Article pubs.acs.org/journal/apchd5
Miniature Endoscope for Multimodal Imaging Xianjin Dai,† Hao Yang,† Tianqi Shan,† HuiKai Xie,‡ Scott A. Berceli,§ and Huabei Jiang*,† †
J. Crayton Pruitt Family Department of Biomedical Engineering, ‡Department of Electrical and Computer Engineering, and Department of Surgery, University of Florida, Gainesville, Florida 32611, United States
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S Supporting Information *
ABSTRACT: A single miniature endoscope capable of concurrently probing multiple contrast mechanisms of tissue in high resolution is highly attractive, as it makes it possible for providing complementary, more complete tissue information on internal organs hard to access. Here we describe such a miniature endoscope only 1 mm in diameter that integrates photoacoustic imaging (PAI), optical coherence tomography (OCT), and ultrasound (US). The integration of PAI/ OCT/US allows for high-resolution imaging of three tissue contrasts including optical absorption (PAI), optical scattering (OCT), and acoustic properties (US). We demonstrate the capabilities of this trimodal endoscope using mouse ear, human hand, and human arteries with atherosclerotic plaques. This 1-mm-diameter trimodal endoscope has the potential to be used for imaging of internal organs such as arteries, GI tracts, esophagus, and prostate in both humans and animals. KEYWORDS: multimodal imaging, photoacoustic imaging, optical coherence tomography, ultrasound, miniature endoscope
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and backscattering information can be obtained. In this regard, we and other groups have made efforts to develop an integrated platform combining PAI and OCT.28−34 These studies have demonstrated the advantages of such a dual-modality system. For example, for in vivo microcirculation studies, PAI provided absorbing components such as blood vessels, while OCT obtained the fine structures of the surrounding tissues. It is conceivable that a multimodal approach integrating PAI, OCT, and US would provide a more powerful tool for tissue imaging. In this regard, we and other groups took initial steps toward the integration of these three modalities in a single probe. In the study of Yang et al.,35 while inspiring, PAI, OCT, and US were not physically integrated in a single probe with a diameter of 5 mm for imaging ovarian tissue, and PAI in their probe could not visualize microvasculature due to its relatively poor spatial resolution. We36 demonstrated a miniature trimodal probe with a diameter of 2 mm, physically integrating OCT, US, and opticalresolution photoacoustic microscopy (OR-PAM) (which is one of the PAI modes). The use of a gold-coated thin film in this probe allowed us, for the first time, to coaxially acquire ORPAM, OCT, and US images of the same area of biological tissue in vivo. While encouraging, this 2-mm-diameter trimodal probe cannot be used for clinical intravascular and transurethral imaging or for preclinical studies of internal organs in small animals. For example, internal organs such as the colon of a nude mouse is so small in size that a 2-mm-diameter probe would simply break the colon.37 Although the urethra of an adult is about 5−7 mm in diameter for men and larger for
ultimodal imaging is always attractive and desired since it can combine the strengths of several different imaging modalities and is able to characterize biological tissue more completely, thus offering the possibility of precision diagnosis of diseases. While multimodality images can be obtained by performing each individual modality separately without integrating them into a single platform, it is, however, timeconsuming to acquire multimodality images through such a process, hard to avoid errors from the required complex image registration, and, more importantly, impossible to catch dynamic biological processes simultaneously. To overcome these limitations, physically integrating multiple modalities into a single platform is highly desired. Among recent advances in biomedical imaging, photoacoustic imaging (PAI) is an emerging technique capable of providing anatomical, functional, and molecular properties of biological tissue with a high resolution.1−9 In PAI, an image is formed through the detection of laser-induced ultrasound waves with an (un)focused ultrasound transducer. Since ultrasound (US) can penetrate into deep tissue, and a common ultrasound transducer can be used for both US and PAI, these two modalities have been combined as a dual-modality approach for obtaining both images of optical absorption property and deep tissue structure.10−18 Optical coherence tomography (OCT) is a widespread imaging technique by measuring back-scattered or backreflected light generated from a light source delivered to the examined tissue, which is able to provide optical scattering property of tissue in high resolution.19,20 While optical coherence tomography (OCT) is ideal for imaging the retina,21−23 it has also been used to visualize other tissues.24−27 Thus, through combing PAI and OCT, both optical absorption © XXXX American Chemical Society
Received: October 31, 2016 Published: December 20, 2016 A
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Figure 1. Integrated multimodal probe. (a) Schematic of the probe. (b) Three-dimensional rendering of the probe.
