This dissertation describes the development of the first CMOS single photon avalanche diode (SPAD) fabricated in a deep-submicron commercial CMOS process. Single photon detection is often necessary for high-sensitivity, high dynamic range time-resolved optical measurements in diverse applications in medicine, biology, military, and optical communication links. Single photon avalanche diode (SPAD) detectors have become the device of choice and have made strong gains in recent years. They are unique in that they provide digital information of the arrival of an individual photon impinging on the detector, thus being a very powerful tool when time-of-arrival information and timing resolution are crucial. Timing precision of the detector will improve contrast in fluorescence lifetime imaging and resolution in laser ranging applications. Traditionally, single photon detectors have been fabricated using custom processes because of the conditions under which the devices operate under. Because of the need to sustain high currents and high electric- fields, special custom fabrication processes have been developed. These fabrication processes have great benefits such as low-noise, high detection efficiencies, low jitter, and tailored spectral responses towards longer wavelengths. However, these fabrication techniques are often undesirable due to increased capacitance from off- chip quenching, recharging, and processing circuitry, resulting in longer detector dead times and slower sampling rates. Furthermore, large-scale production and scalability to arrays is impractical. There has been a trend towards using Complementary Metal-Oxide- Semiconductor (CMOS) technology for constructing SPAD pixels and arrays with integrated circuitry to overcome these limitations. Though commercial CMOS technologies are by nature, generic, and are not designed for SPAD devices, they can still offer considerable advantages in certain areas where custom processes lack. This dissertation describes the modeling, simulation, and full characterization of a CMOS STI-bounded Single Photon Avalanche Diode (SPAD). State-of-the-art sampling rates, dead-time, and jitter performance are characterized, and the device is compared to traditional diffused-guard ring structures for solid-state SPADs. Further, novel applications of the CMOS SPAD for acousto-optic signal enhancement and frequency up-conversion of 1550nm are described. An optical scatter system for acoustic characterization of ultrasound responsive microbubbles and particles is designed and developed. Further, a novel method of fluorescence modulation using dye-loaded microbubbles is demonstrated

Background

Recent studies have shown that circulating branched-chain amino acids (BCAAs) are elevated in obese, insulin-resistant individuals. However, it is not known if supplementation of additional BCAAs will further impair glucose metabolism.

Objectives

The aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals.

Methods

This is a randomized crossover study involving 12 obese individuals with prediabetes. Participants were randomly assigned to receive a daily supplement containing either 20 g BCAA or protein low in BCAAs for 4 wk with a 2-wk washout in between. At each visit, an oral-glucose-tolerance test (OGTT) was performed. Collected blood samples were used to measure glucose, insulin, and insulin resistance-associated biomarkers.

Results

BCAA supplementation tended to decrease the plasma glucose area under the curve (AUC) measured by the OGTT (AUC percentage change from supplementation baseline, BCAA: -3.3% ± 3%; low-BCAA: 10.0% ± 6%; P = 0.08). However, BCAA supplementation did not affect plasma insulin during OGTT challenge (BCAA: -3.9% ± 8%; low-BCAA: 14.8% ± 10%; P = 0.28). The plasma concentrations of nerve growth factor (BCAA: 4.0 ± 1 pg/mL; low-BCAA: 5.7 ± 1 pg/mL; P = 0.01) and monocyte chemoattractant protein-1 (BCAA: -0.4% ± 9%; low-BCAA: 29.0% ± 18%; P = 0.02) were significantly lowered by BCAA supplementation compared to low-BCAA control. Plasma interleukin 1β was significantly elevated by BCAA supplementation (BCAA: 231.4% ± 187%; low-BCAA: 20.6% ± 33%; P = 0.05). BCAA supplementation did not affect the circulating concentrations of the BCAAs leucine (BCAA: 9.0% ± 12%; low-BCAA: 9.2% ± 11%), valine (BCAA: 9.1% ± 11%; low-BCAA: 12.0% ± 13%), or isoleucine (BCAA: 2.5% ± 11%; low-BCAA: 7.3% ± 11%).

Conclusions

Our data suggest that BCAA supplementation did not impair glucose metabolism in obese, prediabetic subjects. Further studies are needed to confirm the results seen in the present study. This study was registered at clinicaltrials.gov as NCT03715010.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

In vitro and animal studies have demonstrated that topical application and oral consumption of pomegranate reduces UVB-induced skin damage. We therefore investigated if oral pomegranate consumption will reduce photodamage from UVB irradiation and alter the composition of the skin microbiota in a randomized controlled, parallel, three-arm, open label study. Seventy-four female participants (30-45 years) with Fitzpatrick skin type II-IV were randomly assigned (1:1:1) to 1000 mg of pomegranate extract (PomX), 8 oz of pomegranate juice (PomJ) or placebo for 12 weeks. Minimal erythema dose (MED) and melanin index were determined using a cutometer (mexameter probe). Skin microbiota was determined using 16S rRNA sequencing. The MED was significantly increased in the PomX and PomJ group compared to placebo. There was no significant difference on phylum, but on family and genus level bacterial composition of skin samples collected at baseline and after 12 week intervention showed significant differences between PomJ, PomX and placebo. Members of the Methylobacteriaceae family contain pigments absorbing UV irradiation and might contribute to UVB skin protection. However, we were not able to establish a direct correlation between increased MED and bacterial abundance. In summary daily oral pomegranate consumption may lead to enhanced protection from UV photodamage.