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Open Access Publications from the University of California

Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

Photoacoustic imaging is an emerging modality which the combination of ultrasound and optical imaging. The combination of these two techniques has many advantages including no use of ionizing radiation compared to radiography, high-resolution deep tissue imaging versus optical coherence tomography (OCT), and higher contrast and faster scanning compared to MRI. Most current equipment uses sophisticated and complicated OPO lasers with tuning and stability features inconsistent with broad clinical deployment. Low fluence illumination sources can facilitate clinical transition of photoacoustic imaging because they are rugged, portable, affordable, and safe. In this dissertation, I will present characterization of the commercial available light emitting diode (LED) based photoacoustic imaging in terms of system specifications, light source characterizations, photoacoustic spatial/temporal resolution, and penetration. Since low fluence light source based photoacoustic imaging devices generate low image quality, I will propose a denoising method using a multi-level wavelet-convolutional neural network to map low fluence illumination source images to its corresponding high fluence excitation map. This part of dissertation will show qualitative and quantitative improvements up to 2.20, 2.25, and 4.3-fold for peak signal-to-noise ratio (PSNR), similarity structural index measurement (SSIM), and contrast-to-noise ratio (CNR) metrics. Next, after improving and enhancing the low fluence light source photoacoustic imaging systems, we report molecular and functional imaging application for LED-based photoacoustic imaging . We demonstrate detection of reactive oxygen and nitrogen species (RONS) with a near-infrared (NIR) absorbing small molecule (CyBA) and LED-based photoacoustic imaging equipment. CyBA produces increasing photoacoustic signal in response to peroxynitrite (ONOO−) and hydrogen peroxide (H2O2) with photoacoustic signal increases of 3.54 and 4.23-fold at 50 μM of RONS at 700 nm, respectively. We also introduced photoacoustic imaging as a non-invasive method for detecting early tissue damage that cannot be visually observed while also staging the disease using quantitative image analysis. Finally, Here we introduce polyacrylamide (PAA) hydrogel as a candidate material for fabricating stable phantoms with well-characterized optical and acoustic properties that are biologically relevant over a broad range of system design parameters. These phantoms may also facilitate future standardization of performance test methodology.