Figure 2. In vivo images of a mouse ear by the integrated multimodal probe. Maximum amplitude projection (MAP) (top row) and cross-sectional images (middle and bottom rows) corresponding to the dotted lines shown in the MAP image of (a) PAI, (b) US, (c) OCT, and (d) fused trimodality. BV, blood vessel; ED, epidermis; D, dermis; CT, cartilage. The scale bars indicate 0.3 mm in length.
focus the light beam including single-mode (indicated by a red dotted line) and multimode (indicated by green area) from the tip of the DCF with 8° angle facial cutting for minimizing backreflection. Traveling through a piece of 45°-angle-tilting reflection slide (which is optically transparent but ultrasonically untransparent), the light beam is then reflected into the sample by a 0.5 mm enhanced-aluminum-coated right-angle prism (MPCH-0.5, Tower Optical Corp.). For OCT, the backscattering light from the sample shares the same optical path with light transmission. For PAI, the light-induced photoacoustic signals reflected by the prism and reflection slide are detected by a custom-made unfocused ultrasound transducer with a center frequency of 40 MHz and dimensions of 0.6 mm × 0.5 mm × 0.2 mm (Blatek, Inc., State College, PA, USA) mounted coaxially with respect to the optical path. The generated photoacoustic signal lost around ∼15% after the two independent reflections, but it was still high enough to obtain good PA images with high contrast. The transducer is also used for US imaging, in which an image is formed by detecting the echo of the pulsed ultrasound generated by the same
women, ureteral wall injury happens very often when ureteroscopy is performed.38 In particular, a critical size of 1 mm or smaller is required for clinical intravascular imaging to avoid tissue injuries.39 It is, however, rather challenging to engineer a tiny multimodal probe having a diameter of 1 mm or smaller. In the following sections, we describe how we tackled the challenges to develop a novel probe integrating PAI, OCT, and US with a diameter of only 1.0 mm based on a double-clad fiber (DCF).
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RESULTS AND DISCUSSION Integrated Multimodal Probe. The structure of the probe is schematically shown in Figure 1. In this probe, a DCF with a dual cladding structure (DCF13, Thorlabs), in which, singlemode light travels in the Ø9 μm core with a numerical aperture (NA) of 0.12 and a spectrum range of 1250−1600 nm, while multimode light propagates in the Ø105 μm inner first cladding (NA = 0.2, 400−2200 nm), is used to deliver light for both PAI (multimode) and OCT (single mode). A custom-designed gradient-index (GRIN) lens with a diameter of 0.25 mm and a working distance of 5 mm (GRINTECH GmbH) is utilized to B
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Figure 3. Cross-sectional images of the skin of a human hand. (a) PAI image, (b) US image, (c) OCT image, (d) color-coded RGB image, and (e) photograph of the scanning location. The scale bars indicate 0.3 mm in length.
