In vivo safety study using radiation at wavelengths and dosages relevant to intravascular imaging.

SIGNIFICANCE: Intravascular photoacoustic (IVPA) imaging can identify native lipid in atherosclerotic plaques in vivo. However, the large number of laser pulses required to produce 3D images is a safety concern that has not been fully addressed. AIM: We aim to evaluate if irradiation at wavelengths and dosages relevant to IVPA imaging causes target vessel damage. APPROACH: We irradiate the carotid artery of swine at one of several energy dosages using radiation at 1064 or 1720 nm and use histological evaluation by a pathologist to identify dose-dependent damage. RESULTS: Media necrosis was the only dose-dependent form of injury. Damage was present at a cumulative fluence of 50 J / cm2 when using 1720 nm light. Damage was more equivocally identified at 700 J / cm2 using 1064 nm. CONCLUSIONS: In prior work, IVPA imaging of native lipid in swine has been successfully conducted below the damage thresholds identified. This indicates that it will be possible to use IVPA imaging in a clinical setting without damaging vessel tissue. Future work should determine if irradiation causes an increase in blood thrombogenicity and confirm whether damaged tissue will heal over longer time points.

Investigation of light delivery geometries for photoacoustic applications using Monte Carlo simulations with multiple wavelengths, tissue types, and species characteristics.

Combined ultrasound and photoacoustic imaging systems are being developed for biomedical and clinical applications. One common probe configuration is to use a linear transducer array with external light delivery to produce coregistered ultrasound and photoacoustic images. The diagnostic capability of these systems is dependent on the effectiveness of light delivery to the imaging target. We use Monte Carlo modeling to investigate the optimal design geometry of an integrated probe. Simulations are conducted with multiple tissue compositions and wavelengths. The effect of a skin layer with the thickness of a mouse or a human is also considered. The model was validated using a tissue-mimicking gelatin phantom and corresponding Monte Carlo simulations. The optimal illumination angle is shallower with human skin thickness, whereas intermediate angles are ideal with mouse skin thickness. The effect of skin thickness explains differences in the results of prior work. The simulations also indicate that even with identical hardware and imaging parameters, light delivery will be up to 3 × smaller in humans than in mice, due to the increased scattering from thicker skin. Our findings have clear implications for the many researchers using mice to test and develop imaging methods for clinical translation.

Laser threshold and cell damage mechanism for intravascular photoacoustic imaging.

OBJECTIVES: Intravascular photoacoustic (IVPA) imaging is being developed to image atherosclerotic plaques, a leading cause of morbidity and mortality in the United States. However, the safety of this imaging modality, which requires repeated irradiation with short laser pulses, has not yet been investigated. This study has two objectives. First, determine in vitro the limit of cumulative fluence that can be applied to cells before death at IVPA relevant wavelengths. Second, evaluate if high single pulse fluences are a potential cause of cell death during IVPA imaging. MATERIALS AND METHODS: Experiments were conducted using endothelial cells, macrophages, and smooth muscle cells. The cumulative fluence experiments were conducted at 1064 and 1197 nm, using a high pulse repetition frequency laser. Cells were irradiated with a wide range of cumulative fluences and evaluated for cell death. The thresholds for death were compared to the maximum expected clinical cumulative fluence. To evaluate the effect of single pulse fluences, cells were irradiated at 1064, 1210, and 1720 nm. Light was delivered at a range of pulse energies to emulate the fluences that cells would be exposed to during clinical IVPA imaging. RESULTS: At 1064 nm, all three cell types remained viable at cumulative fluences above the maximum expected clinical cumulative fluence, which is calculated based on common IVPA imaging protocols. At 1197 nm, cells were viable near or just below the maximum expected clinical cumulative fluence, with some cell type to cell type variation. All three cell types remained viable after irradiation with high single pulse fluences at all three wavelengths. CONCLUSION: The cumulative fluence experiments indicate that safety considerations are likely to put constraints on the amount of irradiation that can be used in IVPA imaging protocols. However, this study also indicates that it will be possible to use IVPA imaging safely, since cumulative fluences could be reduced by as much as two orders of magnitude below the maximum expected clinical cumulative fluence by varying the imaging protocol, albeit at the expense of image quality. The single pulse fluence experiments indicate that cell death from single pulse fluence is not likely during IVPA imaging. Thus, future studies should focus on heat accumulation as the likely mechanism of tissue damage. Lasers Surg. Med. 51:466-474, 2019. © 2018 Wiley Periodicals, Inc.

