Tianheng Wang

Optical scattering coefficient estimated by optical coherence tomography correlates with collagen content in ovarian tissue.

Optical scattering coefficient from ex vivo unfixed normal and malignant ovarian tissue was quantitatively extracted by fitting optical coherence tomography (OCT) A-line signals to a single scattering model. 1097 average A-line measurements at a wavelength of 1310 nm were performed at 108 sites obtained from 18 ovaries. The average scattering coefficient obtained from the normal tissue group consisted of 833 measurements from 88 sites was 2.41 mm(-1) (± 0.59), while the average coefficient obtained from the malignant tissue group consisted of 264 measurements from 20 sites was 1.55 mm(-1) (± 0.46). The malignant ovarian tissue showed significant lower scattering than the normal group (p < 0.001). The amount of collagen within OCT imaging depth was analyzed from the tissue histological section stained with Sirius Red. The average collagen area fraction (CAF) obtained from the normal tissue group was 48.4% (± 12.3%), while the average CAF obtained from the malignant tissue group was 11.4% (± 4.7%). A statistical significance of the collagen content was found between the two groups (p < 0.001). These results demonstrated that quantitative measurements of optical scattering coefficient from OCT images could be a potential powerful method for ovarian cancer detection.

Integrated optical coherence tomography, ultrasound and photoacoustic imaging for ovarian tissue characterization

Ovarian cancer has the lowest survival rate of the gynecologic cancers because it is predominantly diagnosed in Stages III or IV due to the lack of reliable symptoms, as well as the lack of efficacious screening techniques. Detection before the malignancy spreads or at the early stage would greatly improve the survival and benefit patient health. In this report, we present an integrated optical coherence tomography (OCT), ultrasound (US) and photoacoustic imaging (PAI) prototype endoscopy system for ovarian tissue characterization. The overall diameter of the prototype endoscope is 5 mm which is suitable for insertion through a standard 5-12.5mm endoscopic laparoscopic port during minimally invasive surgery. It consists of a ball-lensed OCT sample arm probe, a multimode fiber having the output end polished at 45 degree angle so as to deliver the light perpendicularly for PAI, and a high frequency ultrasound transducer with 35MHz center frequency. System characterizations of OCT, US and PAI are presented. In addition, results obtained from ex vivo porcine and human ovarian tissues are presented. The optical absorption contrast provided by PAI, the high resolution subsurface morphology provided by OCT, and the deeper tissue structure imaged by US demonstrate the synergy of the combined endoscopy and the superior performance of this hybrid device over each modality alone in ovarian tissue characterization.

A low-cost photoacoustic microscopy system with a laser diode excitation

Photoacoustic microscopy (PAM) is capable of mapping microvasculature networks in biological tissue and has demonstrated great potential for biomedical applications. However, the clinical application of the PAM system is limited due to the use of bulky and expensive pulsed laser sources. In this paper, a low-cost optical-resolution PAM system with a pulsed laser diode excitation has been introduced. The lateral resolution of this PAM system was estimated to be 7 µm by imaging a carbon fiber. The phantoms made of polyethylene tubes filled with blood and a mouse ear were imaged to demonstrate the feasibility of this PAM system for imaging biological tissues.

Characterization of ovarian tissue based on quantitative analysis of photoacoustic microscopy images

In this paper, human ovarian tissue with malignant and benign features was imaged ex vivo using an optical-resolution photoacoustic microscopy (OR-PAM) system. The feasibility of PAM to differentiate malignant from normal ovarian tissues was explored by comparing the PAM images morphologically. Based on the observed differences between PAM images of normal and malignant ovarian tissues in microvasculature features and distributions, seven features were quantitatively extracted from the PAM images, and a logistic model was used to classify ovaries as normal or malignant. 106 PAM images from 18 ovaries were studied. 57 images were used to train the seven-parameter logistic model, and a specificity of 92.1% and a sensitivity of 89.5% were achieved; 49 images were then tested, and a specificity of 81.3% and a sensitivity of 88.2% were achieved. These preliminary results demonstrate the feasibility of our PAM system in mapping microvasculature networks as well as characterizing the ovarian tissue, and could be extremely valuable in assisting surgeons for in vivo evaluation of ovarian tissue during minimally invasive surgery.

Targeting tumor hypoxia with 2-nitroimidazole- indocyanine green dye conjugates

Abstract. Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs, and fluorescence optical tomography has tremendous potential to provide clinically useful, functional information by identifying tumor hypoxia. The synthesis of a 2-nitroimidazole-indocyanine green conjugate using a piperazine linker (piperazine-2-nitroimidazole-ICG) capable of robust fluorescent imaging of tumor hypoxia is described. In vivo mouse tumor imaging studies were completed and demonstrate an improved imaging capability of the new dye relative to an earlier version of the dye that was synthesized with an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG). Mouse tumors located at imaging depths of 1.5 and 2.0 cm in a turbid medium were imaged at various time points after intravenous injection of the dyes. On average, the reconstructed maximum fluorescence concentration of the tumors injected with piperazine-2-nitroimidazole-ICG was twofold higher than that injected with ethanolamine-2-nitroimidazole-ICG within 3 h postinjection period and 1.6 to 1.7 times higher beyond 3 h postinjection. The untargeted bis-carboxylic acid ICG completely washed out after 3 h postinjection. Thus, the optimal window to assess tumor hypoxia is beyond 3 h postinjection. These findings were supported with fluorescence images of histological sections of tumor samples and an immunohistochemistry technique for identifying tumor hypoxia.

