror is a key element in the adaptive optics. The proposed system utilizes the extraordinary flexibility of PDMS and the addressable control to manipulate the phase of a propagating optical wave front, which in turn can increase the performance of the adaptive optics. Polydimethylsiloxane (PDMS) has been widely used in microfabrication for microfluidic systems. However, few attentions were paid in the past to mechanical properties of PDMS. Importantly there is no report on influences of microfabrication processes which normally involve chemical reactors and biologically reaction processes. A comprehensive study was made in this work to study fundamental issues such as scaling law effects on PDMS properties, chemical emersion and temperature effects on mechanical properties of PDMS, PDMS compositions and resultant properties, as well as bonding strength, etc. Results achieved from this work will provide foundation of future developments of microfluidics utilizing PDMS

Development of a light-powered microstructure : enhancing thermal actuation with near-infrared absorbent gold nanoparticles.

Development of microscale actuating technologies has considerably added to the toolset for interacting with natural components at the cellular level. Small-scale actuators and switches have potential in areas such as microscale pumping and particle manipulation. Thermal actuation has been used with asymmetric geometry to create large deflections with high force relative to electrostatically driven systems. However, many thermally based techniques require a physical connection for power and operate outside the temperature range conducive for biological studies and medical applications. The work presented here describes the design of an out-of-plane bistable switch that responds to near-infrared light with wavelength-specific response. In contrast to thermal actuating principles that require wired conductive components for Joule heating, the devices shown here are wirelessly powered by near -infrared (IR) light by patterning a wavelength-specific absorbent gold nanoparticle (GNP) film onto the microstructure. An optical window exists which allows near-IR wavelength light to permeate living tissue, and high stress mismatch in the bilayer geometry allows for large actuation at biologically acceptable limits. Patterning the GNP film will allow thermal gradients to be created from a single laser source, and integration of various target wavelengths will allow for microelectromechanical (MEMS) devices with multiple operating modes. An optically induced temperature gradient using wavelength-selective printable or spinnable coatings would provide a versatile method of wireless and non-invasive thermal actuation. This project aims to provide a fundamental understanding of the particle and surface interaction for bioengineering applications based on a “hybrid” of infrared resonant gold nanoparticles and MEMS structures. This hybrid technology has potential applications in light-actuated switches and other mechanical structures. Deposition methods and surface chemistry are integrated with three-dimensional MEMS structures in this work. The long-term goal of this project is a system of light-powered microactuators for exploring cells\u27 response to mechanical stimuli, adding to the fundamental understanding of tissue response to everyday mechanical stresses at the molecular level

Effect of conformational change on nanoscale friction behavior of organic thin films

The overarching theme of this dissertation is to probe relationships between structure of organic thin films and their specific functional property of friction in the context of various engineering applications. Two specific thin film systems were studied - biological macromolecules in total joint replacements and self-assembled alkanethiol monolayers for microdevice applications. Before delving into the actual systems, a thorough understanding of friction at small length scales was required. To address this, a friction study of two material pairs (Si3N4/mica and Si3N4/ultra-high molecular weight polyethylene) was conducted using a microtribometer and atomic force microscope (AFM) at the micro- and nanometer length scales respectively, while keeping the environmental and counterface conditions same at both scales and thereby evaluating contact area dependence in the absence of surface damage and contact area independence when damage occurs. Biological macromolecules such as proteins and lipids are important constituents of the synovial fluid which is the natural lubricant present in all of our human joints. The effect of adsorbed films of proteins and lipids on the micro/nanoscale tribological response of the polymeric materials used in total joint replacements (TJRs) were investigated. The friction and wear response of UHMWPE samples with different crystallinities was studied in the presence of bovine serum albumin protein and phospholipids. The observed friction increase upon exposure to proteins was attributed to the formation of a layer of denatured proteins on the surface. Changing the crystallinity and surface energy of UHMWPE affected the protein adsorption mechanism and the resulting increase in friction behavior. It was also found that increased crystallinity lowered the friction response and increased the scratch and wear resistance at both micro and nanoscales. It was also found that higher crystallinity increased the adsorption of the phospholipid and acted as an effective lubricant reducing the friction response and increasing the wear resistance of the interface. The surface stress generation during the formation of a self-assembled monolayer (SAM) of alkanethiols on a macroscale domain was investigated in order to exploit this effect for sensing systems. To that effect, a curvature interferometry technique was used to study the surface stress generated during the formation of octadecanethiol SAM on a 25 mm x 25 mm mica sample. It was seen that the magnitude of surface stress measured on macroscale domain compared well with previously reported measurement on micron sized domains. The possibility of utilizing a SAM system as a means to achieve active friction modulation of a surface was also investigated. A low-density SAM system, shown to exhibit conformational changes in the presence of an electric field, was synthesized and its friction response was studied using an AFM. Friction experiments showed that in the presence of a positive bias, the film showed a higher friction response (up to 300%) than when a negative bias was applied. The difference in the friction responses was attributed to the changes in the structural and crystalline order of the film between the two bias conditions

Age-related vascular stiffening: causes and consequences

Arterial stiffening occurs with age and is closely associated with the progression of cardiovascular disease. Stiffening is most often studied at the level of the whole vessel because increased stiffness of the large arteries can impose increased strain on the heart leading to heart failure. Interestingly, however, recent evidence suggests that the impact of increased vessel stiffening extends beyond the tissue scale and can also have deleterious microscale effects on cellular function. Altered extracellular matrix (ECM) architecture has been recognized as a key component of the pre-atherogenic state. Here, the underlying causes of age-related vessel stiffening are discussed, focusing on age-related crosslinking of the ECM proteins as well as through increased matrix deposition. Methods to measure vessel stiffening at both the macroscale and microscale are described, spanning from the pulse wave velocity measurements performed clinically to microscale measurements performed largely in research laboratories. Additionally, recent work investigating how arterial stiffness and the changes in the ECM associated with stiffening contributed to endothelial dysfunction will be reviewed. We will highlight how changes in ECM protein composition contribute to atherosclerosis in the vessel wall. Lastly, we will discuss very recent work that demonstrates endothelial cells are mechano-sensitive to arterial stiffening, where changes in stiffness can directly impact endothelial cell health. Overall, recent studies suggest that stiffening is an important clinical target not only because of potential deleterious effects on the heart but also because it promotes cellular level dysfunction in the vessel wall, contributing to a pathological atherosclerotic state