Tumor blood vessels have been known as being heterogeneous because of their chaotic and abundant distribution. Thus, imaging techniques which reveal hemodynamic information of tumor vasculature play significant roles in tumor studies. Photoacoustic (PA) imaging could acquire hemodynamic information based on the intrinsic characteristics of hemoglobin, while ultrasound (US) imaging provides information of structure and blood flow. Therefore, an integrated system was developed for both US microvascular imaging and PA imaging of the tumor region. To further improve the imaging performance, a liquid filled dual-modality microdroplets was designed for both ultrasound flow and PA imaging. The microdroplets were manufactured using the microfluidics technique to produce consistent microbubble with diameters between 23 µm to 25 µm, determining the vascular size for imaging. Additionally, the microdroplets were filled with saline diluted organic nanoparticles as contrast agents for PA imaging, while commercial microbubbles are filled with inert gas. Both in vitro and in vivo studies have been conducted for evaluating the designed contrast agent and system. Results of in vitro experiments, which performed with microtubes submerged in a scattering medium, demonstrated different flow speeds and directions of the designed phantom. Subcutaneous tumor was next tested during in vivo studies. Based on the organic nanoparticle-doped droplet, we were able to obtain the information of total hemoglobin concentration, oxygen saturation and blood flow speed of the tumor angiogenesis region with a higher sensitivity. In the future, our microdroplets could be applied to more applications, such as slow drug release based on its specific structure.
Angiogenesis is a key factor for the growth and expansion of malignant tumors. Recently, non-invasive imaging techniques have been largely employed to observe the functional neovascular status of tumor progression. In this study, we present an integrated hybrid-resolution photoacoustic microscopy (PAM) capable of both optical-resolution (OR: a tightly focused beam for finer lateral resolution at shallower region) and acoustic-resolution (AR: a deeper imaging depth based on its ultrasound-dominated detection with relatively large illumination area) imaging for monitoring the progression of angiogenesis. The hybrid-resolution design is achieved by using a liquid lens to adjust the beam size for OR/AR mode selection. A multimode fiber with small core diameter is used to maintain the fine lateral resolution and deliver the laser light with higher energy for OR and AR illumination, respectively. The imaging resolutions of the proposed PAM are demonstrated by phantom experiments: the lateral resolution of OR mode is ~20 μm at a depth of 1 mm, while the resolution of AR mode is ~80 μm at depths of 2 to 3 mm. Additionally, in vivo experiments are conducted to show the capability of this PAM. Angiogenesis imaging of a subcutaneous tumor model in mice is presented using its intrinsic optical contrast (i.e., hemoglobin). Besides, information of oxygen saturation is also acquired using two wavelengths to indicate the hypoxic region of the tumor. In summary, the developed hybrid-resolution PAM is able to monitor the angiogenesis and provide hemodynamic information of tumor covering a broader depth range with high resolutions.
Cathodal-transcranial direct current stimulation induces therapeutic effects in animal ischemia models by preventing the expansion of ischemic injury during the hyperacute phase of ischemia. However, its efficacy is limited by an accompanying decrease in cerebral blood flow. On the other hand, peripheral sensory stimulation can increase blood flow to specific brain areas resulting in rescue of neurovascular functions from ischemic damage. Therefore, the two modalities appear to complement each other to form an integrated treatment modality. Our results showed that hemodynamics was improved in a photothrombotic ischemia model, as cerebral blood volume and hemoglobin oxygen saturation (SO2) recovered to 71% and 76% of the baseline values, respectively. Furthermore, neural activities, including somatosensory-evoked potentials (110% increase), the alpha-to-delta ratio (27% increase), and the (delta+theta)/(alpha+beta) ratio (27% decrease), were also restored. Infarct volume was reduced by 50% with a 2-fold preservation in the number of neurons and a 6-fold reduction in the number of active microglia in the infarct region compared with the untreated group. Grip strength was also better preserved (28% higher) compared with the untreated group. Overall, this nonpharmacological, nonintrusive approach could be prospectively developed into a clinical treatment modality.
KEYWORDS: Imaging systems, Ischemia, Real time imaging, Photoacoustic spectroscopy, Brain, Hemodynamics, In vivo imaging, Point spread functions, Lead, Blood vessels
Stroke is the second leading cause of death worldwide. Rapid and precise diagnosis is essential to expedite clinical
decision and improve functional outcomes in stroke patients; therefore, real-time imaging plays an important role to
provide crucial information for post-stroke recovery analysis. In this study, based on the multi-wavelength laser and 18.5
MHz array-based ultrasound platform, a real-time handheld photoacoustic (PA) system was developed to evaluate
cerebrovascular functions pre- and post-stroke in rats. Using this system, hemodynamic information such as cerebral
blood volume (CBV) can be acquired for assessment. One rat stroke model (i.e., photothrombotic ischemia (PTI)) was
employed for evaluating the effect of local ischemia. For achieving better intrinsic PA contrast, Vantage and COMSOL
simulations were applied to optimize the light delivery (e.g., interval between two arms) from customized fiber bundle,
while phantom experiment was conducted to evaluate the imaging performance of this system. Results of phantom
experiment showed that hairs (~150 μm diameter) and pencil lead (500 μm diameter) can be imaged clearly. On the
other hand, results of in vivo experiments also demonstrated that stroke symptoms can be observed in PTI model poststroke.
In the near future, with the help of PA specific contrast agent, the system would be able to achieve blood-brain
barrier leakage imaging post-stroke. Overall, the real-time handheld PA system holds great potential in disease models
involving impairments in cerebrovascular functions.
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