transducer. All the components are fixed by three stainless steel tubes (260, 500, and 1000 μm in diameter). In Vivo Imaging of a Mouse Ear. To demonstrate the capabilities of this integrated multimodal probe, in vivo imaging of a mouse ear (mouse weight = 35 g) was first performed. The laser exposure was about 10 mJ/cm2 at the optical focus inside the ear tissue, which is lower than the American National Standards Institute (ANSI) laser safety limit (20 mJ/cm2). An area of 2 mm × 2 mm of the mouse ear was scanned with a scanning step size of 10 μm, which took around 36 min. The top row of Figure 2 shows the maximum amplitude projection (MAP) images of PAI (Figure 2a), US (Figure 2b), OCT (Figure 2c), and fused multimodal pseudo-color-coded RGB images (Figure 2d) obtained from PAI (R, red), OCT (G, green), and US (B, blue). The middle and bottom rows of Figure 2 show the cross-sectional images of PAI, US, OCT, and the fused multimodality, corresponding to the two dotted lines in the respective MAP images. We see that PAI, OCT, and US, respectively, were able to image the microvasculature, fine structures surrounding the blood vessels, and elastic structures. To closely interpret these images, blood vessels in the mouse ear are mapped by PAI with the highest contrast (Figure 2a), elastic structures such as cartilage, which have high ultrasound reflection coefficients, are clearly visualized by US (Figure 2b), while epidermis, dermis, and cartilage are identified in the OCT image (Figure 2c). Through overlapping the PAI, OCT, and US images (Figure 2d), the structures/tissue morphology are better displayed, which shows in vivo imaging feasibilities of the integrated multimodal probe. In Vivo Imaging of a Human Hand. We then conducted in vivo imaging of the back of a human hand to explore the potential clinical capabilities of the integrated multimodal probe. A step size of 10 μm was used for scanning the back of the hand, and it took around 15 s to obtain a b-scan (crosssectional) image. Figure 3a, b, and c, respectively, show the cross-sectional images of the hand from PAI, US, and OCT.
Using the same RGB pseudocoding method as the one used for mouse ear imaging, the fused multimodal image is given in Figure 3d. Figure 3e is the photograph of the scanning location on the surface of the hand indicated by the red dotted line. From Figure 3, it is noted that blood vessels (as indicated by a white arrow in Figure 3a), superficial fine structures, and elastic structures (such as bone, as indicated by a white arrow in Figure 3b) are identified by PAI, OCT, and US, respectively. Since typically the thickness of a mouse ear is less than 2 mm, the deep penetration ability of US was not demonstrated from images shown in Figure 2b. Here, in Figure 3b, it is evident that US can image the structure of tissue up to 5 mm in depth. Carefully examining Figure 3b and c, we note that the superficial surface of tissue having less ultrasonic reflection can be complementarily visualized by OCT with a high resolution. From the fused image (Figure 3d), we can see that the morphology of tissue with a depth of up to 5 mm was mapped by our integrated probe with a high resolution and that different tissues were imaged by the three different imaging modalities. Intravascular Imaging of Human Arteries with Atherosclerotic Plaques. Atherosclerosis, hardening and narrowing of the arteries, is a major cause of deadly diseases such as heart attacks and strokes, primarily due to the rupture of vulnerable atherosclerotic plaques.40,41 It is highly desired to develop an effective imaging tool capable of assessing plaque vulnerability.42 Intravascular ultrasound (IVUS) imaging, which is widely used in clinics, offers high resolution and large penetration depth imaging, but it has limited capacity in characterizing the components of atherosclerotic plaques.43 Intravascular optical coherence tomography (IV-OCT), an emerging technique, provides very high spatial resolution imaging within a limited penetration (1−2 mm).44 Intravascular photoacoustic imaging (IVPA), also an emerging technique, has the potential to offer compositional information on vessel C
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Figure 4. Cross-sectional images of human artery with an atherosclerotic plaque. (a) PAI image, (b) US image, (c) OCT image, (d) color-coded RGB image, and (e) histology using H&E stain. The scale bars indicate 2 mm in length.
