584 research outputs found

    Computer simulation of glioma growth and morphology

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    Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in vitro and in vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g., from histopathology or intra-operative analysis, this model can be used for disease diagnosis/prognosis, hypothesis testing, and to guide surgery and therapy. In particular, this tool identifies and quantifies the effects of vascularization and other cell-scale glioma morphological characteristics as predictors of tumor-scale growth and invasion

    The role of tumour vasculature in fluid flow and drug transport in solid tumours

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    The aberrance of the vasculature in tumours has been linked to increased aggressiveness and poor drug delivery in tumours. Complexities in the microarchitecture of tumour vasculature occurring on microscopic scales can affect fluid flow and drug transport making it difficult to predict tumour response to treatment. Given this, mathematical models can play an important role in understanding the various aspects of the tumour vasculature that can promote invasiveness and limit drug delivery. In this work, computational models are developed to investigate the effect of tumour vasculature on fluid flow and drug distribution and novel imaging methods are assessed for their ability to characterise the tumour vasculature in whole human tumours. A mathematical angiogenesis model is used to generate microscopic details including individual vessel properties on a whole vascular network scale which are coupled with a fluid flow and drug transport model. The interstitial fluid pressure (IFP) in the tumour model was found to be elevated with increased heterogeneity caused by the presence of a necrotic core and heterogenous vessel permeability. Subtle changes to the network on a microscopic scale significantly influenced fluid flow in the tumour vessels and tissue. Delivery of doxorubicin to tumours was found to be highly dependent on the properties of tumour vasculature and blood flow, where regions with excessive branching and vessel tortuosity had reduced drug concentrations due to poor blood flow. Hence, the vascular density was not found to be the main factor in the accumulation of the drug within the tissue space and it’s uptake by cancer cells. An interplay between treatment strategy including dose and administration mode and properties of the vasculature was found by evaluating the spatial intracellular concentration. The fluid flow and drug transport models showed the significant effect of incorporating the microscopic properties of the tumour vasculature which can influence fluid flow and drug distribution on a macroscopic scale. The imaging methods assessed in this work shows that Optical projection tomography combined with fluorescent Immunohistochemistry labelling methods can be used to extract angiogenesis related parameters in whole human tumours. Additionally, the method was able to extract clean network topologies that show promise in application to understanding fluid flow and drug transport in real tumours.Open Acces

    Development of Imaging Paradigms for Drug Distribution and Fate in the Eye

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    Aging-associated vision loss is increasingly prevalent in our population and intravitreal injections are commonly used to administer ocular drugs to the posterior segment of the eye. This work aims to visualize and predict the delivery of ocular drugs by combining micro- computed tomography (micro-CT) imaging and computational fluid dynamics (CFD) modeling. Intravitreal injections were administered into ex vivo porcine eyes and imaged for an extended period of time to track the progression of the injected drug mimic. Non-invasive imaging allowed for precise determination of contrast agent concentration, flow patterns and fate. A computational model was developed that provided quantitative agreement with the concentration values found in the experimental study and allowed for easy manipulation of parameters. The ability to accurately model drug transport following an intravitreal injection provides vital information to better understand the specific concentration and time frame for the drug to reach the target sit

    Light-driven micro-robotics for contemporary biophotonics.

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    Applications of Nanobiotechnology

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    This book is dedicated to the applications of nanobiotechnology, i.e. the way that nanotechnology is used to create devices to study biological systems and phenomena. It includes seven chapters, organized in two sections. The first section (Chapters 1–5) covers a large spectrum of issues associated with nanoparticle synthesis, nanoparticle toxicity, and the role of nanotechnology in drug delivery, tissue engineering, agriculture, and biosensing. The second section (Chapters 6 and 7) is devoted to the properties of nanofluids and the medical and biological applications of computational fluid dymanics modeling

    Applications of polarized metallic nanostructures.

