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Novel Photoacoustic Microscopy and Optical Coherence Tomography Dual-modality Chorioretinal Imaging in Living Rabbit Eyes

Photoacoustic ocular imaging is an emerging ophthalmic imaging technology that can noninvasively visualize ocular tissue by converting light energy into ...

University of Michigan

The feasibility of an innovative biomedical diagnostic technique, thermal photo-acoustic (TPA) measurement, for non-ionizing and non-invasive assessment of bone health is investigated. Unlike conventional photo-acoustic PA methods that are mostly focused on the measurement of absolute signal intensity, TPA targets the change in PA signal intensity as a function of the sample temperature, i.e., the temperature-dependent Grueneisen parameter that is closely relevant to the chemical and molecular properties in the sample. Based on the differentiation measurement, the results from TPA technique are less susceptible to the variations associated with sample and system, and could be quantified with improved accurately. Due to the fact that the PA signal intensity from organic components such as blood changes faster than that from non-organic mineral under the same modulation of temperature, TPA measurement is able to objectively evaluate bone mineral density (BMD) and its loss as a result of osteoporosis. In an experiment on well-established rat models of bone loss and preservation, PA measurements of rat tibia bones were conducted over a temperature range from 37°C to 44°C. The slope of PA signal intensity verses temperature was quantified for each specimen. The comparison among three groups of specimens with different BMD shows that bones with lower BMD have higher slopes, demonstrating the potential of the proposed TPA technique in future clinical management of osteoporosis.

Bone assessment via thermal photo-acoustic measurements.

The dual-pulse nonlinear photoacoustic technique is a recently developed technology based on temperature dependence of the Grüneisen parameter and involves consecutive excitations of biological tissue using two laser pulses with a short time delay. Here we review the principle of the technique and give a discussion about its technical aspects, including selection and combination of excitation laser wavelengths, determination of laser fluence, estimation of thermal relaxation function and probability of photoablation or cavitation. Comparisons between the dual-pulse technique and conventional photoacoustics as well as thermal photoacoustics are also presented. These investigations are supported by experimental results and will give a practical reference and guide for further developments of the technique.

Dual-pulse nonlinear photoacoustic technique: a practical investigation.

The feasibility of diagnostic imaging and tissue characterization based on a new contrast realized by dual-pulse photoacoustic measurement was studied. Unlike current photoacoustic methods which are mostly focused on the measurement of tissue optical absorption, this contrast revealed by a dual-pulse laser excitation process takes advantage of the temperature dependence of the Grüneisen parameter of tissue. The first laser pulse heats the sample and causes a temperature rise in the target tissue, which leads to a change of the Grüneisen parameter and the amplitude of the photoacoustic signal from the second laser pulse. This new contrast is then quantified by percentile change in the second pulse signal as a result of the first laser pulse. Since the temperature-dependent Grüneisen parameter is tissue specific and closely relevant to chemical and molecular properties of the sample, the dual-pulse photoacoustic measurement can differentiate various tissue types and conditions. The preliminary study on phantoms and a mouse model has suggested the capability of the proposed contrast in the characterization of fatty livers and the potential for future clinical diagnosis of liver conditions.

Imaging and sensing based on dual-pulse nonlinear photoacoustic contrast: a preliminary study on fatty liver.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Photoacoustic Tomography (PAT) is a deep-tissue imaging modality, with potential clinical applications in the diagnosis of arthritis, cancer and other disease conditions. Here, we identified Clofazimine (CFZ), a red-pigmented dye and anti-inflammatory FDA-approved drug, as a macrophage-targeting photoacoustic (PA) imaging agent. Spectroscopic experiments revealed that CFZ and its various protonated forms yielded optimal PAT signals at wavelengths -450 to 540 nm. CFZ's macrophage-targeting chemical and structural forms were detected with PA microscopy at a high contrast-to-noise ratio (CNR > 22 dB) as well as with macroscopic imaging using synthetic gelatin phantoms. In vivo, natural and synthetic CFZ formulations also demonstrated significant anti-inflammatory activity. Finally, the injection of CFZ was monitored via a real-time ultrasound-photoacoustic (US-PA) dual imaging system in a live animal and clinically relevant human hand model. These results demonstrate an anti-inflammatory drug repurposing strategy, while identifying a new PA contrast agent with potential applications in the diagnosis and treatment of arthritis.

Repositioning Clofazimine as a Macrophage-Targeting Photoacoustic Contrast Agent.

