Development of Portable Diffuse Optical Spectroscopic Systems For Treatment Monitoring

The goal of this dissertation is to demonstrate the utility of portable, small-scale diffuse optical spectroscopic (DOS) systems for the diagnosis and treatment monitoring of various diseases. These systems employ near-infrared light (wavelength range of 650nm to 950nm) to probe human tissue and are sensitive to changes in scattering and absorption properties of tissues. The absorption is mainly influenced by the components of blood, namely oxy- and deoxy-hemoglobin (HbO2 and Hb) and parameters that can be derived from them (e.g. total hemoglobin concentration [THb] and oxygen saturation, StO2). Therefore, I focused on diseases in which these parameters change, which includes vascular diseases such as Peripheral Atrial Disease (PAD) and Infantile Hemangiomas (IH) as well as musculoskeletal autoimmune diseases such as Rheumatoid Arthritis (RA). In each of these specific diseases, current monitoring techniques are limited by their sensitivity to disease progression or simply do not exist as a quantitative metric. As part of this project, I first designed and built a wireless handheld DOS device (WHDD) that can perform DOS measurements at various tissue depths. This device was used in a 15-patient pilot study for infantile hemangiomas (IH) to differentiate diseased skin from normal skin and monitor the vascular changes during intervention. In another study, I compare the ultra-small form- factor WHDD’s ability to monitor synovitis and disease progression during a patient’s treatment of RA against the capabilities of a proven frequency domain optical tomographic (FDOT) system that has shown to differentiate patients with and without RA. Learning from clinical utility of the WHDD from these two studies, I adapted the WHDD technology to develop a compact multi- channel DOS measurement system to monitor perfusion changes in the lower extremities before and after surgical intervention for patients with peripheral artery disease (PAD). Using this multi- channel system, which we called the vascular optical spectroscopic measurement (VOSM) system, our group conducted a 20-subject pilot study to quantify its ability to monitor blood perfusion before and after revascularization of stenotic arteries in the lower extremities. This proof-of- concept study demonstrated how DOS may help vascular surgeons perform revascularization procedures in the operating room and assists in post-operative treatment monitoring of vascular diseases

Analysis of Cell Signaling Perturbations in Response to Chronic Localized Infections

The tissue-level response to pathogens involves an intricate series of signal transduction events, influenced by immune and healing mediators that alert the host to danger and eliminate the infection. Disruptions to normal signaling events can compromise the host’s ability to respond and lead to the development of chronic infections that cannot be resolved without clinical intervention. Prolonged inflammation due to chronic infection can damage tissues and compromise healing processes, thus, the interactions of immune and healing mediators in signaling cascades are intimately linked to tissue health outcomes. Studying signaling networks relevant to these responses provided a more thorough understanding of localized tissue health to identify the drivers of disruptions to signaling cascades, and this knowledge can lead to the development of improved diagnostic and therapeutic biomarkers to combat chronic infections. The work presented here focused on elucidating the relationships between immune and wound healing factors in an in vivo rodent model and a clinical cohort to understand the tissue-level responses to chronic inflammation and infection. Specifically, extracellular inflammatory immune responses (i.e., cytokines and chemokines) related to intracellular signaling (i.e., phosphorylation of proteins) were investigated to identify alterations in native responses compared to those provoked by chronic inflammation and infection. Reponses in native tissues were compared to tissues with inflammatory and infectious stimuli to test if levels of immune related cytokines were elevated in response to chronic joint infections. Wound healing phosphoproteins were also included to look for shifts in wound healing-related processes across groups. Traditional statistical approaches and network analysis were used to dissect these complex biological datasets and identified drivers of network disruptions in response to inflammation and infection. The spatial analysis suggested that changes in biological responses were related to proximity to inflammation and infection, and the degree of response differed across spatial gradients, which demonstrated the ability for these chronic insults to affect disparate tissues in a clinically-relevant manner. The objective of this research and future related research is to facilitate new clinical strategies to combat chronic infection, and monitoring alterations to cell signaling pathways in this work highlighted the value of using network analysis to approach biological interrogation of signal disruptions related to these insults