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    Gold nanostructures exhibit technologically useful properties when they are polarized in an electric field. In two projects we explore instances where the polarized metal can be used in real world applications. The first project involves gold nanoparticles (GNP) for use in light actuated microelectromechanical systems (MEMS) applications. Although the GNPs were originally designed for volumetric heating in biomedical applications, we treat them as a thin film coating, opening the door for these particles to be used in MEMS applications. This work characterizes the thermal properties of gold nanoparticles on surfaces for spatially-targeted thermal actuation in MEMS systems. The second project deals with metalized nanopore membranes for use in microfluidic applications. For this project several models and experiments were performed on electroosmotic flows driven by charge separation at polarized nanopore surfaces. Until this work, the flow-through geometry remained unexplored for induced charge electroosmotic flow (ICEO)

    Thermal-AFM under aqueous environment

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    The aim of this thesis is to describe the work developing and demonstrating the use of Scanning Thermal Microscopy (SThM) in an aqueous electrically conductive environment for the first time. This has been achieved by using new instrumentation to allow conventional SThM probes to measure and manipulate the temperature of non-biological and biological samples. For the latter, the aqueous environment is crucial to allow in-vitro experimentation, which is important for the future use of SThM in the life sciences. SThM is known to be a powerful technique able to acquire simultaneous topographic and thermal images of samples. It is able to measure the microscopic thermal properties of a surface with nanoscale spatial resolution. However, SThM has traditionally been limited to use in vacuum, air and electrically inert liquids. The aqueous Scanning Thermal Microscopy (a-SThM) described in this thesis is an entirely novel technique that opens up a new field for thermal-AFM. The first challenge addressed in this work was the adaptation of a commercial Multimode Nanoscope IIIa AFM to permit electrical access to a SThM probe completely immersed in aqueous solutions. By employing a newly designed probe holder and electronic instrumentation, the probe could then be electrically biased without inducing electrochemical reactions. This approach permitted conventional microfabricated thermal probes to be operated whilst fully immersed in water. This innovation allowed SThM measurements under deionized (DI) water to be performed on a simple solid sample (Pt on Si3N4) and the results compared with in-air scans and accurate 3D Finite Element (FE) simulations. Once the validity of the technique was proven, its performance was investigated, including crucially the limit of its thermal-spatial resolution; this was investigated using nanofabricated solid samples (Au on Si3N4) with well-defined features. These results were compared to the FE model, allowing an understanding of the mechanisms limiting resolution to be developed. In order to demonstrate the advantages granted by the water’s superior thermal conductivity compared to air or other liquids, non-contact thermal images were also acquired using the same samples. The final part of this thesis was focused on extending SThM into the biological area; a completely new field for this technique. New results are presented for soft 4 samples: I-collagen gel and collagen fibrils, which were thermally manipulated using a self-heated SThM probe. This successfully demonstrated the possibility of using heat to alter a biological sample within a very well localised area while being operated for long time in an aqueous environment. The difference in force response originated from the AFM scans with different levels of self-heating further proved the robustness of the technique. Finally, the technique was employed to study MG-63 living cells: The SThM probe was left in contact with each cell for a pre-determined period of time, with and without self heating. The results demonstrated that only the heated cells, directly beneath the probe tip died, tallying with the highly localised temperature gradient predicted by FE analysis

    Microfluidic device flow field characterization around tumor spheroids with tunable necrosis produced in an optimized off-chip process

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    Tumor spheroids are a 3-D tumor model that holds promise for testing cancer therapies in vitro using microfluidic devices. Tailoring the properties of a tumor spheroid is critical for evaluating therapies over a broad range of possible indications. Using human colon cancer cells (HCT-116), we demonstrate controlled tumor spheroid growth rates by varying the number of cells initially seeded into microwell chambers. The presence of a necrotic core in the spheroids could be controlled by changing the glucose concentration of the incubation medium. This manipulation had no effect on the size of the tumor spheroids or hypoxia in the spheroid core, which has been predicted by a mathematical model in computer simulations of spheroid growth. Control over the presence of a necrotic core while maintaining other physical parameters of the spheroid presents an opportunity to assess the impact of core necrosis on therapy efficacy. Using micro-particle imaging velocimetry (micro-PIV), we characterize the hydrodynamics and mass transport of nanoparticles in tumor spheroids in a microfluidic device. We observe a geometrical dependence on the flow rate experienced by the tumor spheroid in the device, such that the “front” of the spheroid experiences a higher flow velocity than the “back” of the spheroid. Using fluorescent nanoparticles, we demonstrate a heterogeneous accumulation of nanoparticles at the tumor interface that correlates with the observed flow velocities. The penetration depth of these nanoparticles into the tumor spheroid depends on nanoparticle diameter, consistent with reports in the literature

    Three Dimensional Cell Culture: A Window into Transport of Nanomedicine in Tumor Tissue.

