A Silicon Optical Bench-Based Forward-View Two-Axis Scanner for Microendoscopy Applications.

Optical microendoscopy enabled by a microelectromechanical system (MEMS) scanning mirror offers great potential for in vivo diagnosis of early cancer inside the human body. However, an additional beam folding mirror is needed for a MEMS mirror to perform forward-view scanning, which drastically increases the diameter of the resultant MEMS endoscopic probe. This paper presents a new monolithic two-axis forward-view optical scanner that is composed of an electrothermally driven MEMS mirror and a beam folding mirror both vertically standing and integrated on a silicon substrate. The mirror plates of the two mirrors are parallel to each other with a small distance of 0.6 mm. The laser beam can be incident first on the MEMS mirror and then on the beam folding mirror, both at 45°. The MEMS scanner has been successfully fabricated. The measured optical scan angles of the MEMS mirror were 10.3° for the x axis and 10.2° for the y axis operated under only 3 V. The measured tip-tilt resonant frequencies of the MEMS mirror were 1590 Hz and 1850 Hz, respectively. With this compact MEMS design, a forward-view scanning endoscopic probe with an outer diameter as small as 2.5 mm can be made, which will enable such imaging probes to enter the subsegmental bronchi of an adult patient.

In Vivo Evaluation of a Miniaturized Fluorescence Molecular Tomography (FMT) Endoscope for Breast Cancer Detection Using Targeted Nanoprobes.

In this study, in vivo animal experiments with 12 nude mice bearing breast-cancer-patient-tissue-derived xenograft (PDX) tumors were performed aiming to verify the imaging capability of a novel miniaturized fluorescence molecular tomography (FMT) endoscope, in combination with targeted nanoparticle-near-infrared (NIR) dye conjugates. Tumor-bearing mice were divided into two groups by systematic injection with urokinase plasminogen activator receptor-targeted (n = 7) and nontargeted (n = 5) imaging nanoprobes as a contrast agent, respectively. Each mouse was imaged at 6, 24, and 48 h following the injection of nanoprobes using the FMT endoscope. The results show that systemic delivery of targeted nanoprobes produced a 4-fold enhancement in fluorescence signals from tumors, compared with tumors that received nontargeted nanoprobes. This study indicates that our miniaturized FMT endoscope, coupled with the targeted nanoparticle-NIR dye conjugates as a contrast agent, has high sensitivity and specificity, and thus great potential to be used for image-guided detection and removal of a primary tumor and local metastatic tumors during surgery.

A MEMS lens scanner based on serpentine electrothermal bimorph actuators for large axial tuning.

Confocal microscopes and two-photon microscopes are powerful tools for early cancer diagnosis because of their high-resolution 3D imaging capability, but applying them for clinical use in internal organs is hindered by the lack of axially tunable lens modules with small size, high image quality and large tuning range. This paper reports a compact MEMS lens scanner that has the potential to overcome this limitation. The MEMS lens scanner consists of a MEMS microstage and a microlens. The MEMS microstage is based on a unique serpentine inverted-series-connected (ISC) electrothermal bimorph actuator design. The microlens is an aspheric glass lens to ensure optical quality. The MEMS microstage has been fabricated and the lens scanner has been successfully assembled. The entire lens scanner is circular with an outer diameter of 4.4 mm and a clear optical aperture of 1.8 mm. Experiments show that the tunable range reaches over 200 µm at only 10.5 V and the stiffness of the microstage is 6.2 N/m. Depth scan imaging by the MEMS lens scanner has also been demonstrated with a 2.2 µm resolution, only limited by the available resolution target.

Miniature fluorescence molecular tomography (FMT) endoscope based on a MEMS scanning mirror and an optical fiberscope.

We present a novel FMT endoscope by using a MEMS scanning mirror and an optical fiberscope. The diameter of this highly miniaturized FMT device is only 5 mm. To our knowledge, this is the smallest FMT device we found so far. Several phantom experiments based on indocyanine green (ICG) were conducted to demonstrate the imaging ability of this device. Two tumor-bearing mice were systematically injected with tumor-targeted NIR fluorescent probes (ATF-PEG-IO-830) and were then imaged to further demonstrate the ability of this FMT endoscope for imaging small animals.

Portable optical-resolution photoacoustic microscopy for volumetric imaging of multiscale organisms.

Photoacoustic microscopy (PAM) provides a fundamentally new tool for a broad range of studies of biological structures and functions. However, the use of PAM has been largely limited to small vertebrates due to the large size/weight and the inconvenience of the equipment. Here, we describe a portable optical-resolution photoacoustic microscopy (pORPAM) system for 3-dimensional (3D) imaging of small-to-large rodents and humans with a high spatiotemporal resolution and a large field of view. We show extensive applications of pORPAM to multiscale animals including mice and rabbits. In addition, we image the 3D vascular networks of human lips, and demonstrate the feasibility of pORPAM to observe the recovery process of oral ulcer and cancer-associated capillary loops in human oral cavities. This technology is promising for broad biomedical studies from fundamental biology to clinical diseases.

[Progress of the application of optical coherence tomography in gastrointestinal tumor surgery].

