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Abstract Retinal pigment epithelial (RPE) cells play a crucial role in the health of the retina, and their dysfunction is associated with various ocular diseases. The transplantation of RPE cells has been proposed as a potential treatment for numerous degenerative diseases, including geographic atrophy from macular degeneration. However, current models to induce RPE damage in animal models prior to transplantation involve mechanical scraping, chemical administration, or laser photocoagulation techniques, which can damage the overlying neurosensory retina. This study aims to investigate the feasibility and efficacy of nanosecond duration laser treatment to safely remove large areas of RPE cells without causing damage to the adjacent tissue or affecting the retinal architecture. Twelve pigmented rabbits were treated with a nanosecond laser on each eye at a laser energy ranging from 200 to 800 nJ with a treated area of 5 × 5 mm2. Human induced pluripotent stem cells-differentiated to RPE (hiPSC-RPE) cells labeled with indocyanine green (ICG), an FDA approved dye, were transplanted subretinally into the damaged RPE areas at day 14 post-laser treatment. The RPE atrophy and hiPSC-RPE cell survival was evaluated and monitored over a period of 14 days using color photography, fluorescein angiography (FA), photoacoustic microscopy (PAM), and optical coherence tomography (OCT) imaging. All treated eyes demonstrated focal RPE loss with a success rate of 100%. The injured RPE layers and the transplanted hiPSC-RPE cells were visualized in three dimensions using PAM and OCT. By performing PAM at an optical wavelength of 700 nm, the location of hiPSC-RPE cells were identified and distinguished from the surrounding RPE cells, and the induced PA signal increased up to 18 times. Immunohistochemistry results confirmed the grafted hiPSC-RPE replaced regions of RPE damage. This novel technique has the potential to serve as an animal model of RPE degeneration, to improve models of RPE transplantation, and may help accelerate translation of this therapeutic strategy for clinical use.

The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an ex vivo melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the ex vivo tumor model when an ultrasound peak negative pressure of 2 MPa was concurrently applied with a laser fluence of 28 mJ/cm2 at 532 nm optical wavelength for 5 min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5 mm with the use of 1,064 nm laser light at a fluence of 150 mJ/cm2. None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.

Objectives The current clinical pulse lavage technique for flushing fresh osteochondral allografts (OCAs) to remove immunogenic elements from the subchondral bone is ineffective. This study aimed to identify the optimal method for removing immunogenic elements from OCAs. Methods We examined five methods for the physical removal of immunogenic elements from OCAs from the femoral condyle of porcine knees. We distributed the OCAs randomly into the following seven groups: (1) control, (2) saline, (3) ultrasound, (4) vortex vibration (VV), (5) low‐pulse lavage (LPL), (6) high‐pulse lavage (HPL), and (7) high‐speed centrifugation (HSC). OCAs were evaluated using weight measurement, micro‐computed tomography (micro‐CT), macroscopic and histological evaluation, DNA quantification, and chondrocyte activity testing. Additionally, the subchondral bone was zoned to assess the bone marrow and nucleated cell contents. One‐way ANOVA and paired two‐tailed Student's t‐test are used for statistical analysis. Results Histological evaluation and DNA quantification showed no significant reduction in marrow elements compared to the control group after the OCAs were treated with saline, ultrasound, or VV treatments; however, there was a significant reduction in marrow elements after LPL, HPL, and HSC treatments. Furthermore, HSC more effectively reduced the marrow elements of OCAs in the middle and deep zones compared with LPL (p

Purpose: Early detection and diagnosis of cancer is critical for achieving positive therapeutic outcomes. Biomarkers that can provide clinicians with clues to the outcome of a given therapeutic course are highly desired. Oxygen is a small molecule that is nearly universally present in biological tissues and plays a critical role in the effectiveness of radiotherapies by reacting with DNA radicals and subsequently impairing cellular repair of double strand breaks.Techniques for measuring oxygen in biological tissues often use blood oxygen saturation to approximate the oxygen partial pressure in surrounding tissues despite the complex, nonlinear, and dynamic relationship between these two separate oxygen populations. Methods and materials: We combined a directly oxygen-sensitive, tumor-targeted, chemical contrast nanoelement with the photoacoustic lifetime-based (PALT) oxygen imaging technique to obtain image maps of oxygen in breast cancer tumors in vivo. The oxygen levels of patient-derived xenografts in a mouse model were characterized before and after a course of radiotherapy. Results: We show that, independent of tumor size, radiotherapy induced an increase in the overall oxygenation levels of the tumor. Further, this increase in the oxygenation of the tumor significantly correlated with a positive response to radiotherapy, as demonstrated by a reduction in tumor volume over the twenty-day monitoring period following therapy and histological staining. Conclusion: Our PALT imaging presented here is simple, fast, and non-invasive. Facilized by the PALT approach, imaging of tumor reoxygenation may be utilized as a simple, early indicator for evaluating cancer response to radiotherapy. Further characterization of the reoxygenation degree, temporal onset, and possible theragnostic implications are warranted.

The incorporation of gold nanoparticles (GNPs) into retinal imaging signifies a notable advancement in ophthalmology, offering improved accuracy in diagnosis and patient outcomes. This review explores the synthesis and unique properties of GNPs, highlighting their adjustable surface plasmon resonance, biocompatibility, and excellent optical absorption and scattering abilities. These features make GNPs advantageous contrast agents, enhancing the precision and quality of various imaging modalities, including photoacoustic imaging, optical coherence tomography, and fluorescence imaging. This paper analyzes the unique properties and corresponding mechanisms based on the morphological features of GNPs, highlighting the potential of GNPs in retinal disease diagnosis and management. Given the limitations currently encountered in clinical applications of GNPs, the approaches and strategies to overcome these limitations are also discussed. These findings suggest that the properties and efficacy of GNPs have innovative applications in retinal disease imaging.

Photoacoustic (PA) imaging has been extensively investigated in application in biomedicine over the last decade. This article reviews the motivation, significance, and system configuration of a few ongoing studies of implementing photoacoustic technology in musculoskeletal imaging, abdominal imaging, and interstitial sensing. The review then summarizes the methodologies and latest progress of relevant projects. Finally, we discuss our expectations for the future of translation research in PA imaging.

