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This study presents a system-level optimization of spectroscopic photoacoustic (PA) imaging for prostate cancer (PCa) detection in three folds. First, we present a spectral unmixing model to segregate spectral system error (SSE). We constructed two noise models (NMs) for the laser spectrotemporal fluctuation and the ultrasound system noise. We used these NMs in linear spectral unmixing to denoise and to achieve high temporal resolution. Second, we employed a simulation-aided wavelength optimization to select the most effective subset of wavelengths. NMs again were considered so that selected wavelengths were not only robust to the collinearity of optical absorbance, but also to noise. Third, we quantified the effect of frame averaging on improving spectral unmixing accuracy through theoretical analysis and numerical validation. To validate the whole framework, we performed comprehensive studies in simulation and an in vivo experiment which evaluated prostate-specific membrane antigen (PSMA) expression in PCa on a mice model. Both simulation analysis and in vivo studies confirmed that the proposed framework significantly enhances image signal-to-noise ratio (SNR) and spectral unmixing accuracy. It enabled more sensitive and faster PCa detection. Moreover, the proposed framework can be generalized to other spectroscopic PA imaging studies for noise reduction, wavelength optimization, and higher temporal resolution.
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Photothermal therapy has the characteristics of minimal invasiveness, controllability, high efficiency, and strong specificity, which can effectively make up for the toxic side effects and tumor resistance caused by traditional drug treatment. However, due to the limited tissue penetration of infrared light, it is difficult to promote and apply in clinical practice. The eye is the only transparent tissue in human, and infrared light can easily penetrate the eye tissue, so it is expected that photothermal therapy can be used to treat fundus diseases. Here in, a new nano-platform assembled by liposome and indocyanine green (ICG) was used to treat retinoblastoma. ICG was assembled in liposomes to overcome some problems of ICG itself. For example, ICG is easily quenched, self-aggregating and instability. Moreover, liposomes can prevent free ICG from being cleared through the systemic circulation. The construction of the nano-platform not only ensured the stability of ICG in vivo, but also realized imaging-guide photothermal therapy, which created a new strategy for the treatment of retinoblastoma.
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In most multispectral optical-resolution photoacoustic microscopy (OR-PAM), spatial scanning is repeated for each excitation wavelength, which decreases throughput and causes motion artifacts during spectral processing. This study proposes a new spectroscopic OR-PAM technique to acquire information on the photoacoustic signal intensity and excitation wavelength from single spatial scans. The technique involves irradiating an imaging target with two broadband optical pulses with and without wavelength-dependent time delays. The excitation wavelength of the sample is then calculated by measuring the time delay between the photoacoustic signals generated by the two optical pulses. This technique is validated by measuring the excitation wavelengths of dyes in tubes. Furthermore, we demonstrate the three-dimensional spectroscopic OR-PAM of cells stained with suitable dyes. Although the tradeoff between excitation efficiency and excitation bandwidth must be adjusted based on the application, combining the proposed technique with fast spatial scanning methods can significantly contribute to recent OR-PAM applications, such as monitoring quick biological events and microscale tracking of moving materials.
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Photodynamic therapy (PDT) is a well-known cancer therapy that utilizes light to excite a photosensitizer and generate cytotoxic reactive oxygen species (ROS). The efficacy of PDT primarily depends on the photosensitizer and oxygen concentration in the tumor. Hypoxia in solid tumors promotes treatment resistance, resulting in poor PDT outcomes. Hence, there is a need to combat hypoxia while delivering sufficient photosensitizer to the tumor for ROS generation. Here we showcase our unique theranostic perfluorocarbon nanodroplets as a triple agent carrier for oxygen, photosensitizer, and indocyanine green that enables light triggered spatiotemporal delivery of oxygen to the tumors. We evaluated the characteristics of the nanodroplets and validated their ability to deliver oxygen via photoacoustic monitoring of blood oxygen saturation and subsequent PDT efficacy in a murine subcutaneous tumor model. The imaging results were validated with an oxygen sensing probe, which showed a 9.1 fold increase in oxygen content inside the tumor, following systemic administration of the nanodroplets. These results were also confirmed with immunofluorescence. In vivo studies showed that nanodroplets held higher rates of treatment efficacy than a clinically available benzoporphyrin derivative formulation. Histological analysis showed higher necrotic area within the tumor with perfluoropentane nanodroplets. Overall, the photoacoustic nanodroplets can significantly enhance image-guided PDT and has demonstrated substantial potential as a valid theranostic option for patient-specific photodynamic therapy-based treatments.
