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Photoacoustic Imaging and Characterization of the Microvasculature Journal of Biomedical Optics 15͑1͒, 011101 ͑January/February 2010͒ Photoacoustic imaging and characterization of the microvasculature Song Hu Abstract. Photoacoustic ͑optoacoustic͒ tomography, combining opti- Lihong V. Wang cal absorption contrast and highly scalable spatial resolution ͑from Washington University in St. Louis micrometer optical resolution to millimeter acoustic resolution͒, has Department of Biomedical Engineering broken through the fundamental penetration limit of optical ballistic Optical Imaging Laboratory One Brookings Drive imaging modalities—including confocal microscopy, two-photon mi- St. Louis, Missouri 63130-4899 croscopy, and optical coherence tomography—and has achieved high spatial resolution at depths down to the diffusive regime. Optical ab- sorption contrast is highly desirable for microvascular imaging and characterization because of the presence of endogenous strongly light-absorbing hemoglobin. We focus on the current state of mi- crovascular imaging and characterization based on photoacoustics. We first review the three major embodiments of photoacoustic tomog- raphy: microscopy, computed tomography, and endoscopy. We then discuss the methods used to characterize important functional param- eters, such as total hemoglobin concentration, hemoglobin oxygen saturation, and blood flow. Next, we highlight a few representative applications in microvascular-related physiological and pathophysi- ological research, including hemodynamic monitoring, chronic imag- ing, tumor-vascular interaction, and neurovascular coupling. Finally, several potential technical advances toward clinical applications are suggested, and a few technical challenges in contrast enhancement and fluence compensation are summarized. © 2010 Society of Photo-Optical Instrumentation Engineers. ͓DOI: 10.1117/1.3281673͔ Keywords: photoacoustic microscopy; photoacoustic computed tomography; pho- toacoustic endoscopy; microvascular morphology; total hemoglobin concentration; hemoglobin oxygen saturation; blood flow; microhemodynamics; chronic imaging; angiogenesis; neurovascular coupling. Paper 09202VSSR received May 19, 2009; revised manuscript received Sep. 15, 2009; accepted for publication Sep. 21, 2009; published online Jan. 21, 2010. 1 Introduction techniques often lack either sufficient spatial resolution or sat- isfactory contrast ͑or both͒ to be effective for microvascular The main function of the cardiovascular system is to provide, imaging.8 To bridge this gap, optical microscopy has been through perfused vascular beds, the necessities for living tis- widely used to dissect the delicate features of the microvas- sues and organs. The distributing arterial trees transport oxy- culature. Intravital microscopy ͑IVM͒, the gold standard for gen, humoral agents, and nutrients to the vital parts of the microcirculation studies, enables quantification of vessel body; in the mean time, the venous trees collect metabolic count, diameter, length, density, permeability, and blood flow 1 wastes. Microcirculation, the distal functional unit of the car- velocity.9 Nevertheless, to observe capillaries in vivo, IVM diovascular system, provides exchange sites for gases, nutri- generally requires transillumination and surgical preparation, ents, metabolic wastes, and thermal energy between the blood which disturb the intrinsic microvasculature and are restricted and the tissues. Pathologic microcirculation reflects the break- to limited anatomical sites. Moreover, conventional IVM down of homeostasis in organisms, which ultimately leads to lacks the depth resolution that is crucial for characterizing tissue inviability. Thus, in vivo microvascular imaging and three-dimensional ͑3-D͒ microvascular morphology. Confocal characterization is of significant physiological, pathophysi- microscopy and two-photon microscopy ͑TPM͒ avoid such ological, and clinical importance. invasive preparation and enable volumetric visualization of Well-established clinical imaging modalities such as mag- the microvasculature.10,11 However, their imaging contrasts ͑ ͒ ͑ ͒ netic resonance imaging MRI , computed tomography CT , come primarily from exogenous fluorescent agents, which— ͑ ͒ positron emission tomography PET , and ultrasound imaging though having been very successful in laboratory research— have been adopted for vascular imaging.2–7 However, these are still facing challenges in clinical translations.12 Orthogonal polarization spectral ͑OPS͒ imaging enables intrinsic mi- Address correspondence to: Lihong V. Wang, Washington University in St. crovascular imaging;13 however, it provides only a two- Louis, Department of Biomedical Engineering, Optical Imaging Laboratory, One Brookings Drive, St. Louis, Missouri 63130-4899. Tel: 