Abstract This study aimed to demonstrate longitudinal multimodal imaging of laser photocoagulation-induced choroidal neovascularization (CNV) in pigmented rabbits. Six Dutch Belted pigmented rabbits were treated with 12 laser lesions in each eye at a power of 300 mW with an aerial diameter spot size of 500 μm and pulse duration of 100 ms. CNV progression was monitored over a period of 4 months using different imaging techniques including color fundus photography, fluorescein angiography (FA), photoacoustic microscopy (PAM), and optical coherence tomography (OCT). All treated eyes developed CNV with a success rate of 100%. The margin and morphology of CNV were detected and rendered in three dimensions using PAM and OCT. The CNV was further distinguished from the surrounding melanin and choroidal vessels using FDA-approved indocyanine green dye-enhanced PAM imaging. By obtaining PAM at 700 nm, the location and density of CNV were identified, and the induced PA signal increased up to 59 times. Immunohistochemistry with smooth muscle alpha-actin (αSMA) antibody confirmed the development of CNV. Laser photocoagulation demonstrates a great method to create CNV in pigmented rabbits. The CNV was stable for up to 4 months, and the CNV area was measured from FA images similar to PAM and OCT results. In addition, this study demonstrates that contrast agent-enhanced PAM imaging allows for precise visualization and evaluation of the formation of new blood vessels in a clinically-relevant animal model of CNV. This laser-induced CNV model can provide a unique technique for longitudinal studies of CNV pathogenesis that can be imaged with multimodal imaging.

Photo-mediated ultrasound therapy (PUT) is a cavitation-based, highly selective antivascular technique. In this study, the effectiveness and safety of PUT on cutaneous vascular malformation was examined through in vivo experiments in a clinically relevant chicken wattle model, whose microanatomy is similar to that of port-wine stain and other hypervascular dermal diseases in humans. Assessed by optical coherence tomography angiography, the blood vessel density in the chicken wattle decreased by 73.23% after one session of PUT treatment in which 0.707 J/cm2 fluence laser pulses were applied concurrently with ultrasound bursts (n = 7, P < .01). The effectiveness of removing blood vessels in the skin at depth up to 1 mm was further assessed by H&E-stained histology at multiple time points, which included days 1, 3, 7, 14, and 21 after treatment. Additional immunohistochemical analyses with CD31, caspase-3, and Masson’s trichrome stains were performed on day 3 after treatment. The results show that the PUT-induced therapeutic effect was confined and specific to blood vessels only, whereas unwanted collateral damage in other skin tissues such as collagen was avoided. The findings from this study demonstrate that PUT can efficiently and safely remove hypervascular dermal capillaries using laser fluence at a level that is orders of magnitude smaller than that used in conventional laser treatment of vascular lesions, thus offering a safer alternative technique for clinical management of cutaneous vascular malformations.

Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

IntroductionThiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia.MethodsWe proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia. One hundred and twenty-seven IBD participants treated with thiopurine were enrolled, twenty-seven of which have developed thiopurine-induced leucopenia. Plasma lipid profiles were measured using Ultra-High-Performance Liquid Chromatography-Tandem Q-Exactive. Lipidomic alterations were validated with an independent validation cohort (leukopenia n = 26, non-leukopenia n = 74).ResultsUsing univariate and multivariate analysis, there were 16 lipid species from four lipid classes, triglyceride (n = 11), sphingomyelin (n = 1), phosphatidylcholine (n = 1) and lactosylceramide (n = 3) identified. Based on machine learning feature reduction and variable screening strategies, the random forest algorithm established by six lipids showed an excellent performance to distinguish the leukopenia group from the normal group, with a model accuracy of 95.28% (discovery cohort), 79.00% (validation cohort) and an area under the receiver operating characteristic (ROC) curve (ROC-AUC) of 0.9989 (discovery cohort), 0.8098 (validation cohort).DiscussionOur novel findings suggested that lipidomic provided unique insights into formulating individualized medication strategies for thiopurines in IBD patients.

In our previous study, we demonstrated the feasibility of using an all-optical interstitial photoacoustic (PA) needle sensing probe for quantitative study of tissue architectures with PA spectral analysis (PASA). In this work, we integrated the optical components into an 18 G steel needle sheath for clinical translation. The dimensions of the needle probe are identical to those of a core biopsy probe and are fully compatible with standard procedures such as prostate biopsy. To our knowledge, this is the first interstitial PA probe that can acquire signals with sufficient temporal length for statistics-based PASA. We treated the inner surface of the steel needle sheath and successfully suppressed the vibrational PA signals generated at the surface. Purposed at boosting the measurement sensitivity and extending sensing volume, we upgraded the Fabry-Pérot hydrophone with a plano-concave structure. The performance of the translational needle PA sensing probe was examined with phantoms containing microspheres. The trend of the linear spectral slopes shows negatively correlated to the microsphere dimensions while the midband-fits are positively correlated to microsphere diameters and concentrations. The PASA quantifications show the ability to differentiate microspheres with varied dimensions.

Aiming at clinical translation, we developed an automatic 3D imaging system combining the emerging photoacoustic imaging with conventional Doppler ultrasound for detecting inflammatory arthritis. This system was built with a GE HealthCare (GEHC) Vivid™ E95 ultrasound system and a Universal Robot UR3 robotic arm. In this work, the performance of this system was examined with a longitudinal study utilizing a clinically relevant adjuvant induced arthritis (AIA) murine model. After adjuvant injection, daily imaging of the rat ankle joints was conducted until joint inflammation was obvious based on visual inspection. Processed imaging results and statistical analyses indicated that both the hyperemia (enhanced blood volume) detected by photoacoustic imaging and the enhanced blood flow detected by Doppler ultrasound reflected the progress of joint inflammation. However, photoacoustic imaging, by leveraging the highly sensitive optical contrast, detected inflammation earlier than Doppler ultrasound, and also showed changes that are more statistically significant. This side-by-side comparison between photoacoustic imaging and Doppler ultrasound using the same commercial grade GEHC ultrasound machine demonstrates the advantage and potential value of the emerging photoacoustic imaging for rheumatology clinical care of arthritis.

