Interstitial Doppler optical coherence tomography as a local tumor necrosis predictor in photodynamic therapy of prostatic carcinoma: an in vivo study.

We have tested the feasibility of real-time localized blood flow measurements, obtained with interstitial (IS) Doppler optical coherence tomography (DOCT), to predict photodynamic therapy (PDT)-induced tumor necrosis deep within solid Dunning rat prostate tumors. IS-DOCT was used to quantify the PDT-induced microvascular shutdown rate in s.c. Dunning prostate tumors (n=28). Photofrin (12.5 mg/kg) was administered 20 to 24 hours before tumor irradiation, with 635 nm surface irradiance of 8 to 133 mWcm(-2) for 25 minutes. High frequency ultrasound and calipers were used to measure the thickness of the skin covering the tumor and the location of the echogenic IS probe within it. A two-layer Monte Carlo model was used to calculate subsurface fluence rates within the IS-DOCT region of interest (ROI). Treatment efficacy was estimated by percent tumor necrosis within the ROI, as quantified by H&E staining, and correlated to the measured microvascular shutdown rate during PDT treatment. IS-DOCT measured significant PDT-induced vascular shutdown within the ROI in all tumors. A strong relationship (R2=0.723) exists between the percent tumor necrosis at 24 hours posttreatment and the vascular shutdown rate: slower shutdown corresponded to higher treatment efficacy, i.e., more necrosis. Controls (needle+light, no drug, n=3) showed minimal microvascular changes or necrosis (4%+/-1%). This study has correlated a biological end point with a direct and localized measurement of PDT-induced microvascular changes, suggesting a potential clinical role of on-line, real-time microvascular monitoring for optimizing treatment efficacy in individual patients.

Conducting polymer based active catheter for minimally invasive interventions inside arteries.

An active catheter intended for controllable intravascular maneuvers is presented and initial experimental results are shown. A commercial catheter is coated with polypyrrole and laser micromachined into electrodes, which are electrochemically activated, leading to bending of the catheter. The catheter's electro-chemo-mechanical properties are theoretically modeled to design the first prototype device, and used to predict an optimal polypyrrole thickness for the desired degree of bending within approximately 30 seconds. We compared the experimental result of catheter bending to the theoretical model with estimated electrochemical strain, showing reasonable agreement. Finally, we used the model to design an encapsulated catheter with polypyrrole actuation for improved intravascular compatibility and performance.

Doppler optical coherence tomography monitoring of microvascular tissue response during photodynamic therapy in an animal model of Barrett's esophagus.

BACKGROUND: Doppler optical coherence tomography (DOCT) is an imaging modality that allows assessment of the microvascular response during photodynamic therapy (PDT) and may be a powerful tool for treatment monitoring/optimization in conditions such as Barrett's esophagus (BE). OBJECTIVE: To assess the technical feasibility of catheter-based intraluminal DOCT for monitoring the microvascular response during endoluminal PDT in an animal model of BE. DESIGN: Thirteen female Sprague-Dawley rats underwent esophagojejunostomy to induce enteroesophageal reflux for 35 to 42 weeks and the formation of Barrett's mucosa. Of these, 9 received PDT by using the photosensitizer Photofrin (12.5 mg/kg intravenous), followed by 635-nm intraluminal light irradiation 24 hours after drug administration. The remaining 4 surgical rats underwent light irradiation without Photofrin (controls). Another group of 5 normal rats, without esophagojejunostomy, also received PDT. DOCT imaging of the esophagus by using a catheter-based probe (1.3-mm diameter) was performed before, during, and after light irradiation in all rats. RESULTS: Distinct microstructural differences between normal squamous esophagus, BE, and the transition zone between the 2 tissues were observed on DOCT images. Similar submucosal microcirculatory effects (47%-73% vascular shutdown) were observed during PDT of normal esophagus and surgically induced BE. Controls displayed no significant microvascular changes. CONCLUSIONS: No apparent difference was observed in the PDT-induced vascular response between normal rat esophagus and the BE rat model. Real-time monitoring of PDT-induced vascular changes by DOCT may be beneficial in optimizing PDT dosimetry in patients undergoing this therapy for BE and other conditions.

Interstitial Doppler optical coherence tomography monitors microvascular changes during photodynamic therapy in a Dunning prostate model under varying treatment conditions.

We measure the tumor vascular response to varying irradiance rates during photodynamic therapy (PDT) in a Dunning rat prostate model with interstitial Doppler optical coherence tomography (IS-DOCT). Rats are given a photosensitizer drug, Photofrin, and the tumors are exposed to light (635 nm) with irradiance rates ranging from 8 to 133 mWcm(2) for 25 min, corresponding to total irradiance of 12 to 200 Jcm(2) (measured at surface). The vascular index computed from IS-DOCT results shows the irradiance rate and total irradiance dependent microvascular shutdown in the tumor tissue during PDT. While faster rates of vascular shutdown were associated with increasing PDT irradiance rate and total irradiance, a threshold effect was observed as irradiance rates above 66 mWcm(2) (surface), where no further increase in vascular shutdown rate was detected. The maximum post-treatment vascular shutdown (81%) without immediate microcirculatory recovery was reached with the PDT condition of 33 mWcm(2) and 50 Jcm(2). Control groups without Photofrin show no significant microvascular changes. Microvascular shutdown occurs at different rates and shows correlation with PDT total irradiance and irradiance rates. These dependencies may play an important role in PDT treatment planning, feedback control for treatment optimization, and post-treatment assessment.