Figure 5. Spectroscopic photoacoustic images of a human artery with atherosclerotic plaques. PA images at 710 nm (a), 800 nm (b), 900 nm (c), 1100 nm (d), 1150 nm (e), and 1210 nm (f). The top and bottom rows, respectively, show the cross-sectional and three-dimensional images. The scale bars indicate 2 mm in length.
walls/plaques with deep penetration depth and high spatial resolution.45,46,48 To demonstrate the capability of the integrated multimodal probe for intravascular imaging, we conducted ex vivo experiments of human arteries with atherosclerotic plaques. The multimodal images of an artery sample with lipid-rich plaques were acquired by rotatory scanning with 1200 samples/ circle and pulling back with a step size of 60 μm. The artery sample was fixed using a cylindrical holder made of 2% agar solution and coupled with the probe by water. For PAI, light with a wavelength of 1210 nm, at which lipid has an absorption peak,47,48 was utilized to excite the photoacoustic signal. Figure 4a, b, and c, respectively, show the cross-sectional images of the sample from PAI, US, and OCT. The fused multimodal image using RGB pseudocoding is given in Figure 4d, while the histological image of the sample by H&E staining is shown in Figure 4e. By closely inspecting these images in comparison with the histology (Figure 4e), regions of plaque rich in lipid are mapped by PAI with high contrast, as indicated by yellow arrows in Figure 4a (the area in the image with high pixel intensity) and Figure 4e. The superficial structure of the vessel wall like a thin fibrous cap, as indicated by a red arrow in Figure 4c (a thin bright layer with a dark area) and Figure 4e, is clearly imaged by OCT with high resolution, while US is able to obtain the structure of the whole vessel wall (Figure 4b), attributed to the strength of deep tissue penetration of ultrasound. We note that the fused image of PAI, OCT, and US (Figure 4d) certainly provides more complete structural and compositional information on the vessel wall/plaque.
To show the capability of the integrated probe for spectroscopic IVPA, photoacoustic imaging of a human artery sample with atherosclerotic plaques was performed with six wavelengths of 710, 800, 900, 1100, 1150, and 1210 nm (Figure 5). These multispectral PAI images illustrate that multiple chemical components of the plaque can be inferred/obtained for more accurate correlation with plaque vulnerability. For example, elastin and collagen, which have relatively high light absorption coefficients under 1000 nm, would appear as highintensity pixels in the PAI images (Figure 5a−c). While lipid, which has an absorption peak around 1210 nm, showed the brightest areas in Figure 5e and f. Combining this chemical compositional information with the structural images obtained from US (Figure 4b) and OCT (Figure 4c), the properties of the artery wall as well as the plaques can be visualized more completely. We have developed a novel miniature device of only 1.0 mm in diameter that integrates PAI, OCT, and US in a single probe based on a double-clad fiber. The results from the phantom and in vivo/ex vivo experiments have shown that the integrated multimodal probe has the capability of simultaneously obtaining optical absorption and scattering properties of biological tissue as well as tissue elastic characteristics in high resolution. We noted that in our experimental setup the imaging speed was limited by a relatively low repetition frequency of the nanosecond-pulsed Nd:YAG-pumped optical parametric oscillator (OPO) laser (20 Hz) and a relatively slow approach of time-domain OCT. The low imaging speed would affect the images by sample movements during the acquisition process. For example, in the experiments of in vivo imaging of a mouse ear, for scanning an area of 2 mm × 2 mm of the mouse D
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ear (Figure 2) with a scanning step size of 10 μm, it took around 10.8 s to obtain a cross-sectional image and 36 min for a volumetric image. Thus, any movements of the mouse ear within 10.8 s would have a blurring effect in the cross-sectional image and within the 36 min time period would have a blurring effect in the volumetric image. In the experiments of in vivo imaging of the human hand, it took around 15 s to obtain a cross-sectional image. Thus, any movements within 15 s would generate a blurring effect in the cross-sectional image. Nevertheless, the advanced probe presented here can be adapted easily with any high-speed PAI system and state-of-theart OCT imaging system (such as high-speed swept source OCT). We expect that the speed can reach as high as hundreds of kHz per scanning point using a high repetition rate nanosecond pulsed laser for PAI and a swept source for OCT. The highly integrating aspect and miniature size of the probe have the potential to generate significant impact in preclinical and clinical applications such as multimodal intravascular coronary imaging, in vivo imaging of internal organs in small animals, ureteroscopy/transurethral imaging, and minimally invasive interventional therapy.