Optical coherence tomography (OCT) is a real-time, cross-sectional optical imaging technology. It is analogous to ultrasonography, except that OCT uses light waves instead of sound waves, and can provide three-dimensional morphological images of living tissues with a micrometer resolution. Through the use of endoscopes, needles, catheters and laparoscopes, OCT has demonstrated tremendous imaging potential in tumor surgery. The current studies suggest that OCT has potential for clinical applications in the following fields of gastrointestinal tumor surgery: (1) Early tumor detection and diagnosis: OCT can distinguish differences between polyp tissue, normal tissue and malignant tissue. It could possibly identify premalignant lesions or conditions potentially predisposing to malignancy, such as gastric and intestinal metaplasia, gastritis associated with Helicobacter pylori, and early gastric cancer involving the mucosa or submucosa. In addition, OCT can differentiate between adenomatous polyps and hyperplastic polyps. (2) Optical biopsy of lymph nodes: As a high-resolution, near-IR imaging modality, OCT is capable of visualizing microscopic features within tissue, distinguishing lymph node tissue from surrounding adipose tissue, revealing nodal structures such as germinal centers and intra-nodal vessels. Consequently, OCT has the ability to show changes in node microarchitecture during metastatic tumor infiltration. (3) Intraoperative guidance for real-time determination of surgical margins: In other tumors such as oral squamous cell carcinoma and breast cancer, it has been demonstrated that OCT can be used to rapidly scan large areas of tissue, to guide at the cellular level the surgical resection of neoplastic disease, and to scan tumor margins for the presence of residual disease, tumor foci, and potentially even metastasizing tumor cells. It implies that colorectal neoplasms surgeons can possibly use the laparoscopic OCT to detect the intestinal tumor margin and lymph nodes during operation in the future, so as to determine the appropriate range of bowel resection and lymph node dissection. At present, there are few reports about the intra-operative application of OCT in the field of gastrointestinal tumor surgery. Thus there is a tremendous opportunity for further research in this field.

Common-path optical coherence tomography using a microelectromechanical-system-based endoscopic probe.

This paper presents a common-path (CP) swept-source optical coherence tomography (SSOCT) system based on a special endoscopic probe design with an in-line internal reflection as the reference and a two-axis electrothermal microelectromechanical system mirror for image scanning. The rear surface of a gradient reflective index (GRIN) lens inside the probe is set as the reference reflection plane. The length of the GRIN lens is optimized to eliminate the artifacts in SSOCT images successfully. Doppler OCT is also demonstrated based on the CP endoscopic probe. The diameter of the probe is only 2.5 mm, so it can be easily inserted into the biopsy channel of traditional endoscopes to access human internal organs for in vivo diagnoses.

Endoscopic swept-source optical coherence tomography based on a two-axis microelectromechanical system mirror.

A microelectromechanical system (MEMS) mirror based endoscopic swept-source optical coherence tomography (SS-OCT) system that can perform three-dimensional (3-D) imaging at high speed is reported. The key component enabling 3-D endoscopic imaging is a two-axis MEMS scanning mirror which has a 0.8×0.8 mm2 mirror plate and a 1.6×1.4 mm2 device footprint. The diameter of the endoscopic probe is only 3.5 mm. The imaging rate of the SS-OCT system is 50 frames/s. OCT images of both human suspicious oral leukoplakia tissue and normal buccal mucosa were taken in vivo and compared. The OCT imaging result agrees well with the histopathological analysis.

Handheld miniature probe integrating diffuse optical tomography with photoacoustic imaging through a MEMS scanning mirror.

We describe a novel dual-modality imaging approach that integrates diffuse optical tomography (DOT) and photoacoustic imaging (PAI) through a miniaturized handheld probe based on microelectromechanical systems (MEMS) scanning mirror. We validate this dual-modal DOT/PAI approach using extensive phantom experiments, and demonstrate its application for tumor imaging using tumor-bearing mice systematically injected with targeted contrast agents.

Miniature probe combining optical-resolution photoacoustic microscopy and optical coherence tomography for in vivo microcirculation study.

Photoacoustic microscopy (PAM) is sensitive to optical absorption, while optical coherence tomography (OCT) is based on optical backscattering. Combining PAM and OCT can provide complementary information about biological tissue. Here we present a combined optical-resolution PAM (ORPAM) and OCT system that is integrated through a miniature probe with an overall diameter of 2.3 mm, suitable for insertion through a standard endoscopic or laparoscopic port during minimally invasive surgery or endoscopic exam. The hybrid probe consists of a common optical path for OCT (light delivery/detection) and ORPAM (light excitation) and a 10 MHz unfocused ultrasound transducer for photoacoustic detection. The combined system yields a lateral resolution of 15 µm for both ORPAM and OCT.

Microelectromechanical systems scanning-mirror-based handheld probe for fluorescence molecular tomography.