Abstract Previous exposure‐response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure‐response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B‐cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). The trough concentration in the first cycle (C1‐trough) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.00 μg/ml vs. 16.62 μg/ml, p = 0.0016), however, this difference between the two groups disappeared in later cycles. The relationship between rituximab C1‐trough and achieving a CR was confirmed by matched‐pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C1‐trough (≥18.40 μg/ml) was associated with longer progression‐free survival (p < 0.0001) and overall survival (p = 0.0038). The percentages of patients that did not achieve a CR and had recurrence after CR within 24 months were 35% and 22.50%, respectively, for patients with a C1‐trough less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C1‐trough greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C1‐trough, with 51.02% of patients at stage IV with an observed C1‐trough less than 18.40 μg/ml. For these advanced patients, population pharmacokinetic simulations using an established model suggest that a loading dose of 800 mg/m2 may help to improve clinical outcomes.

Sodium has many vital and diverse roles in the human body, including maintaining the cellular pH, generating action potential, and regulating osmotic pressure. In cancer, sodium dysregulation has been correlated with tumor growth, metastasis, and immune cell inhibition. However, most in vivo sodium measurements are performed via Na23 NMR, which is handicapped by slow acquisition times, a low spatial resolution (in mm), and low signal-to-noise ratios. We present here a plasticizer-free, ionophore-based sodium-sensing nanoparticle that utilizes a solvatochromic dye transducer to circumvent the pH cross-sensitivity of most previously reported sodium nano-sensors. We demonstrate that this nano-sensor is non-toxic, boasts a 200 μM detection limit, and is over 1000 times more selective for sodium than potassium. Further, the in vitro photoacoustic calibration curve presented demonstrates the potential of this nano-sensor for performing the in vivo chemical imaging of sodium over the entire physiologically relevant concentration range.

In our previous studies, we demonstrated the ability of an interstitial all-optical needle photoacoustic (PA) sensing probe and PA spectral analysis (PASA) to assess the aggressiveness of prostate cancer. In this clinical translation investigation, we integrated the optical components of the needle PA sensing probe into a 18G steel needle. The translational needle PA sensing probe was evaluated using intact human prostates in a simulated ultrasound-guided transperineal prostate biopsy. PA signals were acquired at 1220 nm, 1370 nm, 800 nm and 266 nm at each interstitial measurement location and quantified by PASA within the frequency range of 8–28 MHz. The measurement locations were stained for establishing spatial correlations between the quantitative measurements and the histological diagnosing. Most of the quantitative PA assessments reveal statistically significant differences between the benign and cancerous regions. Multivariate analysis combining the PASA quantifications shows an accuracy close to 90% in differentiating the benign and cancerous regions in the prostates.

OBJECTIVES/GOALS: The goal of this study was to develop a clinically applicable technique to increase the precision of in vivo dose monitoring during radiation therapy by mapping the dose deposition and resolving the temporal dose accumulation while the treatment is being delivered in real time. METHODS/STUDY POPULATION: Ironizing radiation acoustic imaging (iRAI) is a novel imaging concept with the potential to map the delivered radiation dose on anatomic structure in real time during external beam radiation therapy without interrupting the clinical workflow. The iRAI system consisted of a custom-designed two-dimensional (2D) matrix transducer array with integrated preamplifier array, driven by a clinic-ready ultrasound imaging platform. The feasibility of iRAI volumetric imaging in mapping dose delivery and real-time monitoring of temporal dose accumulation in a clinical treatment plan were investigated with a phantom, a rabbit model, and a cancer patient. RESULTS/ANTICIPATED RESULTS: The total dose deposition and temporal dose accumulation in 3D space of a clinical C-shape treatment plan in a targeted region were first imaged and optimized in a phantom. Then, semi-quantitative iRAI measurements were achieved in an in vivo rabbit model. Finally, for the first time, real-time visualization of radiation dose delivered deep in a patient with liver metastases was performed with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the radiation dose deposition during treatment. DISCUSSION/SIGNIFICANCE: Described here is the pioneering role of an iRAI system in mapping the 3D radiation dose deposition of a complex clinical radiotherapy treatment plan. iRAI offers a cost-effective and practical solution for real-time visualization of 3D radiation dose delivery, potentially leading to personalized radiotherapy with optimal efficacy and safety.

Based on the observations made in rheumatology clinics, autoimmune disease (AD) patients on immunosuppressive (IS) medications have variable vaccine site inflammation responses, whose study may help predict the long-term efficacy of the vaccine in this at-risk population. However, the quantitative assessment of the inflammation of the vaccine site is technically challenging. In this study analyzing AD patients on IS medications and normal control subjects, we imaged the inflammation of the vaccine site 24 h after mRNA COVID-19 vaccinations were administered using both the emerging photoacoustic imaging (PAI) method and the established Doppler ultrasound (US) method. A total of 15 subjects were involved, including 6 AD patients on IS and 9 normal control subjects, and the results from the two groups were compared. Compared to the results obtained from the control subjects, the AD patients on IS medications showed statistically significant reductions in vaccine site inflammation, indicating that immunosuppressed AD patients also experience local inflammation after mRNA vaccination but not in as clinically apparent of a manner when compared to non-immunosuppressed non-AD individuals. Both PAI and Doppler US were able to detect mRNA COVID-19 vaccine-induced local inflammation. PAI, based on the optical absorption contrast, shows better sensitivity in assessing and quantifying the spatially distributed inflammation in soft tissues at the vaccine site.