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    Recent growth in nanotechnology has been accelerating the identification and evaluation of new drug candidates. The development, optimization of nanomedicine and preclinical drug screening is critical but long and expensive. These studies are challenging due to the lack of test platforms that can incorporate sufficient human-relevant physiological complexity for reliable and standardized prediction. Current preclinical models based on animals are expensive and has poor predictivity due to the variety of animals and limitation of imaging technologies. Two-dimensional (2D) cell cultures used in the preclinical phase drug screening cannot adequately restore original cellular behaviors to nanomedicine in three-dimensional (3D) tissues. 3D cell culture models with the ability to independently manipulate microenvironmental factors can be used as a platform, to explore fundamental biological response to novel therapeutic nanoparticles. Transport of nanomedicine through solid tumors can be adequately evaluated in specially prepared 3D cell culture as platform. This is important for validating drug doses and administration regimens required to achieve desired therapeutic effects. In coupling with Monte-Carlo sampling and analysis of conditioned microenvironment, the standardized and uniform-sized liver tumor spheroids culture model in Inverted Colloidal Crystal (ICC) scaffolds can be used to quantitatively identify or validate predictive nanoparticle (NP) transport, while transparency of the platform allowed convenient real-time monitoring with high resolution. This dissertation established the experimental and conceptual framework for quantitative evaluation of NP transport in the tumor tissue ex vivo as a part of drug discovery, and explored a new opportunity of carbon nanotubes as a promising nano-sized carrier for drug delivery. Beside, this platform has been improved to develop patient/disease-specific model for individualized study of drug safety and efficacy or drug–drug interactions with 3D stem cell culture. In this part of dissertation, ICC scaffolds with uniform, controllable porous structure combined with a layer-by-layer (LBL) bone mimetic modification technique served as a platform for engineered stem cells. Overall, this dissertation introduces a promising and standardized 3D cell culture platform as a window to fundamental understanding of nanomedicine, as well as a practical and valuable tool for drug discovery regarding drug delivery and transport through complex 3D tissues.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/120907/1/yichunw_1.pd

    Improving FRAP and SPT for mobility and interaction measurements of molecules and nanoparticles in biomaterials

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    An increasing amount of pharmaceutical technologies are being developed in which nanoparticles play a crucial role. The rational development of these technologies requires detailed knowledge of the mobility and interaction of the nanoparticles inside complex biomaterials. The aim of this PhD thesis is to improve fluorescence microscopy based methods that allow to extract this information from time sequences of images. In particular, the fluorescence microscopy techniques Fluorescence Recovery After Photobleaching (FRAP) and Single Particle Tracking (SPT) are considered. FRAP modelling is revisited in order to incorporate the effect of the microscope's scanning laser beam on the shape of the photobleached region. The new model should lead to more straightforward an accurate FRAP measurements. SPT is the main focus of the PhD thesis, starting with an investigation of how motion during image acquisition affects the experimental uncertainty with which the nanoparticle positions are determined. This knowledge is used to develop a method that is able to identify interactions between nanoparticles in high detail, by scanning their trajectories for correlated positions. The method is proven to be useful in the context of drug delivery, where it was used to study the intracellular trafficking of polymeric gene complexes. Besides SPT data analysis, it is also explored how light sheet illumination, which allows to strongly reduce the out of focus fluorescence that degrades the contrast in SPT experiments, can be generated by a planar waveguide that is incorporated on a disposable chip. The potential as platform for diagnostic measurements was demonstrated by using the chip to perform SPT size and concentration measurements of cell-derived membrane vesicles. The results of this PhD thesis are expected to contribute to the effort of making accurate SPT and FRAP measurements of nanoparticle properties in biomaterials more accessible to the pharmaceutical research community
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