A novel handheld probe based on a microelectromechanical systems (MEMS) scanning mirror for three-dimensional (3D) fluorescence molecular tomography (FMT) is described. The miniaturized probe consists of a MEMS mirror for delivering an excitation light beam to multiple preselected points at the tissue surface and an optical fiber array for collecting the fluorescent emission light from the tissue. Several phantom experiments based on indocyanine green, an FDA approved near-infrared (NIR) fluorescent dye, were conducted to assess the imaging ability of this device. Tumor-bearing mice with systematically injected tumor-targeted NIR fluorescent probes were scanned to further demonstrate the ability of this MEMS-based FMT for imaging small animals.

Evaluation of breast tumor margins in vivo with intraoperative photoacoustic imaging.

The use of photoacoustic effect is a promising approach for biomedical imaging in living tissues. Photoacoustic tomography (PAT) has been demonstrated to image breast cancer, brain vasculature, arthritis and seizure focus owing to its rich optical contrast and high resolution in a single imaging modality. Here we report a microelectromechanical systems (MEMS)-based intraoperative PAT (iPAT) technique, and demonstrate its ability to accurately map tumors in three-dimension and to inspect the completeness of tumor resection during surgery in a tumor-bearing mouse model. The MEMS imaging probe is small and has the potential to be conveniently used to guide surgical resection of tumors in the breast.

MEMS-based 3D optical microendoscopy.

Microelectromechanical systems (MEMS) devices have the advantages of small size, fast speed and low cost. MEMS-based miniature imaging probes have been developed for various optical "biopsy" imaging systems. These MEMS based optical imaging systems enable in vivo endoscopic optical "biopsy", resulting in a paradigm shift of optical imaging of internal organs. In particular, MEMS based endoscopic optical coherence tomography (OCT) imaging, nonlinear optical imaging and confocal imaging will be discussed.

Three-dimensional nonlinear optical endoscopy.

The development of miniaturized nonlinear optical microscopy or endoscopy is essential to complement the current imaging modalities for diagnosis and monitoring of cancers. We report on a nonlinear optical endoscope based on a double-clad photonic crystal fiber and a two-dimensional (2-D) microelectromechanical system mirror, enabling the three-dimensional (3-D) nonlinear optical imaging through in vitro gastrointestinal tract tissue and human breast cancer tissue with a penetration depth of approximately 100 mum and axial resolution of 10 mum. The 3-D high-resolution and high-sensitive imaging ability of the nonlinear optical endoscope facilitates the visualization of 3-D morphologic and cell nuclei arrangement within tissue, and therefore will be important for histopathologic interpretation without the need of tissue excision.

In vivo bladder imaging with microelectromechanical-systems-based endoscopic spectral domain optical coherence tomography.

We report the recent technical improvements in our microelectromechanical systems (MEMS)-based spectral-domain endoscopic OCT (SDEOCT) and applications for in vivo bladder imaging diagnosis. With the technical advances in MEMS mirror fabrication and endoscopic light coupling methods, the new SDEOCT system is able to visualize morphological details of the urinary bladder with high image fidelity close to bench-top OCT (e.g., 10 mum12 mum axial/lateral resolutions, >108 dB dynamic range) at a fourfold to eightfold improved frame rate. An in vivo animal study based on a porcine acute inflammation model following protamine sulfate instillation is performed to further evaluate the utility of SDEOCT system to delineate bladder morphology and inflammatory lesions as well as to detect subsurface blood flow. In addition, a preliminary clinical study is performed to identify the morphological features pertinent to bladder cancer diagnosis, including loss of boundary or image contrast between urothelium and the underlying layers, heterogeneous patterns in the cancerous urothelium, and margin between normal and bladder cancers. The results of a human study (91% sensitivity, 80% specificity) suggest that SDEOCT enables a high-resolution cross-sectional image of human bladder structures to detect transitional cell carcinomas (TCC); however, due to reduced imaging depth of SDEOCT in cancerous lesions, staging of bladder cancers may be limited to T1 to T2a (prior to muscle invasion).

Endoscopic optical coherence tomography with a modified microelectromechanical systems mirror for detection of bladder cancers.

Experimental results of a modified micromachined microelectromechanical systems (MEMS) mirror for substantial enhancement of the transverse laser scanning performance of endoscopic optical coherence tomography (EOCT) are presented. Image distortion due to buckling of MEMS mirror in our previous designs was analyzed and found to be attributed to excessive internal stress of the transverse bimorph meshes. The modified MEMS mirror completely eliminates bimorph stress and the resultant buckling effect, which increases the wobbling-free angular optical actuation to greater than 37 degrees, exceeding the transverse laser scanning requirements for EOCT and confocal endoscopy. The new optical coherence tomography (OCT) endoscope allows for two-dimensional cross-sectional imaging that covers an area of 4.2 mm x 2.8 mm (limited by scope size) and at roughly 5 frames/s instead of the previous area size of 2.9 mm x 2.8 mm and is highly suitable for noninvasive and high-resolution imaging diagnosis of epithelial lesions in vivo. EOCT images of normal rat bladders and rat bladder cancers are compared with the same cross sections acquired with conventional bench-top OCT. The results clearly demonstrate the potential of EOCT for in vivo imaging diagnosis and precise guidance for excisional biopsy of early bladder cancers.