Evaluating the aggressiveness of prostate cancer (PCa) is crucial for PCa diagnosis and prognosis. Previously, studies have shown that photoacoustic spectral analysis (PASA) can assess prostate tissue microarchitecture for evaluating the aggressiveness of PCa. In this study, in a transgenic mouse (TRAMP) model of PCa, we utilized methylene blue polyacrylamide nanoparticles (MB PAA NPs) to label the cancer cells in prostate in vivo. MB PAA NPs can specifically target proliferating cancer cells as a contrast agent, allowing photoacoustic (PA) imaging to better detect PCa tumors, and also assessing prostate glandular architecture. With the PA signals from the prostates measured simultaneously by a needle hydrophone and a PA and ultrasound (US) dual-imaging system, we conducted PASA and correlated the quantified spectral parameter slopes with the cancer grading from histopathology. The PASA results from 18 mice showed significant differences between normal and cancer, and also between low-score cancer and high-score cancer. This study in the clinically relevant TRAMP model of PCa demonstrated that PA imaging and PASA, powered by MB PAA NPs that can label the PCa microarchitectures in vivo after systemic administration, can detect PCa and, more importantly, evaluate cancer aggressiveness.

This manuscript presents ultrapure chain-like gold nanoparticle clusters with red shifted absorption and shows their potential for in vivo imaging in living rabbits. The nanoparticles demonstrate a 17-fold increase in photoacoustic microscopy signal and 176% increase in optical coherence tomography signal.

The investigation of neuronal activity in non-human primate models is of critical importance due to their genetic similarity to human brains. In this study, we tested the feasibility of using photoacoustic imaging for the detection of cortical and subcortical responses due to peripheral electrical stimulation in a squirrel monkey model. Photoacoustic computed tomography and photoacoustic microscopy were applied on squirrel monkeys for real-time deep subcortical imaging and optical-resolution cortical imaging, respectively. The electrically evoked hemodynamic changes in primary somatosensory cortex, premotor cortices, primary motor cortex, and underlying subcortical areas were measured. Hemodynamic responses were observed in both cortical and subcortical brain areas at the cortices during external stimulation, demonstrating the feasibility of photoacoustic technique for functional imaging of non-human primate brain.

Individual variations in concentrations of rituximab in different B cell non-Hodgkin’s lymphoma subtypes and their relevance to efficacy were still unclear. From 2016 to 2021, a prospective clinical trial was conducted, and 510 samples with 6 uncommon subtypes of B-cell lymphoma were enrolled to examine the pharmacokinetic behaviour of rituximab and its impact on clinical outcomes, including complete response (CR), progression-free survival (PFS) and overall survival (OS). Considerable variability was observed in the rituximab trough concentration in the first cycle (C1-trough, 1.16–55.52 μg/ml) in patients with different lymphoma subtypes. Patients with “double-hit” lymphoma (4.01 ± 0.77 μg/ml) or mantle cell lymphoma (MCL; 15.65 ± 16.45 μg/ml) had much lower C1-trough and worse outcomes. Great individual variation in the C1-trough existed among patients with mucosa-associated lymphoma (MALT), and the high C1-trough observed in patients treated with the RB regimen was associated with a better response than was obtained with R-CHOP (38.41 ± 14.13 μg/ml vs 15.49 ± 8.80 μg/ml, p = 0.0029). Despite the high aggressiveness of the cancer, Burkitt lymphoma patients receiving intensive chemotherapy had the highest C1-trough (28.85 ± 9.35 μg/ml) and maintained long-term PFS. The C1-trough in patients with mixed, unclassifiable B-cell lymphoma was close to 20 μg/ml, and these patients had acceptable outcomes. Overall, a low rituximab C1-trough was associated with adverse consequences, including persistent progression, early recurrence and a short OS, however, some high-risk factors appeared to be balanced by the presence of a high C1-trough. Basal levels of circulating CD19+ lymphocytes differed between and within patients with diverse lymphoma subtypes and were negatively correlated with C1-trough. Therefore, the traditional doses of rituximab are inadequate for patients with “double-hit” lymphoma and MCL. Increasing the initial rituximab dose according to the disease, high-risk factors and even the baseline CD19+ lymphocyte count will be new methods to optimize therapeutic regimens for patients with different lymphoma subtypes.

The photoacoustic (PA) technique is uniquely positioned for biomedical applications primarily due to its ability to visualize optical absorption contrast in deep tissue at ultrasound resolution. In this work, via both three-dimensional (3D) numerical simulations and in vivo experiments on human subjects, we investigated the possibility of PA measurement of human calcaneus bones in vivo in a non-invasive manner, as well as its feasibility to differentiate osteoporosis patients from normal subjects. The results from the simulations and the experiments both demonstrated that, when one side of the heel is illuminated by laser with light fluence under the ANSI safety limit, the PA signal generated in the human calcaneus bone can be detected by an ultrasonic transducer at the other side of the heel (i.e. transmission mode). Quantitative power spectral analyses of the calcaneus bone PA signals were also conducted, demonstrating that the microarchitectural changes in calcaneus bone due to osteoporosis can be detected, as reflected by enhanced high frequency components in detected PA bone signal. Further statistical analysis of the experimental results from 10 osteoporosis patients and 10 healthy volunteers showed that the weighted frequency as a quantified PA spectral parameter can differentiate the two subject groups with statistical significance.

Geobacterales is a recently proposed order comprising members who originally belonged to the well-known family Geobacteraceae, which is a key group in terrestrial ecosystems involved in biogeochemical cycles and has been widely investigated in bioelectrochemistry and bioenergy fields. Previous studies have illustrated the taxonomic structure of most members in this group based on genomic phylogeny; however, several members are still in a pendent or chaotic taxonomic status owing to the lack of genome sequences. To address this issue, we performed this taxonomic reassignment using currently available genome sequences, along with the description of two novel paddy soil-isolated strains, designated Red51T and Red69T, which are phylogenetically located within this order. Phylogenomic analysis based on 120 ubiquitous single-copy proteins robustly separated the species Geobacter luticola from other known genera and placed the genus Oryzomonas (fam. Geobacteraceae) into the family ‘Pseudopelobacteraceae’; thus, a novel genus Geomobilimonas is proposed, and the family ‘Pseudopelobacteraceae’ was emended. Moreover, genomic comparisons with similarity indexes, including average amino acid identity (AAI), percentage of conserved protein (POCP), and average nucleotide identity (ANI), showed proper thresholds as genera boundaries in this order with values of 70%, 65%, and 74% for AAI, POCP, and ANI, respectively. Based on this, the three species Geobacter argillaceus, Geobacter pelophilus, and Geobacter chapellei should be three novel genera, for which the names Geomobilibacter, Geoanaerobacter, and Pelotalea are proposed, respectively. In addition, the two novel isolated strains phylogenetically belonged to the genus Geomonas, family Geobacteraceae, and shared genomic similarity values higher than those of genera boundaries, but lower than those of species boundaries with each other and their neighbors. Taken together with phenotypic and chemotaxonomic characteristics similar to other Geomonas species, these two strains, Red51T and Red69T, represent two novel species in the genus Geomonas, for which the names Geomonas azotofigens sp. nov. and Geomonas diazotrophica sp. nov. are proposed, respectively.