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Skin diseases are the most common human diseases and manifest in distinct structural and functional changes to skin tissue components such as basal cells, vasculature, and pigmentation. Although biopsy is the standard practice for skin disease diagnosis, it is not sufficient to provide in vivo status of the skin and highly depends on the timing of diagnosis. Noninvasive imaging technologies that can provide structural and functional tissue information in real time would be invaluable for skin disease diagnosis and treatment evaluation. Among the modern medical imaging technologies, photoacoustic (PA) tomography (PAT) shows great promise as an emerging optical imaging modality with high spatial resolution, high imaging speed, deep penetration depth, rich contrast, and inherent sensitivity to functional and molecular information. Over the last decade, PAT has undergone an explosion in technical development and biomedical applications. Particularly, PAT has attracted increasing attention in skin disease diagnosis, providing structural, functional, metabolic, molecular, and histological information. In this concise review, we introduce the principles and imaging capability of various PA skin imaging technologies. We highlight the representative applications in the past decade with a focus on imaging skin vasculature and melanoma. We also envision the critical technical developments necessary to further accelerate the translation of PAT technologies to fundamental skin research and clinical impacts.
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Measuring neuroactivity underlying complex behaviors facilitates understanding the microcircuitry that supports these behaviors. We have developed a functional and molecular photoacoustic tomography (F/M-PAT) system which allows direct imaging of Fos-expressing neuronal ensembles in Fos-LacZ transgenic rats with a large field-of-view and high spatial resolution. F/M-PAT measures the beta-galactosidase catalyzed enzymatic product of exogenous chromophore X-gal within ensemble neurons. We used an ex vivo imaging method in the Wistar Fos-LacZ transgenic rat, to detect neuronal ensembles in medial prefrontal cortex (mPFC) following cocaine administration or a shock-tone paired stimulus. Robust and selective F/M-PAT signal was detected in mPFC neurons after both conditions (compare to naive controls) demonstrating successful and direct detection of Fos-expressing neuronal ensembles using this approach. The results of this study indicate that F/M-PAT can be used in conjunction with Fos-LacZ rats to monitor neuronal ensembles that underlie a range of behavioral processes, such as fear learning or addiction.
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Gold nanostars (GNSs) are promising contrast agents for simultaneous photothermal therapy and photoacoustic imaging (PAI) owing to their excellent photothermal conversion efficiency. However, GNSs are easily reshaped under transient high-intensity laser pulses, which can cause a rapid shift in the light absorption peak, resulting in a decrease in both therapeutic and monitoring effects. In this work, we synthesized GNSs without toxic surfactants and coated them with a silica shell to retain their shape, thus maintaining their photostability. The excellent performance of these silica-coated GNSs was verified through both in vitro and in vivo PAI experiments. The silica-coated GNSs exhibited a threefold improvement in photoacoustic stability, as compared with the non-coated GNSs. The proposed silica coating method for GNSs was found to improve the photostability of GNSs, making them efficient, safe, and reliable nanoparticles for PAI.
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In this study, we investigated the feasibility of using photoacoustic time-frequency spectral analysis (PA-TFSA) for evaluating the bone mineral density (BMD) and bone structure. Simulations and ex vivo experiments on bone samples with different BMDs and mean trabecular thickness (MTT) were conducted. All photoacoustic signals were processed using the wavelet transform-based PA-TFSA. The power-weighted mean frequency (PWMF) was evaluated to obtain the main frequency component at different times. The y-intercept, midband-fit, and slope of the linearly fitted curve of the PWMF over time were also quantified. The results show that the osteoporotic bone samples with lower BMD and thinner MTT have higher frequency components and lower acoustic frequency attenuation over time, thus higher y-intercept, midband-fit, and slope. The midband-fit and slope were found to be sensitive to the BMD; therefore, both parameters could be used to distinguish between osteoporotic and normal bones (p < 0.05).