314-935-6152; Fax: 314- 935-7448; E-mail: [email protected] 1083-3668/2010/15͑1͒/011101/15/$25.00 © 2010 SPIE Journal of Biomedical Optics 011101-1 January/February 2010 b Vol. 15͑1͒ Downloaded From: http://biomedicaloptics.spiedigitallibrary.org/ on 07/01/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx Hu and Wang: Photoacoustic imaging and characterization of the microvasculature Table 1 Comparison between PAT and well-established in vivo microvascular microscopy and clinical angiography. Blood Contrast Invasive or Modality Depth ͑mm͒ Resolution ͑␮m͒ Three Dimensional Oxygenation HbT Imaging Contrast Source Radiative IVM 0.2–0.5 1–2 Optical scattering, Exogenousa ͱ fluorescence CM 0.2–0.5 1–2 ͱ Optical scattering, Exogenousa fluorescence TPM 0.5–1 1–2 ͱ Fluorescence Exogenous OPS 0.5–1 1–5 ͱ Optical Endogenous absorptionb D-OCT 1–2 1–20 ͱ Flow Endogenous PAT 0.7–50c 5–800c ͱͱͱOptical absorption Endogenous MRI 100–200 1000 ͱͱNuclear magnetic Endogenous resonance x-ray CT 200 100 ͱ x-ray absorption Exogenous ͱ PET 200 1000 ͱͱ Positron Exogenous ͱ annihilation US 100–200 500–1000 ͱ Ultrasonic Endogenous scattering, flow CM, confocal microscopy; US, ultrasound imaging. aAlthough IVM and CM can trace endogenous optical scattering contrast, fluorescent labeling is required for capillary imaging. bDifferent from PAT, OPS provides negative absorption contrast. cScalable. dimensional ͑2-D͒ visualization of the microvasculature and coustics was investigated by the biomedical imaging commu- lacks the measurement consistency required for chronic nity for tomographic imaging. In PAT, the target is irradiated studies.14 Doppler optical coherence tomography ͑D-OCT͒ by a short-pulsed or intensity-modulated continuous-wave demonstrates the intrinsic imaging of microvascular perfusion ͑cw͒ laser beam, and ultrasonic waves ͑referred to as photoa- 15 by extracting blood flow information, but its resolution and coustic waves͒ are induced as a result of the transient ther- sensitivity are not yet sufficient to image single capillaries. moelastic expansion.21,22 By detecting the excited photoacous- More importantly, among the mainstream techniques already tic signals, PAT can reveal the physiologically specific mentioned, only OPS imaging can assess the functional pa- absorption signatures of endogenous chromophores, such as ͑ ͒ rameter of total hemoglobin concentration HbT , and none of hemoglobin and melanin in vivo. More importantly, with them have direct access to hemoglobin oxygen saturation ͑ ͒ spectroscopic measurements, PAT can quantify hemoglobin sO2 —another important functional parameter. To measure oxygenation within single vessels, providing important meta- sO in vivo, the following strategies have been adopted. First, 2 bolic information about the microcirculation. A comprehen- Raman spectroscopy has been integrated into IVM; however, sive comparison of PAT with the well-established in vivo mi- the resonance Raman signals generated in tissue compart- crovascular microscopy and clinical angiography can be ments other than blood could interfere with the analysis of hemoglobin.16 Second, hyperspectral imaging has been inte- found in Table 1. ͑ ͒ The advantages of PAT are summarized as follows. First, grated into optical coherence tomography OCT ; neverthe- 23–25 less, it requires transillumination and provides only 2-D endogenous optical absorption contrast enables label-free mapping.17 Finally, TPM has recently made exciting progress imaging of the microvasculature with a high SNR. Second, in 18,19 vivo vascular imaging of small animal models can cover the in terms of label-free imaging. With TPM, microvascular 25 morphology and oxygenation have been imaged in vivo with- length scale from a superficial capillary to an abdominal aorta,26 demonstrating the potential of PAT to bridge the res- out fluorescence labeling; however, sO2 quantification is not yet available due to the limited signal-to-noise ratio19 ͑SNR͒. olution and penetration gaps between microvascular micros- In contrast, photoacoustic tomography ͑PAT͒ can over- copy and clinical angiography. Third, spectroscopic measure- come these limitations. Photoacoustics, a physical phenom- ment enables vessel-by-vessel mapping of blood enon first reported for wireless communication,20 describes oxygenation.27,28 Fourth, time-resolved ultrasonic detection the generation of acoustic waves from an object absorbing avoids depth scanning. Finally, working in reflection or or- pulsed or intensity-modulated optical irradiation. With techni- thogonal mode noninvasively makes this technique applicable cal advances in laser sources and ultrasonic detectors, photoa- to more anatomical sites in vivo. Journal of Biomedical Optics 011101-2 January/February 2010 b Vol. 15͑1͒ Downloaded From: http://biomedicaloptics.spiedigitallibrary.org/
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