Optimizing Irradiation Geometry in LED-Based Photoacoustic Imaging with 3D Printed Flexible and Modular Light Delivery System.

Photoacoustic (PA) imaging-a technique combining the ability of optical imaging to probe functional properties of the tissue and deep structural imaging ability of ultrasound-has gained significant popularity in the past two decades for its utility in several biomedical applications. More recently, light-emitting diodes (LED) are being explored as an alternative to bulky and expensive laser systems used in PA imaging for their portability and low-cost. Due to the large beam divergence of LEDs compared to traditional laser beams, it is imperative to quantify the angular dependence of LED-based illumination and optimize its performance for imaging superficial or deep-seated lesions. A custom-built modular 3-D printed hinge system and tissue-mimicking phantoms with various absorption and scattering properties were used in this study to quantify the angular dependence of LED-based illumination. We also experimentally calculated the source divergence of the pulsed-LED arrays to be 58° ± 8°. Our results from point sources (pencil lead phantom) in non-scattering medium obey the cotangential relationship between the angle of irradiation and maximum PA intensity obtained at various imaging depths, as expected. Strong dependence on the angle of illumination at superficial depths (-5°/mm at 10 mm) was observed that becomes weaker at intermediate depths (-2.5°/mm at 20 mm) and negligible at deeper locations (-1.1°/mm at 30 mm). The results from the tissue-mimicking phantom in scattering media indicate that angles between 30-75° could be used for imaging lesions at various depths (12 mm-28 mm) where lower LED illumination angles (closer to being parallel to the imaging plane) are preferable for deep tissue imaging and superficial lesion imaging is possible with higher LED illumination angles (closer to being perpendicular to the imaging plane). Our results can serve as a priori knowledge for the future LED-based PA system designs employed for both preclinical and clinical applications.

Spatial resolution in optical coherence elastography of bounded media.

Dynamic optical coherence elastography (OCE) tracks mechanical wave propagation in the subsurface region of tissue to image its shear modulus. For bulk shear waves, the lateral resolution of the reconstructed modulus map (i.e., elastographic resolution) can approach that of optical coherence tomography (OCT), typically a few tens of microns. Here we perform comprehensive numerical simulations and acoustic micro-tapping OCE experiments to show that for the typical situation of guided wave propagation in bounded media, such as cornea, the elastographic resolution cannot reach the OCT resolution and is mainly defined by the thickness of the bounded tissue layer. We considered the excitation of both broadband and quasi-harmonic guided waves in a bounded, isotropic medium. Leveraging the properties of broadband pulses, a robust method for modulus reconstruction with minimum artifacts at interfaces is demonstrated. In contrast, tissue bounding creates large instabilities in the phase of harmonic waves, leading to serious artifacts in modulus reconstructions.

Probing elastic anisotropy of human skin in vivo with light using non-contact acoustic micro-tapping OCE and polarization sensitive OCT.

Skin broadly protects the human body from undesired factors such as ultraviolet radiation and abrasion and helps conserve body temperature and hydration. Skin's elasticity and its level of anisotropy are key to its aesthetics and function. Currently, however, treatment success is often speculative and subjective, and is rarely based on skin's elastic properties because there is no fast and accurate non-contact method for imaging of skin's elasticity. Here we report on a non-contact and non-invasive method to image and characterize skin's elastic anisotropy. It combines acoustic micro-tapping optical coherence elastography (AµT-OCE) with a nearly incompressible transversely isotropic (NITI) model to quantify skin's elastic moduli. In addition, skin sites were imaged with polarization sensitive optical coherence tomography (PS-OCT) to help define fiber orientation. Forearm skin areas were investigated in five volunteers. Results clearly demonstrate elastic anisotropy of skin in all subjects. AµT-OCE has distinct advantages over competitive techniques because it provides objective, quantitative characterization of skin's elasticity without contact, which opens the door for broad translation into clinical use. Finally, we demonstrate that a combination of multiple OCT modalities (structural OCT, OCT angiography, PS-OCT and AµT-OCE) may provide rich information about skin and can be used to characterize scar.

Hydrophobically Modified Silica-Coated Gold Nanorods for Generating Nonlinear Photoacoustic Signals.

In this work, we report that gold nanorods coated with hydrophobically-modified mesoporous silica shells not only enhance photoacoustic (PA) signal over unmodified mesoporous silica coated gold nanorods, but that the relationship between PA amplitude and input laser fluence is strongly nonlinear. Mesoporous silica shells of ~14 nm thickness and with ~3 nm pores were grown on gold nanorods showing near infrared absorption. The silica was rendered hydrophobic with addition of dodecyltrichlorosilane, then re-suspended in aqueous media with a lipid monolayer. Analysis of the PA signal revealed not only an enhancement of PA signal compared to mesoporous silica coated gold nanorods at lower laser fluences, but also a nonlinear relationship between PA signal and laser fluence. We attribute each effect to the entrapment of solvent vapor in the mesopores: the vapor has both a larger expansion coefficient and thermal resistance than silica that enhances conversion to acoustic energy, and the hydrophobic porous surface is able to promote phase transition at the surface, leading to a nonlinear PA response even at fluences as low as 5 mJ cm-2. At 21 mJ cm-2, the highest laser fluence tested, the PA enhancement was >12-fold over mesoporous silica coated gold nanorods.

Improved forward model for quantitative pulse-echo speed-of-sound imaging.