Background: Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. Methods: Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. Findings: CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. Interpretation: OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation. Keywords: Nitro-fatty acids, Non-alcoholic fatty liver disease, Non-alcoholic Steatohepatitis, Non-invasive liver imaging, liver fibrosis

With the capability of assessing high resolution optical contrast in soft tissues, photoacoustic imaging (PAI) can offer valuable structural and functional information of human joints, and hold potential for diagnosis and treatment monitoring of inflammatory arthritis. Recent studies have demonstrated that PAI can map 2D and 3D morphology of the cartilage, synovium, vascularity, and bone tissue in human peripheral joints. Initial trials with patients affected by inflammatory arthritis have also suggested that PAI can detect the hemodynamic properties in articular tissues as well as their changes due to active inflammation. This review focuses on the recent progress in technical development of PAI for human musculoskeletal imaging and inflammation detection. PAI can provide non-invasive and non-ionizing serial measurements for monitoring of therapeutic interventions with the potential for higher sensitivity than existing imaging modalities such as ultrasound. However, further investigation is needed to validate the value of PAI in rheumatology clinical settings. Keywords: Photoacoustic tomography, Human joint, Inflammatory arthritis

Thirty-five gem-quality turquoise samples with various colours were investigated using energy-dispersive X-ray fluorescence spectroscopy, ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy and scanning electron microscopy. Sample chemical and spectral analyses indicate that Fe3+ contributes to green hue of turquoise, whose absorption band exhibits a bathochromic shift from 426 to 428 nm with increasing V content in the solid-solution series turquoise-chalcosiderite. V3+ enhances absorption in the blue and orange regions, and Cr3+ increases absorption in the green region, both of which are responsible for the vivid greenish yellow in faustite. Substitutions of Al by medium-sized trivalent cations (primarily Fe3+ and V3+) enhance polarity of the phosphate group (PO4)3−, resulting in strong absorption in the infrared spectra for analogues of turquoise. The reflectivity ratio (ROH) of the double absorption peaks at 781 and 833 cm−1 allows faustite to be distinguished from turquoise and chalcosiderite, with a value greater than 1, while V-rich faustite only has a single absorption peak at 798 cm−1. An increasing amount of absorbed water contributes to blue chroma in turquoise and has a negative effect on lightness based on the CIE 1976 L*a*b* colour system. Loose turquoise with a low specific gravity tends to display greater colour differences with a significant decrease in lightness.

Background: Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed. Methods: The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort. Results: The survival for patients with rash was significantly higher than that of patients without rash (p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958–11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067–72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032–33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710–0.951). Conclusions: Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.

The goal of this study is to further develop a multi-modality eye imaging system and evaluate its feasibility of acquiring images of different modalities simultaneously. An integrated multimodality imaging system combining spectral-domain optical coherence tomography (SD-OCT), photoacoustic microscopy (PAM), and fluorescence microscopy (FM) was developed, and its performance for eye imaging was validated on multiple clinically-relevant retinal disease models in vivo in rabbits. OCT imaging allows for visualization of the different anatomic retinal layers with high axial resolution. PAM can be used to image vasculature, angiogenesis, and hemorrhages. The leakage of neovascularization can be verified with FM and fluorescein dye. Simultaneous imaging with OCT, PAM, and FM ensures co-registration of the three modalities without being affected by motion artifacts caused by breathing, body or eye movements, and heartbeat. This simultaneous multi-modality eye imaging system could be a new tool for applications both in ophthalmology and other fields.

Photo-mediated ultrasound therapy (PUT) is a novel technique using combined laser and ultrasound to generate enhanced cavitation activity inside blood vessels. The stresses produced by oscillating bubbles during PUT are believed to be responsible for the induced bio-effects in blood vessels. However, the magnitudes of these stresses are unclear. In this study, a two-dimensional axisymmetric finite element method-based numerical model was developed to investigate the oscillating bubble-produced shear and circumferential stresses during PUT. The results showed that increased stresses on the vessel wall were produced during PUT as compared with ultrasound-alone. For a 50-nm radius bubble in a 50-μm radius blood vessel, the produced circumferential and shear stresses were in the range of 100 kPa–400 kPa and 10 Pa–100 Pa, respectively, during PUT with the ultrasound frequency of 1 MHz, ultrasound amplitude of 1400 kPa–1550 kPa, and laser fluence of 20 mJ/cm2, whereas the circumferential and shear stresses produced with ultrasound-alone were less than 2 kPa and 1 Pa, respectively, using the same ultrasound parameters. In addition, the produced stresses increased when the ultrasound pressure and laser fluence were increased but decreased when the ultrasound frequency and vessel size were increased. For bubbles with a radius larger than 100 nm, however, the stresses produced during PUT were similar to those produced during ultrasound-alone, indicating the effect of the laser was only significant for small bubbles.