An overview of optical coherence tomography for ovarian tissue imaging and characterization

Ovarian cancer has the lowest survival rate among all the gynecologic cancers because it is predominantly diagnosed at late stages due to the lack of reliable symptoms and efficacious screening techniques. Optical coherence tomography (OCT) is an emerging technique that provides high-resolution images of biological tissue in real time, and demonstrates great potential for imaging of ovarian tissue. In this article, we review OCT studies for visualization and diagnosis of human ovaries as well as quantitative extraction of ovarian tissue optical properties for classifying normal and malignant ovaries. OCT combined with other imaging modalities to further improve ovarian tissue diagnosis is also reviewed.

Design of miniaturized illumination for transvaginal co-registered photoacoustic and ultrasound imaging

A novel lens-array based illumination design for a compact co-registered photoacoustic/ultrasound transvaginal probe has been demonstrated. The lens array consists of four cylindrical lenses that couple the laser beams into four 1-mm-core multi-mode optical fibers with optical coupling efficiency of ~87%. The feasibility of our lens array was investigated by simulating the lenses and laser beam profiles using Zemax. The laser fluence on the tissue surface was experimentally measured and was below the American National Standards Institute (ANSI) safety limit. Spatial distribution of hemoglobin oxygen saturation (sO2) of a mouse tumor was obtained in vivo using photoacoustic measurements at multiple wavelengths. Furthermore, benign and malignant ovaries were imaged ex vivo and evaluated histologically. The co-registered images clearly showed different patterns of blood vasculature. These results highlight the clinical potential of our system for noninvasive photoacoustic and ultrasound imaging of ovarian tissue and cancer detection and diagnosis.

Design of optimal light delivery system for co-registered transvaginal ultrasound and photoacoustic imaging of ovarian tissue

A hand-held transvaginal probe suitable for co-registered photoacoustic and ultrasound imaging of ovarian tissue was designed and evaluated. The imaging probe consists of an ultrasound transducer and four 1-mm-core multi-mode optical fibers both housed in a custom-made sheath. The probe was optimized for the highest light delivery output and best beam uniformity on tissue surface, by simulating the light fluence and power output for different design parameters. The laser fluence profiles were experimentally measured through chicken breast tissue and calibrated intralipid solution at various imaging depths. Polyethylene tubing filled with rat blood mimicking a blood vessel was successfully imaged up to ∼30 mm depth through porcine vaginal tissue at 750 nm. This imaging depth was achieved with a laser fluence on the tissue surface of 20 mJ/cm2, which is below the maximum permissible exposure (MPE) of 25 mJ/cm2 recommended by the American National Standards Institute (ANSI). Furthermore, the probe imaging capability was verified with ex vivo imaging of benign and malignant human ovaries. The co-registered images clearly showed different vasculature distributions on the surface of the benign cyst and the malignant ovary. These results suggest that our imaging system has the clinical potential for in vivo imaging and characterization of ovarian tissues.

A three-parameter logistic model to characterize ovarian tissue using polarization-sensitive optical coherence tomography

In this paper, a logistic prediction model is introduced to characterize the ovarian tissue. A new parameter, the phase retardation rate, was extracted from phase images of polarization-sensitive optical coherence tomography (PS-OCT). Statistical significance of this parameter between normal and malignant ovarian tissues was demonstrated (p<0.0001). Linear regression analysis showed that this parameter was positively correlated (R = 0.74) with collagen content, which was associated with the development of ovarian tissue malignancy. When this parameter and the optical scattering coefficient and the phase retardation estimated from the 33 ovaries were used as input predictors to the logistic model, 100% sensitivity and specificity in classifying malignant and normal ovaries were achieved. Ten additional ovaries were imaged and used to validate the prediction model and 100% sensitivity and 83.3% specificity were achieved. These results showed that the three-parameter prediction model based on quantitative parameters estimated from PS-OCT images could be a powerful tool to detect and diagnose ovarian cancer.

Quantitative analysis of estimated scattering coefficient and phase retardation for ovarian tissue characterization

In this report, optical scattering coefficient and phase retardation quantitatively estimated from polarization-sensitive OCT (PSOCT) were used for ovarian tissue characterization. A total of 33 ex vivo ovaries (normal: n = 26, malignant: n = 7) obtained from 18 patients were investigated. A specificity of 100% and a sensitivity of 86% were achieved by using estimated scattering coefficient alone; and a specificity of 100% and a sensitivity of 43% were obtained by using phase retardation alone. However, a superior specificity of 100% and sensitivity of 100% were achieved if these two parameters were used together for classifying normal and malignant ovaries. Quantitative measurement of collagen content obtained from Sirius red histology sections shows that it correlates with estimated scattering coefficient and phase retardation. Our initial results demonstrate that quantitative analysis of PSOCT could be a potentially valuable method for distinguishing normal from malignant ovarian tissues during minimally invasive surgery and help guide surgical intervention.