Computed ultrasound tomography in echo mode (CUTE) allows determining the spatial distribution of speed-of-sound (SoS) inside tissue using handheld pulse-echo ultrasound (US). This technique is based on measuring the changing phase of beamformed echoes obtained under varying transmit (Tx) and/or receive (Rx) steering angles. The SoS is reconstructed by inverting a forward model describing how the spatial distribution of SoS is related to the spatial distribution of the echo phase shift. Thanks to the straight-ray approximation, this forward model is linear and can be inverted in real-time when implemented in a state-of-the art system. Here we demonstrate that the forward model must contain two features that were not taken into account so far: (a) the phase shift must be detected between pairs of Tx and Rx angles that are centred around a set of common mid-angles, and (b) it must account for an additional phase shift induced by the offset of the reconstructed position of echoes. In a phantom study mimicking hepatic and cancer imaging, we show that both features are required to accurately predict echo phase shift among different phantom geometries, and that substantially improved quantitative SoS images are obtained compared to the model that has been used so far. The importance of the new model is corroborated by a preliminary volunteer result.

Role of Ultrasound and Photoacoustic Imaging in Photodynamic Therapy for Cancer.

Photodynamic therapy (PDT) is a phototoxic treatment with high spatial and temporal control and has shown tremendous promise in the management of cancer due to its high efficacy and minimal side effects. PDT efficacy is dictated by a complex relationship between dosimetry parameters such as the concentration of the photosensitizer at the tumor site, its spatial localization (intracellular or extracellular), light dose and distribution, oxygen distribution and concentration, and the heterogeneity of the inter- and intratumoral microenvironment. Studying and characterizing these parameters, along with monitoring tumor heterogeneity pre- and post-PDT, provides essential data for predicting therapeutic response and the design of subsequent therapies. In this review, we elucidate the role of ultrasound (US) and photoacoustic imaging in improving PDT-mediated outcomes in cancer-from tracking photosensitizer uptake and vascular destruction, to measuring oxygenation dynamics and the overall evaluation of tumor responses. We also present recent advances in multifunctional theranostic nanomaterials that can improve either US or photoacoustic imaging contrast, as well as deliver photosensitizers specifically to tumors. Given the wide availability, low-cost, portability and nonionizing nature of US and photoacoustic imaging, together with their capabilities of providing multiparametric morphological and functional information, these technologies are thusly inimitable when deployed in conjunction with PDT.

Mutual impact of clinically translatable near-infrared dyes on photoacoustic image contrast and in vitro photodynamic therapy efficacy.

Photodynamic therapy (PDT), a spatially localized phototoxic therapy that involves irradiation of a photosensitizer (PS) with specific wavelengths of light, has shown exceptional promise in impacting cancer treatment outcomes, particularly oral cancer. To reduce PDT outcome variability, attempts toward image-guided personalized PDT are being pursued by monitoring PS uptake either via fluorescence or photoacoustic imaging (PAI), a nonionizing modality dependent on optical absorption properties of the tissue. PAI-guided PDT requires a near-infrared contrast agent for deep tissue imaging with minimal photobleaching effect. We evaluate the impact of PDT agent, benzoporphyrin derivative (BPD), on PAI agent indocyanine green (ICG) and vice versa, given that they have different optical absorption properties and singlet oxygen quantum yields for PDT. Specifically, we demonstrate in two oral squamous cell carcinoma lines (FaDu and SCC4) that ICG has minimal effect on BPD PDT efficacy when irradiated with either a continuous or pulsed laser. Furthermore, the impact of BPD on ICG photodegradation was monitored with PAI in tissue-mimicking phantoms. These studies inform us that the combination of BPD and ICG can be utilized for PAI-guided PDT. However, researchers need to consider the photodegradation effects of ICG in the presence of BPD when designing their drug delivery strategies for PAI-guided PDT.

Mutual impact of clinically translatable near-infrared dyes on photoacoustic image contrast and in vitro photodynamic therapy efficacy (Erratum).

The erratum corrects an error in the y-axis labels of Fig. 4 and Fig. S2.

Picosecond laser ultrasonics for imaging of transparent polycrystalline materials compressed to megabar pressures.

Picosecond laser ultrasonics is an all-optical experimental technique based on ultrafast high repetition rate lasers applied for the generation and detection of nanometric in length coherent acoustic pulses. In optically transparent materials these pulses can be detected not only on their arrival at the sample surfaces but also all along their propagation path inside the sample providing opportunity for imaging of the sample material spatial inhomogeneities traversed by the acoustic pulse. Application of this imaging technique to polycrystalline elastically anisotropic transparent materials subject to high pressures in a diamond anvil cell reveals their significant texturing/structuring at the spatial scales exceeding dimensions of the individual crystallites.

New methodology for the thermal characterization of thermoelectric liquids.

A new and accurate method for the thermal characterization of thermoelectric liquids is proposed. The experiment is based on a self-generated voltage due to the Seebeck effect. This voltage is provided by the sample when one of its two faces is thermally excited using a modulated laser. The sample used is tetradodecylammonium nitrate salt/1-octanol mixture, with high Seebeck coefficient. The thermal properties of the used sample (thermal diffusivity, effusivity, and conductivity) are found and compared to those obtained by other photothermal techniques. In addition to this, a study of the electrolyte thermal parameters with the variation of tetradodecylammonium nitrate concentration was also carried out. This new method is promising due to its accuracy and its simplicity.