Several studies have investigated the effect of photo-mediated ultrasound therapy (PUT) on the treatment of neovascularization. This study explores the impact of PUT on the release of the vasoactive agents nitric oxide (NO) and prostacyclin (PGI2) from the endothelial cells in an in vitro blood vessel model. In this study, an in vitro vessel model containing RF/6A chorioretinal endothelial cells was used. The vessels were treated with ultrasound-only (0.5, 1.0, 1.5 and 2.0 MPa peak negative pressure at 0.5 MHz with 10% duty cycle), laser-only (5, 10, 15 and 20 mJ/cm2 at 532 nm with a pulse width of 5 ns), and synchronized laser and ultrasound (PUT) treatments. Passive cavitation detection was used to determine the cavitation activities during treatment. The levels of NO and PGI2 generally increased when the applied ultrasound pressure and laser fluence were low. The increases in NO and PGI2 levels were significantly reduced by 37.2% and 42.7%, respectively, from 0.5 to 1.5 MPa when only ultrasound was applied. The increase in NO was significantly reduced by 89.5% from 5 to 20 mJ/cm2, when only the laser was used. In the PUT group, for 10 mJ/cm2 laser fluence, the release of NO decreased by 76.8% from 0.1 to 1 MPa ultrasound pressure. For 0.5 MPa ultrasound pressure in the PUT group, the release of PGI2 started to decrease by 144% from 15 to 20 mJ/cm2 laser fluence. The decreases in NO and PGI2 levels coincided with the increased cavitation activities in each group. In conclusion, PUT can induce a significant reduction in the release of NO and PGI2 in comparison with ultrasound-only and laser-only treatments.

Photoacoustic microscopy (PAM) is an emerging retinal imaging technique that can provide high spatial resolution and high contrast of chorioretinal vessels. PAM is compatible with optical coherence tomography (OCT) and fluorescence imaging, allowing for development of a multimodal imaging system that combines these imaging modalities into one. This study presents a non-invasive, label-free in vivo imaging of retinal and choroidal vascular occlusion using multimodal imaging system, including PAM and OCT. Both retinal vein occlusion (RVO) and choroidal vascular occlusion (CVO) were clearly identified selectively using a spectroscopic PAM imaging. RVO and CVO were created in six rabbits using laser photocoagulation. The dynamic changes of retinal vasculature were observed and evaluated using color fundus photography, fluorescein angiography, OCT, and PAM. The position of RVO and CVO were imaged with different wavelengths ranging from 532 to 600 nm. The data shows that occluded vessels were clearly distinguished from the surrounding retinal vessels on the PAM images. This advanced imaging system is a promising technique for imaging retinal ischemia in preclinical disease models.

Objective and Impact Statement. To study the feasibility of combined functional photoacoustic (PA) and quantitative ultrasound (US) for diagnosis of osteoporosis in vivo based on the detection of chemical and microarchitecture (BMA) information in calcaneus bone. Introduction. Clinically available X-ray or US technologies for the diagnosis of osteoporosis do not report important parameters such as chemical information and BMA. With unique advantages, including good sensitivity to molecular and metabolic properties, PA bone assessment techniques hold a great potential for clinical translation. Methods. By performing multiwavelength PA measurements, the chemical information in the human calcaneus bone, including mineral, lipid, oxygenated-hemoglobin, and deoxygenated-hemoglobin, were assessed. In parallel, by performing PA spectrum analysis, the BMA as an important bone physical property was quantified. An unpaired t-test and a two-way ANOVA test were conducted to compare the outcomes from the two subject groups. Results. Multiwavelength PA measurement is capable of assessing the relative contents of several chemical components in the trabecular bone in vivo, including both minerals and organic materials such as oxygenated-hemoglobin, deoxygenated-hemoglobin, and lipid, which are relevant to metabolic activities and bone health. In addition, PA measurements of BMA show good correlations (R2 up to 0.65) with DEXA. Both the chemical and microarchitectural measurements from PA techniques can differentiate the two subject groups. Conclusion. The results from this initial clinical study suggest that PA techniques, by providing additional chemical and microarchitecture information relevant to bone health, may lead to accurate and early diagnosis, as well as sensitive monitoring of the treatment of osteoporosis.

Objective. The goal is to increase the precision of radiation delivery during radiotherapy by tracking the movements of the tumor and other surrounding normal tissues due to respiratory and other body motions. Introduction. This work presents the recent advancement of X-ray-induced radiation acoustic imaging (xRAI) technology and the evaluation of its feasibility for real-time monitoring of geometric and morphological misalignments of the X-ray field with respect to the target tissue by combining xRAI with established ultrasound (US) imaging, thereby improving radiotherapy tumor eradication and limiting treatment side effects. Methods. An integrated xRAI and B-mode US dual-modality system was established based on a clinic-ready research US platform. The performance of this dual-modality imaging system was evaluated via experiments on phantoms and ex vivo and in vivo rabbit liver models. Results. This system can alternatively switch between the xRAI and the US modes, with spatial resolutions of 1.1 mm and 0.37 mm, respectively. 300 times signal averaging was required for xRAI to reach a satisfactory signal-to-noise ratio, and a frame rate of 1.1 Hz was achieved with a clinical linear accelerator. The US imaging frame rate was 22 Hz, which is sufficient for real-time monitoring of the displacement of the target due to internal body motion. Conclusion. Our developed xRAI, in combination with US imaging, allows for mapping of the dose deposition in biological samples in vivo, in real-time, during radiotherapy. Impact Statement. The US-based image-guided radiotherapy system presented in this work holds great potential for personalized cancer treatment and better outcomes.

Abstract With the capability of presenting endogenous tissue contrast or exogenous contrast agents in deep biological samples at high spatial resolution, photoacoustic (PA) imaging has shown significant potential for many preclinical and clinical applications. However, due to strong background signals from various intrinsic chromophores in biological tissue, such as hemoglobin, achieving highly sensitive PA imaging of targeting probes labeled by contrast agents has remained a challenge. In this study, we introduce a novel technique called transient triplet differential (TTD) imaging which allows for substantial reduction of tissue background signals. TTD imaging detects directly the triplet state absorption, which is a special characteristic of phosphorescence capable dyes not normally present among intrinsic chromophores of biological tissue. Thus, these triplet state absorption PA images can facilitate “true” background free molecular imaging. We prepared a known phosphorescent dye probe, methylene blue conjugated polyacrylamide nanoparticles, with peak absorption at 660 nm and peak lowest triplet state absorption at 840 nm. We find, through studies on phantoms and on an in vivo tumor model, that TTD imaging can generate a superior contrast-to-noise ratio, compared to other image enhancement techniques, through the removal of noise generated by strongly absorbing intrinsic chromophores, regardless of their identity.

