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<p>   </p> <p>Subcutaneous injection is a biotherapeutic drug delivery method that is currently growing due to low cost, better patient compliance, minimally invasive, and the convenience that it can be done at home. Common injection sites for subcutaneous injection include the upper outer arms, abdomen, buttocks, and upper outer thigh. Heterogeneity of the tissue exists between and within each of these locations. The subcutaneous tissue space is made up of adipose tissue, proteins, collagen, and blood vessels and each of these components has an impact on the mass transport of the injected biotherapeutics and how they are absorbed into the vascular system and then distributed to the body. The current methods used to model the subcutaneous tissue space are either very expensive and not feasible for multiple repetitions, cannot incorporate fibrillar proteins or cellular components, or model a more homogeneous tissue space. These limitations do not allow for these models to accurately represent the subcutaneous tissue space. The engineering objective for this project was to develop a platform with tunable matrix architecture and biochemical composition for evaluating mass transport. This project utilizes collagen and the primary matrix due to the large abundance of collagen in the body.  We explored the effects that a change in polymerization temperature of the collagen and collagen concentration had on the fiber architecture and pore diameter. The results showed that higher polymerization temperatures of the collagen gels resulted in smaller fiber and pore diameters and an increase in concentration resulted in an increase in fiber volume fraction and a decrease in pore diameter. Fibronectin (FN) and hyaluronic acid (HA) were added to the collagen gels to analyze the impact on the structure of collagen gels with a change in polymerization temperature and collagen concentration. The addition of FN did not strongly alter the collagen fiber architecture between polymerization temperatures and collagen concentrations. Through staining and imaging, we saw an aggregation of FN around the collagen fibrils due to their opposing charges causing them to bind. The addition of HA had moderate impact on collagen fiber architecture across all polymerization temperatures and between collagen concentrations. The collagen + FN gels were used for the mass transport study. The results showed that there was little to no difference between the recovery rates of macromolecules of different charges and size between the collagen and collagen + FN gels, indicating that the transport of molecules through both of the collagen gels was impacted by a steric effect rather than an effect in charge.</p> <p>  </p>

Optics are a powerful probe of chemical structure that can often be linked to theoretical predictions, providing robustness as a measurement tool. Not only do optical interactions like second harmonic generation (SHG), single and two-photon excited fluorescence (TPEF), and infrared absorption provide chemical specificity at the molecular and macromolecular scale, but the ability to image enables mapping heterogeneous behavior across complex systems such as biological tissue. This thesis will discuss nonlinear and linear optics, leveraging theoretical predictions to provide frameworks for interpreting analytical measurement. In turn, the causal mechanistic understanding provided by these frameworks will enable structurally specific quantitative tools with a special emphasis on application in biological imaging. The thesis will begin with an introduction to 2nd order nonlinear optics and the polarization analysis thereof, covering both the Jones framework for polarization analysis and the design of experiment. Novel experimental architectures aimed at reducing 1/f noise in polarization analysis will be discussed, leveraging both rapid modulation in time through electro-optic modulators (Chapter 2), as well as fixed-optic spatial modulation approaches (Chapter 3). In addition, challenges in polarization-dependent imaging within turbid systems will be addressed with the discussion of a theoretical framework to model SHG occurring from unpolarized light (Chapter 4). The application of this framework to thick tissue imaging for analysis of collagen local structure can provide a method for characterizing changes in tissue morphology associated with some common cancers (Chapter 5). In addition to discussion of nonlinear optical phenomena, a novel mechanism for electric dipole allowed fluorescence-detected circular dichroism will be introduced (Chapter 6). Tackling challenges associated with label-free chemically specific imaging, the construction of a novel infrared hyperspectral microscope for chemical classification in complex mixtures will be presented (Chapter 7). The thesis will conclude with a discussion of the inherent disadvantages in taking the traditional paradigm of modeling and measuring chemistry separately and provide the multi-agent consensus equilibrium (MACE) framework as an alternative to the classic meet-in-the-middle approach (Chapter 8). Spanning topics from pure theoretical descriptions of light-matter interaction to full experimental work, this thesis aims to unify these two fronts. <br>