We demonstrate high contrast optical-resolution photoacoustic
microscopy
(OR-PAM) imaging by using biocompatible, indirect band gap silicon
nanoparticles (SiNPs) as contrast agents. The SiNPs were synthesized
by high-energy ball milling of crystalline silicon wafers, followed
by hydrosilylation with bifunctional olefinic ligands to enable water
solubility and bioconjugation. When uniformly dispersed in water,
the SiNPs with an average particle size of about 114 nm showed remarkably
high extinction coefficients, more than 2 × 1010 M–1 cm–1, from the visible to near-infrared
spectral range. For the first OR-PAM imaging demonstration, the SiNPs
were microinjected to live zebrafish embryonic cells. As the embryo
developed, the distribution of the cells carrying the SiNPs can be
clearly traced by the spread of the photoacoustic signals. Second,
photoacoustic-fluorescence dual-modality imaging was demonstrated
on live zebrafish larvae which were microinjected with a mixture of
the SiNPs and dextran-rhodamine dyes. Due to the large difference
in size, the two agents exhibited very different biodistributions
after being injected at the same instant. Third, immuno-photoacoustic
imaging, as an autofluorescence-free alternative to the conventional
immunofluorescence imaging, was demonstrated on SKOV-3 cancer cells
immunostained with the anti-HER2-conjugated SiNPs. Lastly, advantages
of the SiNPs compared to other photoacoustic contrast agents were
characterized and discussed.
In this study, a novel photoacoustic microscopy (PAM) probe integrating white‐light microscopy (WLM) modality that provides guidance for PAM imaging and complementary information is implemented. One single core of an imaging fiber bundle is employed to deliver a pulsed laser for photoacoustic excitation for PAM mode, which provides high resolution with deep penetration. Meanwhile, for WLM mode, the imaging fiber bundle is used to transmit two‐dimensional superficial images. Lateral resolution of 7.2 μm for PAM is achieved. Since miniature components are used, the probe diameter is only 1.7 mm. Imaging of phantom and animals in vivo is conducted to show the imaging capability of the probe. The probe has several advantages by introducing the WLM mode, such as being able to conveniently identify regions of interest and align the focus for PAM mode. The prototype of an endoscope shows potential to facilitate clinical photoacoustic endoscopic applications.
Children infected by SARS-CoV-2 Omicron variant may develop neurological complications. To study the pathogenesis in the growing brain, we intranasally challenged newly-weaned or mature hamsters with SARS-CoV-2 Omicron BA.2, BA.5, or Delta variant. Omicron BA.2 and Delta infection produced a significantly lower viral load in the lung tissues of newly-weaned than mature hamsters despite comparable histopathological damages. Newly-weaned hamsters had higher brain viral load, significantly increased cerebrospinal fluid concentration of TNF-α and CXCL10 and inflammatory damages including mild meningitis and parenchymal vascular congestion, despite sparse expression of nucleocapsid antigen in brain cells. Furthermore, 63.6% (28/44) of all SARS-CoV-2 infected newly-weaned hamsters showed microgliosis in olfactory bulb (OB), cerebral cortex, and hippocampus. In infected mature hamsters, microgliosis was observed mainly in OB and olfactory cortex of 35.3% (12/34) of their brains. Neuronal degeneration was found in 75% (33/44) of newly-weaned hamsters affecting multiple regions including OB, olfactory cortex, midbrain cortex, and hippocampus, while such changes were mainly observed in the hippocampus of mature hamsters. Importantly, similar brain histopathology was also observed in Omicron BA.5-infected newly-weaned hamsters. Our study suggested that SARS-CoV-2 may affect the brain at a young age. This kind of brain involvement and histological changes are not virus variant or subvariant specific. Incidentally, a moderate amount of eosinophilic infiltration was observed in the mucosa of nasal turbinate and trachea of newly-weaned hamsters infected by Omicron BA.2 and BA.5 but not Delta variant. This histological finding is consistent with the higher incidence of laryngotracheobronchitis in young children infected by the Omicron variant.
Summary
Intranasal infection of newly-weaned Syrian hamsters by SARS-CoV-2 Omicron variants can lead to brain inflammation and neuron degeneration with detectable low level of viral load and sparse expression of viral nucleoprotein.
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