The ability to slow down wave propagation in materials has attracted significant research interest. A successful solution will give rise to manageable enhanced wave-matter interaction, freewheeling phase engineering and spatial compression of wave signals. The existing methods are typically associated with constructing dispersive materials or structures with local resonators, thus resulting in unavoidable distortion of waveforms. Here we show that, with helical-structured acoustic metamaterials, it is now possible to implement dispersion-free sound deceleration. The helical-structured metamaterials present a non-dispersive high effective refractive index that is tunable through adjusting the helicity of structures, while the wavefront revolution plays a dominant role in reducing the group velocity. Finally, we numerically and experimentally demonstrate that the helical-structured metamaterials with designed inhomogeneous unit cells can turn a normally incident plane wave into a self-accelerating beam on the prescribed parabolic trajectory. The helical-structured metamaterials will have profound impact to applications in explorations of slow wave physics.

Implementation of dispersion-free slow acoustic wave propagation and phase engineering with helical-structured metamaterials.

Detection and imaging of single cancer cells is critical for cancer diagnosis and understanding of cellular dynamics. Photoacoustic imaging (PAI) provides a potential tool for the study of cancer cell dynamics, but faces the challenge that most cancer cells lack sufficient endogenous contrast. Here, a type of colloidal gold nanoparticles (AuNPs) are physically fabricated and are precisely functionalized with quantitative amounts of functional ligands (i.e., polyethyleneglycol (PEG) and (Arginine(R)-Glycine(G)-Aspartic(D))4 (RGD) peptides) to serve as an exogenous contrast agent for PAI of single cells. The functionalized AuNPs, with a fixed number of PEG but different RGD densities, are delivered into human prostate cancer cells. Radioactivity and photoacoustic analyses show that, although cellular uptake efficiency of the AuNPs linearly increases along with RGD density, photoacoustic signal generation efficiency does not and only maximize at a moderate RGD density. The functionalization of the AuNPs is in turn optimized based on the experimental finding, and single cancer cells are imaged using a custom photoacoustic microscopy with high-resolution. The quantitatively functionalized AuNPs together with the high-resolution PAI system provide a unique platform for the detection and imaging of single cancer cells, and may impact not only basic science but also clinical diagnostics on a range of cancers.

Plasmonic Nanoparticles with Quantitatively Controlled Bioconjugation for Photoacoustic Imaging of Live Cancer Cells.

Most current photoacoustic imaging (PAI) systems employ piezoelectric transducers to receive photoacoustic signals, which requires coupling medium to facilitate photoacoustic wave propagation and are not favored in many applications. Here, we report an all-optical non-contact PAI system based on a commercial heterodyne interferometer working at 1550 nm. The interferometer remotely detects ultrasound-induced surface vibration and does not involve any physical contact with the sample. The theoretically predicated and experimentally measured noise equivalent detection limits of the optical sensor are about 4.5 and 810 Pa over 1.2 MHz bandwidth. Using a raster-scan PAI system equipped with the non-contact design, stereotactic boundaries of an artificial tumor in a pig brain were accurately delineated. The non-contact design also enables the tomographic PAI of biological tissue samples in a non-invasive manner. The preliminary results and analyses reveal that the heterodyne interferometer-based non-contact PAI system holds good potential in biomedical imaging.

Non-Contact Photoacoustic Imaging Using a Commercial Heterodyne Interferometer.

We experimentally demonstrate and theoretically analyze high Q-factor (~10(7)) 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.

Air-coupled ultrasound detection using capillary-based optical ring resonators.

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10-89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

Article	Year
Bone assessment via thermal photo-acoustic measurements. Optics letters\| PubMed ID: 25872057	2015
Dual-pulse nonlinear photoacoustic technique: a practical investigation. Biomedical optics express\| PubMed ID: 26309756	2015
Imaging and sensing based on dual-pulse nonlinear photoacoustic contrast: a preliminary study on fatty liver. Optics letters\| PubMed ID: 26393712	2015
Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nature genetics\| PubMed ID: 26482879	2015
Repositioning Clofazimine as a Macrophage-Targeting Photoacoustic Contrast Agent. Scientific reports\| PubMed ID: 27000434	2016
Implementation of dispersion-free slow acoustic wave propagation and phase engineering with helical-structured metamaterials. Nature communications\| PubMed ID: 27198887	2016
Plasmonic Nanoparticles with Quantitatively Controlled Bioconjugation for Photoacoustic Imaging of Live Cancer Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 27981012	2016
Non-Contact Photoacoustic Imaging Using a Commercial Heterodyne Interferometer. IEEE sensors journal\| PubMed ID: 28210188	2016
Air-coupled ultrasound detection using capillary-based optical ring resonators. Scientific reports\| PubMed ID: 28250443	2017
Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nature communications\| PubMed ID: 28537254	2017
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nature genetics\| PubMed ID: 29083406	2017

Chao Tian

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