    Cover page: Toward Practical Deployment of Photoacoustic Imaging
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2019)
    LED-based photoacoustic imaging has practical value in that it is affordable and rugged; however, this technology has largely been confined to anatomic imaging with limited applications into functional or molecular imaging. Here, we report molecular imaging reactive oxygen and nitrogen species (RONS) with a near-infrared (NIR) absorbing small molecule (CyBA) and LED-based photoacoustic imaging equipment. CyBA produces increasing photoacoustic signal in response to peroxynitrite (ONOO-) and hydrogen peroxide (H2O2) with photoacoustic signal increases of 3.54 and 4.23-fold at 50 µM of RONS at 700 nm, respectively. CyBA is insensitive to OCl-, ˙NO, NO2-, NO3-, tBuOOH, O2-, C4H9O˙, HNO, and ˙OH, but can detect ONOO- in whole blood and plasma. CyBA was then used to detect endogenous RONS in macrophage RAW 246.7 cells as well as a rodent model; these results were confirmed with fluorescence microscopy. Importantly, CyB suffers photobleaching under a Nd:YAG laser but the signal decrease is <2% with the low-power LED-based photoacoustic system and the same radiant exposure time. To the best of our knowledge, this is the first report to describe molecular imaging with an LED-based photoacoustic scanner. This study not only reveals the sensitive photoacoustic detection of RONS but also highlights the utility of LED-based photoacoustic imaging.
      Cover page: Molecular imaging of oxidative stress using an LED-based photoacoustic imaging system
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2022)
      Periodontitis is a public issue and imaging periodontal pocket is important to evaluate periodontitis. Regular linear transducers have limitations in imaging the posterior teeth due to their geometry restrictions. Here we characterized a transducer that can image the posterior teeth including assessment of periodontal pockets via a combination of photoacoustic and ultrasound imaging. Unlike conventional transducer design, this device has a toothbrush-shaped form factor with a side-view transducer to image molars (total size: 1 ×1.9 cm). A laser diode was integrated as the light source to reduce the cost and size and facilitates clinical transition. The in vivo imaging of a molar of a periodontal patient demonstrated that the transducer could image in the posterior area of gum in vivo; the value determined by imaging was within 7 % of the value measured clinically.
        Cover page: Posterior photoacoustic/ultrasound imaging of the periodontal pocket with a compact intraoral transducer
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2020)
        Accumulation of reactive oxygen and nitrogen species (RONS) can induce cell damage and even cell death. RONS are short-lived species, which makes direct, precise, and real-time measurement difficult. Biologically-relevant RONS levels are in the nM-μM scale; hence, there is a need for highly sensitive RONS probes. We previously used hybrid gold-core silver-shell nanoparticles with mM sensitivity to H2O2. These particles reported the presence of RONS via spectral shifts which could easily be quantified via photoacoustic imaging. Here, we used halide doping to tune the electrochemical properties of these materials to better match the oxidation potential of RONS. This work describes the synthesis, characterization, and application of these AgI-coated gold nanorods (AgI/AuNR). The I : Ag molar ratio, pH, and initial Ag shell thickness were optimized for good RONS detection limits. Halide doping lowers the reduction potential of Ag from to resulting in a 1000-fold increase in H2O2 and 100 000-fold increase in ONOO- sensitivity. The AgI/AuNR system also etches 45-times faster than undoped Ag/AuNR. The AgI/AuNR easily reported the endogenously produced RONS in established cells lines as well as murine models.
          Cover page: Iodide-doped precious metal nanoparticles: measuring oxidative stress in vivo via photoacoustic imaging
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2019)
          Transvaginal ultrasound is widely used for ovarian cancer screening but has a high false positive rate. Photoacoustic imaging provides additional optical contrast to supplement ultrasound and might be able to improve the accuracy of screening. Here, we report two copper sulfide (CuS) nanoparticles types (nanodisks and triangular nanoprisms) as the photoacoustic contrast agents for imaging ovarian cancer. Both CuS nanoprisms and nanodisks were ~6 nm thick and ~26 nm wide and were coated with poly(ethylene glycol) to make them colloidally stable in phosphate buffered saline (PBS) for at least 2 weeks. The CuS nanodisks and nanoprisms revealed strong localized surface plasmon resonances with peak maxima at 1145 nm and 1098 nm, respectively. Both nanoparticles types had strong and stable photoacoustic intensity with detection limits below 120 pM. The circular CuS nanodisk remained in the circulation of nude mice (n=4) and xenograft 2008 ovarian tumors (n=4) 17.9-fold and 1.8-fold more than the triangular nanoprisms, respectively. Finally, the photoacoustic intensity of the tumors from the mice (n=3) treated with CuS nanodisks was 3.0-fold higher than the baseline. The tumors treated with nanodisks had a characteristic peak at 920 nm in the spectrum to potentially differentiate the tumor from adjacent tissues.
            Cover page: Copper Sulfide Nanodisks and Nanoprisms for Photoacoustic Ovarian Tumor Imaging.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2019)
            Contrast-enhanced ultrasound (CEUS) offers the exciting prospect of retaining the ease of ultrasound imaging while enhancing imaging clarity, diagnostic specificity, and theranostic capability. To advance the capabilities of CEUS, the synthesis and understanding of new ultrasound contrast agents (UCAs) is a necessity. Many UCAs are nano- or micro-scale materials composed of a perfluorocarbon (PFC) and stabilizer that synergistically induce an ultrasound response that is both information-rich and easily differentiated from natural tissue. In this work, we probe the extent to which CEUS is modulated through variation in a PFC stabilized with fluorine-modified polydopamine nanoparticles (PDA NPs). The high level of synthetic tunability in this system allows us to study signal as a function of particle aggregation and PFC volatility in a systematic manner. Separation of aggregated and non-aggregated nanoparticles lead to a fundamentally different signal response, and for this system, PFC volatility has little effect on CEUS intensity despite a range of over 50 °C in boiling point. To further explore the imaging tunability and multimodality, Fe3+-chelation was employed to generate an enhanced photoacoustic (PA) signal in addition to the US signal. In vitro and in vivo results demonstrate that PFC-loaded PDA NPs show stronger PA signal than the non-PFC ones, indicating that the PA signal can be used for in situ differentiation between PFC-loading levels. In sum, these data evince the rich role synthetic chemistry can play in guiding new directions of development for UCAs.
              Cover page: Tuning the ultrasonic and photoacoustic response of polydopamine-stabilized perfluorocarbon contrast agents
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2019)
              Heparin is an indispensable drug in anticoagulation therapy but with a narrow therapeutic window, which dictates regular testing and dose adjustment. However, current monitoring tools have a long turnaround time or are operator intensive. In this work, we describe a cellulose-based photoacoustic sensor for heparin. The sensors have a turnaround time of 6 min for whole blood samples and 3 min for plasma samples regardless of heparin concentration. These sensors have a limit of detection of 0.28 U/ml heparin in human plasma and 0.29 U/ml in whole blood with a linear response (Pearson's r = 0.99) from 0 to 2 U/ml heparin in plasma and blood samples. The relative standard deviation was < 12.5% in plasma and < 17.5% in whole blood. This approach was validated with heparin-spiked whole human blood and had a linear correlation with the activated partial thromboplastin time (aPTT) (r = 0.99). We then studied 16 sets of clinical samples-these had a linear correlation with the activated clotting time (ACT) (Pearson's r = 0.86, P < 0.0001). The photoacoustic signal was also validated against the cumulative heparin dose (Pearson's r = 0.71, P < 0.0001). This approach could have applications in bed-side heparin assays for continuous heparin monitoring.
                Cover page: A cellulose-based photoacoustic sensor to measure heparin concentration and activity in human blood samples
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