Yi-Ting Tsai

Graduation Semester and Year

2013

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Liping Tang

Abstract

Persistent inflammatory cell reactions are responsible for the pathogenesis of a variety of inflammatory diseases. Although many non-invasive imaging methods have been used in the clinics to monitor the extent of inflammatory responses, almost all of them are based on indirect detection of inflammation-associated anatomical or structure changes of tissues and organs. To fill the gap, our laboratory has focused research efforts on detecting different processes of inflammatory responses. Our results can be summarized in the sequence of inflammatory responses - edema formation, inflammatory cell recruitment, inflammatory product release, and cell death. Shortly after medical device implantation or injury, edema results from fibrin deposition in tissue at the implant/injury site. A near-infrared (NIR)-based fibrin probe was fabricated to detect fibrin deposition. We found that the fibrin probe can be used to quantify the extent of fibrin formation in vitro as early as 15 minutes post subcutaneous particle implantation in vivo. Subsequent studies also revealed that fibrin deposition is mediated by mast cell activation and there is a good relationship between short term fibrin deposition and long term inflammatory responses to biomaterial implants. The accumulation of inflammatory cells, especially macrophages and neutrophils, is a hallmark of inflammatory responses. For the detection of neutrophils and macrophages, formyl peptide receptor-targeting and folate receptor-targeting NIR probes were fabricated, respectively. Both probes can be used to monitor neutrophil and macrophage recruitment at the biomaterial implant sites. These probes similarly have a strong relationship with the acquired fluorescent intensities and the inflammatory cell counts from histological analyses. Both probes can be used to non-invasively monitor inflammatory responses, including foreign body reactions and infection, in real time. Activated inflammatory cells, particularly polymorphonuclear neutrophils (PMNs), can release reactive oxygen species (ROS) to eradicate foreign bodies and microorganisms. We find that L-012-associated chemiluminescence imaging can be used to identify and to quantify the extent of inflammatory responses. Furthermore, regardless of differences among animal models, there is a good linear relationship between chemiluminescence intensity and PMN numbers surrounding inflamed tissue. The release of inflammatory products and associated cell death will lead to the reduction of pH in tissue also called as tissue acidosis. A novel pH ratiometric optical probe was fabricated carrying both pH-sensitive and pH-insensitive fluorescence dyes for in vivo optical imaging. By taking the ratio of fluorescence intensities at different wavelengths, these probes provide excellent measurement, distribution, and change of tissue pH at different times. We find that the ratiometric pH changes are a good indicator of inflammatory responses, further confirmed by histological analyses. Finally, to explore the possibility of monitoring fluorescence distribution via 3D models, we developed a 3D reconstruction model to enable mapping of the spatio-temporal distribution of fluorescence probes. This model may lead to enhanced understanding of in vivo fluorescent imaging modalities providing detailed location and anatomical structure information. We present the evaluation of the system and method in recovering three-dimensional surfaces from phantom data and living mice. The results obtained in this study showed our 3D reconstruction model could provide the shape, depth, and bio-distribution information for our inflammation model.

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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