Hybrid diffuse optics for monitoring of tissue hemodynamics with applications in oncology

Noninvasive measurement of hemodynamics at the microvascular level may have a great impact on oncology in clinics for diagnosis, therapy planning and monitoring, and, in preclinical studies. To this end, diffuse optics is a strong candidate for noninvasive, repeated, deep tissue monitoring. In this multi-disciplinary, translational work, I have constructed and deployed hybrid devices which are the combination of two qualitatively different methods, near infrared diffuse optical spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS), for simultaneous measurement of microvascular total hemoglobin concentration, blood oxygen saturation and blood flow. In a preclinical study, I applied the hybrid device to monitor the response of renal cell carcinoma in mice to antiangiogenic therapy. The results suggest that we can predict the output of therapy from early hemodynamic changes, which provide us with valuable information for better understanding of the tumor resistance mechanism to antiangiogenic therapies. In two in vivo studies in human volunteers, I have developed protocols and probes to demonstrate the feasibility of noninvasive diffuse optical spectroscopy to investigate the pathophysiology of bone. First study was study on the physiology of the patella microvasculature, the other introduced the manubrium as a site that is rich in red bone mar- row and accessible to diffuse optics as a potential window to monitor the progression of hematological malignancies. Overall, during my Ph.D., I have developed instrumentation, algorithms and protocols and, then, applied this technique for preclinical and clinical investigations. My research is a link between preclinical and clinical studies and it opens new areas of applications in oncology.La medición no invasiva de la hemodinámica a nivel microvascular puede alcanzar un gran impacto en oncología: en las clínicas para el diagnóstico, la planeación y monitorización de las terapias, y en estudios preclínicos. La óptica difusa es una fuerte candidata para la monitorización no invasiva y repetida del tejido profundo. En este trabajo multidisciplinario y traslacional, construí e implementé dispositivos híbridos que son la combinación de dos métodos cualitativamente diferentes: espectroscopía infrarroja de óptica difusa -near infrared diffuse optical spectroscopy (NIRS)- y espectroscopía de correlación de luz difusa -diffuse correlation spectroscopy (DCS)-. Estos híbridos permiten la medición simultánea de la concentración de hemoglobina total en sangre, la saturación de oxígeno y el flujo sanguíneo. En un estudio preclínico, apliqué el dispositivo híbrido para monitorizar la respuesta de carcinomas de células renales, implantados en ratones, a terapias antiangiogénicas. Los resultados sugieren que podemos predecir la evolución de la terapia con base en cambios hemodinámicos tempranos, lo cual proporciona información valiosa para un mejor entendimiento del mecanismo de resistencia de los tumores a las terapias antiangiogénicas. En dos estudios in vivo realizados en pacientes voluntarios, desarrollé protocolos y sondas para demostrar la viabilidad de la espectroscopía de óptica difusa no invasiva en el estudio de la patofisiología ósea. El primer estudio se concentró en la fisiología microvascular de la rótula y en el otro se muestra que el manubrio, hueso rico en médula ósea roja, es un sitio accesible para la óptica difusa, y se presenta como una ventana para monitorizar la progresión de enfermedades hematológicas malignas. En resumen, durante mi trabajo doctoral, desarrollé instrumentación, algoritmos y protocolos que posteriormente apliqué en estudios preclínicos y clínicos. Mi trabajo de investigación constituye así un enlace entre estos estudios y abre nuevas áreas de aplicación en oncología

Multidistance diffuse correlation spectroscopy for simultaneous estimation of blood flow index and optical properties

Traditionally, diffuse correlation spectroscopy (DCS) measures microvascular blood flow by fitting a physical model to the measurement of the intensity autocorrelation function from a single source-detector pair. This analysis relies on the accurate knowledge of the optical properties, absorption, and reduced scattering coefficients of the medium. Therefore, DCS is often deployed together with diffuse optical spectroscopy. We present an algorithm that employs multidistance DCS (MD-DCS) for simultaneous measurement of blood flow index, as well as an estimate of the optical properties of the tissue. The algorithm has been validated through noise-free and noise-added simulated data and phantom measurements. A longitudinal in vivo measurement of a mouse tumor is also shown. MD-DCS is introduced as a stand-alone system for small source-detector separations (<2  cm) for noninvasive measurement of microvascular blood flow.Peer ReviewedPostprint (published version

Scanning, non-contact, hybrid broadband diffuse optical spectroscopy and diffuse correlation spectroscopy system

A scanning system for small animal imaging using non-contact, hybrid broadband diffuse optical spectroscopy (ncDOS) and diffuse correlation spectroscopy (ncDCS) is presented. The ncDOS uses a two-dimensional spectrophotometer retrieving broadband (610-900 nm) spectral information from up to fifty-seven source-detector distances between 2 and 5 mm. The ncDCS data is simultaneously acquired from four source-detector pairs. The sample is scanned in two dimensions while tracking variations in height. The system has been validated with liquid phantoms, demonstrated in vivo on a human fingertip during an arm cuff occlusion and on a group of mice with xenoimplanted renal cell carcinoma. (C) 2016 Optical Society of Americ

Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics

The longitudinal effect of an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (DC 101) therapy on a xenografted renal cell carcinoma (RCC) mouse model was monitored using hybrid diffuse optics. Two groups of immunosuppressed male nude mice (seven treated, seven controls) were measured. Tumor microvascular blood flow, total hemoglobin concentration and blood oxygenation were investigated as potential biomarkers for the monitoring of the effect of therapy twice a week and were related to the final treatment outcome. These hemodynamic biomarkers have shown a clear differentiation between two groups by day four. Moreover, we have observed that pre-treatment values and early changes in hemodynamics are highly correlated with the therapeutic outcome demonstrating the potential of diffuse optics to predict the therapy response at an early time point. (C) 2017 Optical Society of Americ

Noninvasive characterization of the healthy human manubrium using di use optical spectroscopies

The abnormal, uncontrolled production of blood cells in the bone marrow causes hematological malignancies which are common and tend to have a poor prognosis. These types of cancers may alter the hemodynamics of bone marrow. Therefore, noninvasive methods that measure the hemodynamics in the bone marrow have a potential impact on the earlier diagnosis, more accurate prognosis, and in treatment monitoring. In adults, the manubrium is one of the few sites of bone marrow that is rich in hematopoietic tissue and is also relatively superficial and accessible. To this end we have combined time resolved spectroscopy and diffuse correlation spectroscopy to evaluate the feasibility of the noninvasive measurement of the hemodynamics properties of the healthy manubrium in 32 subjects. The distribution of the optical properties (absorption and scattering) and physiological properties (hemoglobin concentration, oxygen saturation and blood flow index) of this tissue are presented as the first step toward investigating its pathology.Peer ReviewedPostprint (author's final draft

Evaluation of mechanisms of colistin resistance in Klebsiella pneumoniae strains isolated from patients with urinary tract infection in ICU

Background and Objectives: One of the major causes of urinary tract infections is Klebsiella pneumoniae. Currently, few studies investigated the mechanisms of resistance to colistin in Iran. The current study aimed to determine the prevalence of plasmid and chromosome-mediated resistance to colistin in K. pneumoniae isolates. Materials and Methods: 177 urine samples were collected from patients with urinary tract infections hospitalized in the intensive care unit (ICU) of hospitals in the city of Qazvin. K. pneumoniae isolates were identified by standard biochemical methods, resistance to colistin among K. pneumoniae isolates were tested by disk diffusion and microbroth dilution methods. The chromosomal mutation and presence of the mcr genes in colistin-resistant K. pneumoniae were evaluated by PCR. Results: Out of 177 samples, 65 K. pneumoniae were obtained from patients in the ICU. Six colistin-resistant isolates were isolated with MIC values ≥4 μg/mL, none of them was positive for mcr1-5. In 4 isolates, missense mutation in mgrB gene resulted in amino acid substitutions and in one isolate of mgrB gene was found intact mgrB gene. Conclusion: The results suggest that mgrB mutation was the main mutation among colistin-resistant isolates and plasmid-borne colistin resistance was not expanded among strains

Development and characterization of a multidistance and multiwavelength diffuse correlation spectroscopy system

This paper presents a multidistance and multiwavelength diffuse correlation spectroscopy (DCS) approach and its implementation to simultaneously measure the optical proprieties of deep tissue as well as the blood flow. The system consists of three long coherence length lasers at different wavelengths in the near-infrared, eight single-photon detectors, and a correlator board. With this approach, we collect both light intensity and DCS data at multiple distances and multiple wavelengths, which provide unique information to fit for all the parameters of interest: scattering, blood flow, and hemoglobin concentration. We present the characterization of the system and its validation with phantom measurements.We thank Zachary Starkweather for building the optical probes, Ryan Stocking for help assembling the instrument, and Jason Sutin for scientific discussion. This research was supported by NIH R01GM116177, R21NS093259, and R21NS094828 and the Baby Alex Foundation. (R01GM116177 - NIH; R21NS093259 - NIH; R21NS094828 - NIH; Baby Alex Foundation)https://www.spiedigitallibrary.org/journals/neurophotonics/volume-5/issue-01/011015/Development-and-characterization-of-a-multidistance-and-multiwavelength-diffuse-correlation/10.1117/1.NPh.5.1.011015.fullPublished versio

Erratum: Prolonged monitoring of cerebral blood flow and autoregulation with diffuse correlation spectroscopy in neurocritical care patients

Corrected disclosures for the article “Prolonged monitoring of cerebral blood flow and autoregulation with diffuse correlation spectroscopy in neurocritical care patients.” DOI: 10.1117/1.NPh.5.4.045005.Published versio

Chemotherapeutic drug-specific alteration of microvascular blood flow in murine breast cancer as measured by diffuse correlation spectroscopy

The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cyclophosphamide, and paclitaxel at clinically relevant doses were investigated. Treatments with cyclophosphamide increased blood flow as early as 3 days after administration, whereas paclitaxel induced a transient blood flow decrease at 1 day after administration. Early blood flow changes correlated strongly with the treatmePeer ReviewedPostprint (published version