Ex vivo imaging of chronic total occlusions using forward-looking optical coherence tomography.

BACKGROUND AND OBJECTIVES: Percutaneous coronary interventions (PCI) of chronic total occlusions (CTOs) of arteries are more challenging lesions to treat with angioplasty and stenting than stenotic vessels due primarily to the difficulty in guiding the wire across the lesion. Angiography alone is unable to differentiate between the occluded lumen and the vessel wall and to characterize the content of the occlusion. New technologies to aid in interventional guidance are therefore highly desirable. We sought to evaluate tissue characterization in arterial (CTOs) by imaging ex vivo peripheral arterial samples with optical coherence tomography (OCT). STUDY DESIGN/MATERIALS AND METHODS: Ex vivo arterial samples were obtained from patients undergoing peripheral limb amputation. Samples were imaged in an enface orientation using an OCT system, enabling sequential acquisition of longitudinal images and volumetric reconstruction of cross-sectional views of the occluded arteries. Histology was performed for comparison. RESULTS: OCT imaging reliably differentiated between the occluded lumen and the underlying arterial wall in peripheral CTOs. OCT correctly identified tissue composition within the CTO, such as the presence of collagen and calcium and was also able to identify intraluminal microchannels. CONCLUSIONS: OCT imaging of CTO anatomy and tissue characteristics may potentially lead to substantial improvements in PCI interventions by providing novel guiding capabilities.

Feasibility of interstitial Doppler optical coherence tomography for in vivo detection of microvascular changes during photodynamic therapy.

INTRODUCTION: Doppler optical coherence tomography (DOCT) is an emerging imaging modality that provides subsurface microstructural and microvascular tissue images with near histological resolution and sub-mm/second velocity sensitivity. A key drawback of OCT for some applications is its shallow (1-3 mm) penetration depth. This fundamentally limits DOCT imaging to transparent, near-surface, intravascular, or intracavitary anatomical sites. Consequently, interstitial Doppler OCT (IS-DOCT) was developed for minimally-invasive in vivo imaging of microvasculature and microstructure at greater depths, providing access to deep-seated solid organs. Using Dunning prostate cancer in a rat xenograft model, this study evaluated the feasibility of IS-DOCT monitoring of microvascular changes deep within a tumor caused by photodynamic therapy (PDT). MATERIALS AND METHODS: The DOCT interstitial probe was constructed using a 22 G (diameter approximately 0.7 mm) needle, with an echogenic surface finish for enhanced ultrasound visualization. The lens of the probe consisted of a gradient-index fiber, fusion spliced to an angle-polished coreless tip to allow side-view scanning. The lens was then fusion spliced to a single-mode optical fiber that was attached to the linear scanner via catheters and driven along the longitudinal axis of the needle to produce a 2D subsurface DOCT image. The resultant IS-DOCT system was used to monitor microvascular changes deep within the tumor mass in response to PDT in the rat xenograft model of Dunning prostate cancer. Surface PDT was delivered at 635 nm with 40 mW of power, for a total light dose of 76 J/cm(2), using 12.5 mg/kg of Photofrin as the photosensitizer dose. RESULTS: IS-DOCT demonstrated its ability to detect microvasculature in vivo and record PDT-induced changes. A reduction of detected vascular cross sectional area during treatment and partial recovery post-treatment were observed. CONCLUSIONS: IS-DOCT is a potentially effective tool for real-time visualization and monitoring of the progress of PDT treatments. This capability may play an important role in elucidating the mechanisms of PDT in tumors, pre-treatment planning, feedback control for treatment optimization, determining treatment endpoints and post-treatment assessments.

Microfabricated system for parallel single-cell capillary electrophoresis.

Performing single-cell electrophoresis separations using multiple parallel microchannels offers the possibility of both increasing throughput and eliminating cross-contamination between different separations. The instrumentation for such a system requires spatial and temporal control of both single-cell selection and lysis. To address these problems, a compact platform is presented for single-cell capillary electrophoresis in parallel microchannels that combines optical tweezers for cell selection and electromechanical lysis. Calcein-labeled acute myloid leukemia (AML) cells were selected from an on-chip reservoir and transported by optical tweezers to one of four parallel microfluidic channels. Each channel entrance was manufactured by F2-laser ablation to form a 20- to 10-microm tapered lysis reservoir, creating an injector geometry effective in confining the cellular contents during mechanical shearing of the cell at the 10-microm capillary entrance. The contents of individual cells were simultaneously injected into parallel channels resulting in electrophoretic separation as recorded by laser-induced fluorescence of the labeled cellular contents.