PhD Defence: CHARACTERIZATION OF PHOTOACOUSTIC RESPONSE OF A NOVEL INDOCYANINE GREEN J-AGGREGATE FORMULATION AND TRANSCRANIAL PHOTOACOUSTIC IMAGING FOR DETECTION OF SYSTEMIC INFLAMMATION IN A RAT MODEL

Student: Filip Bodera

Supervisors: Dr. Michael Kolios and Dr. Mark McVey

Abstract

Systemic inflammation caused by infection, trauma, or surgery can alter vascular function and contribute to morbidity and mortality. Current clinical imaging methods are limited in their ability to provide rapid, minimally invasive bedside assessments of inflammation-associated cerebral changes. Photoacoustic (PA) imaging combines optical absorption contrast with ultrasound detection and is well suited for imaging vascular and contrast-agent dynamics, which may be used to detect systemic inflammation. This dissertation describes simulations (Chapter 2), in-vitro phantom imaging (Chapter 3), and in-vivo preclinical imaging (Chapter 4) to evaluate indocyanine green (ICG) J-aggregates (J-aggs) as near-infrared (NIR) contrast agents for detection of systemic inflammation by analyzing cerebral PA signals transcranially.

Optical and acoustic simulations were designed to estimate the contrast-to-tissue ratio (CTR) of a J-aggs-like contrast agent in an anatomically realistic brain model. Monte Carlo optical modelling and k-Wave acoustic modelling were implemented in a Digimouse model with assigned optical properties to simulate an infantile rat. Two PA imaging geometries based on commercial devices were simulated: a low-frequency curved-array (LFCA) configuration and a high-frequency linear- array (HFLA) configuration. Estimated CTRs were comparable at shallow cortical depth between the two system configurations; however, the HFLA provided high spatial resolution in superficial tissues, and the LFCA maintained consistent signal at depth and across brain tissues.

Next, J-aggs were experimentally characterized using two commercial PA imaging systems in a polyurethane phantom to determine the minimum detectable concentration (MDC) for each system. Multispectral PA imaging revealed superior MDC in the LFCA; however, system-specific spectral sensitivity was reduced due to fluence-related photodegradation of J-aggs during imaging, which may reduce spectral unmixing performance. Continuous irradiation in the HFLA revealed signal decay consistent with photodegradation observed in the LFCA.

Finally, J-aggs were evaluated using transcranial PA imaging in a rat model of lipopolysaccharide (LPS)-induced systemic inflammation. Intravenous J-aggs produced sustained cerebral PA enhancement in sham animals, whereas LPS-treated animals showed attenuated and variable enhancement four hours after LPS administration, where time-group interactions were found to be statistically significant. The combination of simulations, in-vitro phantom imaging, and in-vivo studies demonstrates the utility of J-aggs as an NIR contrast agent for transcranial imaging of cerebral vessels for detection of systemic inflammation.