Changes of physiological pH are correlated with several pathologies, therefore the development of more effective medical pH imaging methods is of paramount importance. Here, we report on an in vivo pH mapping nanotechnology. This subsurface chemical imaging is based on tumor-targeted, pH sensing nanoprobes and multi-wavelength photoacoustic imaging (PAI). The nanotechnology consists of an optical pH indicator, SNARF-5F, 5-(and-6)-Carboxylic Acid, encapsulated into polyacrylamide nanoparticles with surface modification for tumor targeting. Facilitated by multi-wavelength PAI plus a spectral unmixing technique, the accuracy of pH measurement inside the biological environment is not susceptible to the background optical absorption of biomolecules, i.e., hemoglobins. As a result, both the pH levels and the hemodynamic properties across the entire tumor can be quantitatively evaluated with high sensitivity and high spatial resolution in in vivo cancer models. The imaging technology reported here holds the potential for both research on and clinical management of a variety of cancers.
Using low cost and small size light emitting diodes (LED) as the alternative illumination source for photoacoustic (PA) imaging has many advantages, and can largely benefit the clinical translation of the emerging PA imaging technology. Here, we present our development of LED-based PA imaging integrated with B-mode ultrasound. To overcome the challenge of achieving sufficient signal-to-noise ratio by the LED light that is orders of magnitude weaker than lasers, extensive signal averaging over hundreds of pulses is performed. Facilitated by the fast response of the LED and the high-speed driving as well as the high pulse repetition rate up to 16 kHz, B-mode PA images superimposed on gray-scale ultrasound of a biological sample can be achieved in real-time with frame rate up to 500 Hz. The LED-based PA imaging could be a promising tool for several clinical applications, such as assessment of peripheral microvascular function and dynamic changes, diagnosis of inflammatory arthritis, and detection of head and neck cancer.
By using our dual-modality system enabling simultaneous real-time ultrasound (US) and photoacoustic (PA) imaging of human peripheral joints, we explored the potential contribution of PA imaging modality to rheumatology clinic. By performing PA imaging at a single laser wavelength, the spatially distributed hemoglobin content reflecting the hyperemia in synovial tissue in metacarpophalangeal (MCP) joints of 16 patients were imaged, and compared to the results from 16 healthy controls. In addition, by performing PA imaging at two laser wavelengths, the spatially distributed hemoglobin oxygenation reflecting the hypoxia in inflammatory joints of 10 patients were imaged, and compared to the results from 10 healthy controls. The statistical analyses of the PA imaging results demonstrated significant differences (p < 0.001) in quantified hemoglobin content and oxygenation between the unequivocally arthritic joints and the normal joints. Increased hyperemia and increased hypoxia, two important physiological biomarkers of synovitis reflecting the increased metabolic demand and the relatively inadequate oxygen delivery in affected synovium, can both be objectively and non-invasively evaluated by PA imaging. The proposed dual-modality system has the potential of providing additional diagnostic information over the traditional US imaging approaches and introducing novel imaging biomarkers for diagnosis and treatment evaluation of inflammatory arthritis.
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.
Ion-selective optodes (ISOs), the optical analog of ion-selective electrodes, have played an increasingly important role in chemical and biochemical analysis. Here we extend this technique to ion-selective photoacoustic optodes (ISPAOs) that serve at the same time as fluorescence-based ISOs, and apply it specifically to potassium (K+). Notably, the potassium ion is one of the most abundant cations in biological systems, involved in numerous physiological and pathological processes. Furthermore, it has been recently reported that the presence of abnormal extracellular potassium concentrations in tumors suppresses the immune responses and thus suppresses immunotherapy. However, unfortunately, sensors capable of providing potassium images in vivo are still a future proposition. Here, we prepared an ion-selective potassium nanosensor (NS) aimed at in vivo photoacoustic (PA) chemical imaging of the extracellular environment, while being also capable of fluorescence based intracellular ion-selective imaging. This potassium nanosensor (K+ NS) modulates its optical properties (absorbance and fluorescence) according to the potassium concentration. The K+ NS is capable of measuring potassium, in the range of 1 mM to 100 mM, with high sensitivity and selectivity, by ISPAO based measurements. Also, a near infrared dye surface modified K+ NS allows fluorescence-based potassium sensing in the range of 20 mM to 1 M. The K+ NS serves thus as both PA and fluorescence based nanosensor, with response across the biologically relevant K+ concentrations, from the extracellular 5 mM typical values (through PA imaging) to the intracellular 150 mM typical values (through fluorescence imaging).
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