Traditional methods for the assembly of plasmonic nanoparticles into photo-responsive probes suffer from multiple problems. Here the authors use split fluorescent protein fragments as molecular glue to form stable nanoclusters for surface enhanced Raman scattering and photoacoustic imaging in live cells.

Background optical absorption of several biomolecules impedes an effective in vivo pH imaging in tumors. Here, the authors developed a visible light-based in vivo pH mapping method by coupling photoacoustic imaging and pH-responsive modified nanoparticles that selectively target tumor cells.

Abstract We experimentally demonstrate and theoretically analyze high Q-factor (~107) capillary-based optical ring resonators for non-contact detection of air-coupled ultrasound. Noise equivalent pressures in air as low as 215 mPa/√Hz and 41 mPa/√Hz at 50 kHz and 800 kHz in air, respectively, are achieved. Furthermore, non-contact detection of air-coupled photoacoustic pulses optically generated from a 200 nm thick Chromium film is demonstrated. The interaction of an acoustic pulse and the mechanical mode of the ring resonator is also studied. Significant improvement in detection bandwidth is demonstrated by encapsulating the ring resonator in a damping medium. Our work will enable compact and sensitive ultrasound detection in many applications, such as air-coupled non-destructive ultrasound testing, photoacoustic imaging, and remote sensing. It will also provide a model system for fundamental study of the mechanical modes in the ring resonator.

Prostate cancer was the most common form and had the second highest death rate of male cancer in the United States in 2015. Current diagnosis techniques, such as prostate-specific antigen tests, transrectal ultrasound scans, and biopsies, are often inconclusive, and in the latter case, invasive. Here, we explore the use of clofazimine hydrochloride nanoparticles (CFZ-HCl NPs), a repurposed formulation from an FDA-approved antimycobacterial agent, as a photoacoustic contrast agent for the evaluation of prostate cancer due to its macrophage-targeting capabilities and high optical absorbance at 495 nm. Using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, our results indicate a preferential accumulation of intravenously injected CFZ-HCl NPs in cancerous prostates over normal prostates. Differences in accumulation of CFZ-HCl NPs between cancerous and normal prostates were determined using a two-wavelength unmixing technique via ex vivo photoacoustic imaging. Thus, intravenous injection of CFZ-HCl NPs leads to differences in the interactions of the particles with cancerous vs normal prostates, while allowing for photoacoustic detection and analysis of prostate cancer. These findings could lead to the development of a new noninvasive technique for the detection and monitoring of prostate cancer progression in an animal model that can potentially be translated to human patients.

In this study, the feasibility of assessing the chemical composition in bone using the multi-wavelength photoacoustic analysis (MWPA) method was investigated. By illuminating a bone specimen using laser light with a wavelength tunable over an optical spectrum from 680 nm to 950 nm, the optical absorption spectrum of the bone was acquired. Then, with the optical absorption spectra of all the optically absorbing chemical components in the bone known, a spectral unmixing procedure was performed to quantitatively assess the relative content of each chemical component. The experimental results from porcine rib bones demonstrated that the contents of the chemical components, including not only non-organic materials such as minerals and water but also organic materials including oxygenated hemoglobin, deoxygenated hemoglobin, lipid, and collagen, can all be assessed by MWPA. As the chemical composition in the bone is directly associated with functional and metabolic activities, the finding from this study suggests that the MWPA method could offer a new diagnostic tool for the non-invasive evaluation of bone health.

Three-dimensional photoacoustic microscopy (PAM) has gained considerable attention within the biomedical imaging community during the past decade. Detecting laser-induced photoacoustic waves by optical sensing techniques facilitates the idea of all-optical PAM (AOPAM), which is of particular interest as it provides unique advantages for achieving high spatial resolution using miniaturized embodiments of the imaging system. The review presents the technology aspects of optical-sensing techniques for ultrasound detection, such as those based on optical resonators, as well as system developments of all-optical photoacoustic systems including PAM, photoacoustic endoscopy, and multi-modality microscopy. The progress of different AOPAM systems and their representative applications are summarized.

Photoacoustic microscopy is a novel, non-ionizing, non-invasive imaging technology that evaluates tissue absorption of short-pulsed light through the sound waves emitted by the tissue and has numerous biomedical applications. In this study, a custom-built multimodal imaging system, including photoacoustic microscopy (PAM) and optical coherence tomography (OCT), has been developed to evaluate choroidal vascular occlusion (CVO). CVO was performed on three living rabbits using laser photocoagulation. Longitudinal imaging of CVO was obtained using multiple imaging tools such as color fundus photography, fluorescein angiography, indocyanine green angiography (ICGA), OCT, and PAM. PAM images were acquired at different wavelengths, ranging from 532 to 700 nm. The results demonstrate that the CVO was clearly observed on PAM in both two dimensions (2D) and 3D with high resolution longitudinally over 28 days. In addition, the location and margin of the CVO were distinguished from the surrounding choroidal vasculature after the injection of ICG contrast agent. PAM imaging was achieved using a laser energy of approximately 80 nJ, which is about half of the American National Standards Institute safety limit. The proposed imaging technique may provide a potential tool for the evaluation of different chorioretinal vascular disease pathogeneses and other biological studies.

The standard diagnostic procedure for prostate cancer (PCa) is transrectal ultrasound (TRUS)-guided needle biopsy. However, due to the low sensitivity of TRUS to cancerous tissue in the prostate, small yet clinically significant tumors can be missed. Magnetic resonance imaging (MRI) with TRUS fusion biopsy has recently been introduced as a way to improve the identification of clinically significant PCa in men. However, the spatial errors in coregistering the preprocedural MRI with the real-time TRUS causes false negatives. A real-time and intraprocedural imaging modality that can sensitively detect PCa tumors and, more importantly, differentiate aggressive from nonaggressive tumors could largely improve the guidance of biopsy sampling to improve diagnostic accuracy and patient risk stratification. In this work, we seek to fill this long-standing gap in clinical diagnosis of PCa via the development of a dual-modality imaging device that integrates the emerging photoacoustic imaging (PAI) technique with the established TRUS for improved guidance of PCa needle biopsy. Unlike previously published studies on the integration of TRUS with PAI capabilities, this work introduces a novel approach for integrating a focused light delivery mechanism with a clinical-grade commercial TRUS probe, while assuring much-needed ease of operation in the transrectal space. We further present the clinical potential of our device by (i) performing rigorous characterization studies, (ii) examining the acoustic and optical safety parameters for human prostate imaging, and (iii) demonstrating the structural and functional imaging capabilities using deep-tissue-mimicking phantoms. Our TRUSPA experimental studies demonstrated a field-of-view in the range of 130 to 150 degrees and spatial resolutions in the range of 300 μm to 400 μm at a soft tissue imaging depth of 5 cm.