Exogenous imaging contrast and therapeutic agents for intravascular photoacoustic imaging and image-guided therapy.

Intravascular photoacoustic (IVPA) imaging has been developed in recent years as a viable imaging modality for the assessment of atherosclerotic plaques. Exogenous imaging contrast and therapeutic agents further enhance this imaging modality and provide significant benefits. Imaging contrast agents can significantly increase photoacoustic signal, resulting in enhanced plaque detection and characterization. The ability to use these particles to molecularly target markers of disease progression makes it possible to determine patient-specific levels of risk and plan treatments accordingly. With improved diagnosis, clinicians will be able to use therapeutic agents that are synergistic with IVPA imaging to treat atherosclerotic patients. Pre-clinical and clinical studies with relevance to IVPA imaging have shown promise in the area of diagnosis and therapeutics. In this review, we present a variety of imaging contrast agents that are either designed for or are compatible with IVPA imaging, cover uses of therapeutic agents that compliment this imaging modality, and discuss future directions of research in the field.

Optimization of dual-wavelength intravascular photoacoustic imaging of atherosclerotic plaques using Monte Carlo optical modeling.

Coronary heart disease (the presence of coronary atherosclerotic plaques) is a significant health problem in the industrialized world. A clinical method to accurately visualize and characterize atherosclerotic plaques is needed. Intravascular photoacoustic (IVPA) imaging is being developed to fill this role, but questions remain regarding optimal imaging wavelengths. We utilized a Monte Carlo optical model to simulate IVPA excitation in coronary tissues, identifying optimal wavelengths for plaque characterization. Near-infrared wavelengths (≤1800 nm) were simulated, and single- and dual-wavelength data were analyzed for accuracy of plaque characterization. Results indicate light penetration is best in the range of 1050 to 1370 nm, where 5% residual fluence can be achieved at clinically relevant depths of ≥2 mm in arteries. Across the arterial wall, fluence may vary by over 10-fold, confounding plaque characterization. For single-wavelength results, plaque segmentation accuracy peaked at 1210 and 1720 nm, though correlation was poor (<0.13). Dual-wavelength analysis proved promising, with 1210 nm as the most successful primary wavelength (≈1.0). Results suggest that, without flushing the luminal blood, a primary and secondary wavelength near 1210 and 1350 nm, respectively, may offer the best implementation of dual-wavelength IVPA imaging. These findings could guide the development of a cost-effective clinical system by highlighting optimal wavelengths and improving plaque characterization.

Capillary driven flow of polydimethylsiloxane in open rectangular microchannels.

The flow of liquid polydimethylsiloxane (PDMS, Dow Corning Sylgard 184, 10 : 1 base to cross-linker ratio) in open, rectangular silicon microchannels, with and without a coating (100 nm) of poly-tetra-fluoro-ethylene (PTFE), was studied. Photolithographic patterning and etching of silicon wafers was used to create microchannels with a range of widths (∼5-50 µm) and depths (5-20 µm). Experimental PDMS flow rates in both PTFE-coated and uncoated channels were compared to an analytical model based on the work of Lucas and Washburn. The experimental flow rates matched the predicted flow rates reasonably well when the channel aspect ratio (width to depth), p, was less than 2. For channels with p > 2, the observed flow rates progressively lagged model predictions with increasing p. The experimental data, including zero flow rates in certain high aspect ratio PTFE-coated channels, can largely be explained by changes in the front and upper meniscus morphology of the flow as the channel aspect ratio is varied. The results strongly suggest that meniscus morphology needs to be taken into account to accurately model capillary flow in microchannels, especially those with large aspect ratios.