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Translation of stem cell therapies to treat injuries and diseases of the spinal cord is hindered by lack of real-time monitoring techniques to guide regenerative therapies intra- and postoperatively. Thus, we developed an ultrasound (US), photoacoustic (PA), and magnetic resonance (MR) imaging approach augmented with Prussian blue nanocubes (PBNCs) to guide stem cell injections intraoperatively and monitor stem cell therapies in the spinal cord postoperatively. Per the clinical procedure, a multi-level laminectomy was performed in rats ex vivo, and PBNC-labeled stem cells were injected directly into the spinal cord while US/PA images were acquired. US/PA/MR images were also acquired post-surgery. Several features of the imaging approach were demonstrated including detection of low stem cell concentrations, real-time needle guidance and feedback on stem cell delivery, and good agreement between US/PA/MR images. These benefits span intra- and postoperative environments to support future development of this imaging tool.
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Photoacoustic imaging (or optoacoustic imaging) is an upcoming biomedical imaging modality availing the benefits of optical resolution and acoustic depth of penetration. With its capacity to offer structural, functional, molecular and kinetic information making use of either endogenous contrast agents like hemoglobin, lipid, melanin and water or a variety of exogenous contrast agents or both, PAI has demonstrated promising potential in a wide range of preclinical and clinical applications. This review provides an overview of the rapidly expanding clinical applications of photoacoustic imaging including breast imaging, dermatologic imaging, vascular imaging, carotid artery imaging, musculoskeletal imaging, gastrointestinal imaging and adipose tissue imaging and the future directives utilizing different configurations of photoacoustic imaging. Particular emphasis is placed on investigations performed on human or human specimens.
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EGFR is a promising cell surface target for in vivo imaging that is highly overexpressed in hepatocellular carcinoma (HCC), a common cancer worldwide. Peptides penetrate easily into tumors for deep imaging, and clear rapidly from the circulation to minimize background. We aim to demonstrate use of an EGFR specific peptide to detect HCC xenograft tumors in mice with photoacoustic imaging. Nude mice implanted with human HCC cells that overexpress EGFR were injected intravenously with Cy5.5-labeled EGFR and scrambled control peptides respectively. Photoacoustic images collected from 0 to 24 h. Photoacoustic signal peaked in tumors at 3 h post-injection. Images from 0 to 1.8 cm beneath the skin revealed increased target-to-background (T/B) ratio from tumors. The T/B ratio was significantly greater for the EGFR versus control peptide. Clearance of signal was observed by â¼24 h. EGFR overexpression was validated with immunofluorescence and immunohistochemistry. A peptide specific for EGFR delivered systemically can detect HCC xenograft tumors in vivo with photoacoustic imaging.
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Imaging of cellular electric potential via calcium-ion sensitive contrast agents is a useful tool, but current it lacks sufficient depth penetration. We explore contrast-enhanced photoacoustic (PA) imaging, using Arsenazo III dye, to visualize cardiac myocyte depolarization in vitro. Phantom results show strong linearity of PA signal with dye concentration (R 2 > 0.95), and agree spectrally with extinction measurements with varying calcium concentration. Cell studies indicate a significant (> 100-fold) increase in PA signal for dye-treated cells, as well as a 10-fold increase in peak-to-peak variation during a 30-second window. This suggests contrast-enhanced PA imaging may have sufficient sensitivity and specificity for depth-resolved visualization of tissue depolarization in real-time.
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Assessment of molecular signatures of tumors in addition to their anatomy and morphology is desired for effective diagnostic and therapeutic procedures. Development of in vivo imaging techniques that can identify and monitor molecular composition of tumors remains an important challenge in pre-clinical research and medical practice. Here we present a molecular photoacoustic imaging technique that can visualize the presence and activity of an important cancer biomarker - epidermal growth factor receptor (EGFR), utilizing the effect of plasmon resonance coupling between molecular targeted gold nanoparticles. Specifically, spectral analysis of photoacoustic images revealed profound changes in the optical absorption of systemically delivered EGFR-targeted gold nanospheres due to their molecular interactions with tumor cells overexpressing EGFR. In contrast, no changes in optical properties and, therefore, photoacoustic signal, were observed after systemic delivery of non-targeted gold nanoparticles to the tumors. The results indicate that multi-wavelength photoacoustic imaging augmented with molecularly targeted gold nanoparticles has the ability to monitor molecular specific interactions between nanoparticles and cell-surface receptors, allowing visualization of the presence and functional activity of tumor cells. Furthermore, the approach can be used for other cancer cell-surface receptors such as human epidermal growth factor receptor 2 (HER2). Therefore, ultrasound-guided molecular photoacoustic imaging can potentially aid in tumor diagnosis, selection of customized patient-specific treatment, and monitor the therapeutic progression and outcome in vivo.