Photoacoustic imaging, with the capability to provide simultaneous structural, functional, and molecular information, is one of the fastest growing biomedical imaging modalities of recent times. As a hybrid modality, it not only provides greater penetration depth than the purely optical imaging techniques, but also provides optical contrast of molecular components in the living tissue. Conventionally, photoacoustic imaging systems utilize bulky and expensive class IV lasers, which is one of the key factors hindering the clinical translation of this promising modality. Use of LEDs which are portable and affordable offers a unique opportunity to accelerate the clinical translation of photoacoustics. In this paper, we first review the development history of LED as an illumination source in biomedical photoacoustic imaging. Key developments in this area, from point-source measurements to development of high-power LED arrays, are briefly discussed. Finally, we thoroughly review multiple phantom, ex-vivo, animal in-vivo, human in-vivo, and clinical pilot studies and demonstrate the unprecedented preclinical and clinical potential of LED-based photoacoustic imaging.

The purpose of this study is to examine the capability of photoacoustic (PA) imaging (PAI) in assessing the unique molecular and architectural features in ocular tumors. A real-time PA and ultrasonography (US) parallel imaging system based on a research US platform was developed to examine retinoblastoma in mice in vivo and human retinoblastoma and uveal melanoma ex vivo. PA signals were generated by optical illumination at 720, 750, 800, 850, 900 and 950 nm delivered through a fiber optical bundle. The optical absorption spectra of the tumors were derived from the PA images. The optical absorption spectrum of each tumor was quantified by fitting to a polynomial model. The microscopic architectures of the tumors were quantified by frequency domain analysis of the PA signals. Both the optical spectral and architectural features agree with the histological findings of the tumors. The mouse and human retinoblastoma showed comparable total optical absorption spectra at a correlation of 0.95 (p

Biomedical photoacoustic (or optoacoustic) tomography (PAT), or more generally, photoacoustic imaging (PAI), has been an active area of study and development in the last two decades [...]

The pathological process of neovascularization of the retina plays a critical role in causing vision loss in several diseases, including diabetes, retinal vein occlusion, and sickle cell disease. Retinal neovascularization can lead to vitreous hemorrhage and retinal detachment, yet the pathological process of neovascularization is a complex phenomenon under active investigation. Understanding and monitoring retinal neovascularization is critically important in clinical ophthalmology. This study describes a novel multimodal ocular imaging system which combines photoacoustic microscopy (PAM) and a spectral domain optical coherence tomography (SD-OCT) to improve the visualization of retinal neovascularization (RNV), their depth, and the surrounding anatomy in living rabbits. RNV was induced in New Zealand rabbits by intravitreal injection of vascular endothelial growth factor (VEGF). The retinal vasculature before and after injection at various times was monitored and evaluated using multimodal imaging including color fundus photography, fluorescein angiography (FA), OCT, and PAM. In vivo experiments demonstrate that PAM imaging distinctly characterized the location as well as the morphology of individual RNV with high contrast at a safe laser energy of 80 nJ. SD-OCT was used to identify a cross-sectional structure of RNV. In addition, dynamic changes in the retinal morphology and retinal neovascularization were observed at day 4, 5, 6, 7, 9, 11, 14, 28, and day 35 after VEGF injection. PAM demonstrated high-resolution optical absorption of hemoglobin and vascular imaging of the retina and choroid with increased depth of penetration. With the current multimodal imaging system, RNV can be easily visualized in both 2D and 3D angiography. This multimodal ocular imaging system provides improved characterization of the microvasculature in a safe manner in larger rabbit eyes.

A photoacoustic (PA) signal of an ideal optical absorbing particle is a single N-shape wave. PA signals are a combination of several individual N-shape waves. However, the N-shape wave basis leads to aliasing between adjacent micro-structures, which deteriorates the quality of final PA images. In this paper, we propose an image optimization method by processing raw PA signals with deconvolution and empirical mode decomposition (EMD). During the deconvolution procedure, the raw PA signals are de-convolved with a system dependent deconvolution kernel, which is measured in advance. EMD is subsequently adopted to further process the PA signals adaptively with two restrictive conditions: positive polarity and spectrum consistency. With this method, signal aliasing is alleviated, and the micro-structures and detail information, previously buried in the reconstructing images, can now be revealed. To validate our proposed method, numerical simulations and phantom studies are implemented, and reconstructed images are used for illustration.

Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy.

Viewing individual cells and ambient microvasculature simultaneously is crucial for understanding tumor angiogenesis and microenvironments. We developed a confocal fluorescence microscopy (CFM) and photoacoustic microscopy (PAM) dual-modality imaging system that can assess fluorescent contrast and optical absorption contrast in biologic samples simultaneously. After staining tissues with fluorescent dye at an appropriate concentration, each laser pulse can generate not only sufficient fluorescent signals from cells for CFM but also sufficient photoacoustic signals from microvessels for PAM. To explore the potential of this system for diagnosis of bladder cancer, experiments were conducted on a rat bladder model. The CFM image depicts the morphology of individual cells, showing not only large polygonal umbrella cells but also intracellular components. The PAM image acquired at the same time provides complementary information on the microvascular distribution in the bladder wall, ranging from large vessels to capillaries. This device provides an opportunity to realize both histologic assay and microvascular characterization simultaneously. The combination of the information of individual cells and local microvasculature in the bladder offers the capability of envisioning the viability and activeness of these cells and holds promise for more comprehensive study of bladder cancer in vivo.