(Supplementary Figure 3), consisting of four convex lenses and a short-pass dichroic mirror (DMSP1180, Thorlabs), the integrated probe was coupled with both PAI and OCT systems based on the DCF. A data acquisition card (PCI-5124, National Instrument) embedded in a computer with a 12-bit resolution and a sampling rate of 200 MS/s was utilized as the data acquisition system. For US imaging, an ultrasound pulser/ receiver (5073PR, Olympus) with an integrated amplifier and a bandwidth of 75 MHz was utilized to generate ultrasound and to receive echoes. By scanning the probe in the x−y plane with a two-dimensional linear stage, a volumetric image of the sample could be obtained. Animal Preparation. Before the experiment, the hair on the ear of the mouse was gently removed using a human-hairremoving cream. The mouse was placed on a homemade animal holder and anesthetized by a solution of ketamine (85 mg/kg) and xylazine. The mouse was sacrificed according to the University of Florida Institutional Animal Care and Use Committee (IACUC)-approved techniques after the experiment. Strict animal-care procedures approved by the University of Florida IACUC and based on guidelines from the National Institutes of Health (NIH) for the Care and Use of Laboratory Animals were followed. Human Artery Sample Preparation. Human artery samples with atherosclerotic plaques were collected from the Department of Surgery of Shands Hospital at the University of Florida. Before the experiments, the samples were immersed into formalin solution. The samples were first utilized for multimodal imaging with the integrated probe and then sent to the Molecular Pathology Core at the University of Florida for histology examination using H&E staining.
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METHODS Assembly of the Integrated Multimodal Probe. The procedure of assembling the probe is shown in Supplementary Figure 1a. We assembled the probe under a microscope. First, a DCF was mounted into stainless steel tubing (SST) 1 (MicroGroup Corp.) with an inner diameter (ID) of 130 μm and an outer diameter (OD) of 260 μm. SST 1 was then fixed with a GRIN lens by SST 2 (ID, 270 μm; OD, 500 μm). Two uncoated right-angle prisms (MPU-0.5, Tower Optical Corp.) were glued using optical adhesive into a prism pair as a reflection slide (Figure 1). Because of the high acoustic impedance of BK7 glass, of which the prism is made, it was ideal to reflect ultrasound through the hypotenuse of the prism while the bottom of the prism pair was mounted in parallel with the axis of SST 2. Finally, all components were mounted into SST 3 (ID, 920 μm; OD, 1000 μm) using epoxy glue. The axes of these three tubes were parallel to each other. The key to the assembling procedure is that the ultrasound transducer should be placed coaxially with the optical path with respect to the prism pair and coated prism. After the components were fixed in position, we did simple testing for both optics and ultrasound to make sure the assembly was optimized. The photograph of the integrated probe is shown in Supplementary Figure 1b following this procedure. Integrated Multimodal Imaging System. The integrated multimodal imaging system is schematically shown in Supplementary Figure 2. For PAI, a nanosecond-pulsed Nd:YAG-pumped OPO laser having a repetition frequency of 20 Hz was used as light source. The light beam, attenuated by a neutral density filter and then shaped by a small iris, was focused by a convex lens (L1); the light beam then passed through a 100 μm pinhole for spatial filtering and was coupled into a multimode fiber (FG105LCA, Thorlabs). Since a timedomain OCT system was available in our laboratory, hereafter it was used to demonstrate the feasibility of the integrated probe (this OCT system is compatible to any state-of-the-art OCT system such as swept source OCT). A broadband light source with a full width at half-maximum of 75 nm and a center wavelength of 1310 nm was utilized for the time-domain OCT system, the optical interface of which was a single-mode fiber (SMF-28e+, Thorlabs). Through a homemade DCF coupler
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsphotonics.6b00852.
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Additional information (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]fl.edu. ORCID
Xianjin Dai: 0000-0003-1189-9763 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the generous financial support from the J. Crayton Pruitt Family Endowment.
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DOI: 10.1021/acsphotonics.6b00852 ACS Photonics XXXX, XXX, XXX−XXX
