Multimodal optical clearing to minimize light attenuation in biological tissues.

The biggest obstacle to optical imaging is light attenuation in biological tissues. Conventional clearing techniques, such as agent-based clearing, improve light penetration depth by reducing scattering, but they are hampered by drawbacks including toxicity, low efficiency, slowness, and superficial performance, which prevent them from resolving the attenuation problem on their own. Therefore, quick, safe, and effective procedures have been developed. One of them involves using standing ultrasonic waves to build light waveguides that function effectively in the tissue depth while minimizing scattering. Temporal optical clearing is another agent-free strategy that we introduced in our previous article. Whereas not deep, this technique minimizes both light absorption and scattering by pulse width variation in ultra-short pulse regime. Consequently, it can be a complementary method for ultrasonic optical clearing. In this work, we enhanced the light penetration depth in chicken breast tissue by 10 times (0.67-6.7 cm), setting a record in literature by integrating three clearing methods: agent-based, ultrasound-based, and temporal. Here, optical coherence tomography, Bear-Lambert, and fluorescence tests have been used to study the light penetration depth and optical clearing efficiency. Presented work is an essential step in development of diagnostic techniques for human body, from cells to organs.

Method for tissue clearing: temporal tissue optical clearing.

Light absorption and scattering in biological tissue are significant variables in optical imaging technologies and regulating them enhances optical imaging quality. Optical clearing methods can decrease light scattering and improve optical imaging quality to some extent but owing to their limited efficacy and the potential influence of optical clearing agents on tissue functioning, complementing approaches must be investigated. In this paper, a new strategy of optical clearing proposed as time-dependent or temporal tissue optical clearing (TTOC) is described. The absorption and scattering in light interaction with tissue are regulated in the TTOC technique by altering the pulse width. Here, the dependence of optical properties of matter on the pulse width in a gelatin-based phantom was investigated experimentally. Then, a semi-classical model was introduced to computationally study of Ultra-short laser/matter interaction. After studying phantom, the absorption and scattering probabilities in the interaction of the pulse with modeled human skin tissue were investigated using the proposed model for pulse widths ranging from 1µs to 10fs. The propagation of the pulse through the skin tissue was simulated using the Monte Carlo technique by computing the pulse width-dependent optical properties (absorption coefficient µa, scattering coefficient µs, and anisotropy factor g). Finally, the penetration depth of light into the tissue and reflectance for different pulse widths was found.

The effect of trehalose administration on vascular inflammation in patients with coronary artery disease.

BACKGROUND: In recent years, several trials investigated the role of anti-inflammatory agents in reducing cardiovascular events. Trehalose is a natural disaccharide able to reduce inflammation by enhancing macrophage autophagic activity. This action has been demonstrated to attenuate atherosclerotic plaque development in various pro-atherogenic animal models. However, at present, no data about the efficacy of this compound in human subjects have been published. METHODS: We performed a randomized, double-blind trial involving 15 patients with history of myocardial infarction and evidence of systemic inflammation (defined as C-reactive protein > 2 mg/L). The patients were randomly assigned, in 2:1 ratio, to receive either intravenous trehalose (15 g once weekly) or placebo for 12 weeks. The primary efficacy end-point was the change in arterial wall inflammation, assessed by quantifying 18F-FDG PET/CT uptake in carotid arteries and ascending aorta. RESULTS: The MDS TBR change of the index vessel at 3-month follow-up was not significant in treatment and placebo groups. Furthermore, we could not demonstrate any significant difference between the trehalose group and control group in changes of cIMT from baseline to 3 months in the overall population. No significant changes in echocardiographic measurement were noted after trehalose treatment. Except for the change in urea level in placebo group (31.00 ± 6.59 vs. 25.60 ± 6.402 P = 0.038) no other changes were detected after treatment. Also, there was a significant difference between changes in alanine aminotransferase (ALT) trehalose and placebo groups. CONCLUSION: This was the first study that specifically assessed the effects of intravenous trehalose on atherogenesis in human subjects. Trehalose treatment was characterized by an optimal safety profile, but no significant reduction in arterial wall inflammation could be observed. This might be a consequence of the small sample size of this trial. Larger studies are needed to better assess the efficacy of this compound in this clinical context.

Optical neural stimulation using the thermoplasmonic effect of gold nano-hexagon.

The use of nanoparticle photothermal effect as adjuvants in neuromodulation has recently received much attention, with many open questions about new nanostructures' effect on the action potential. The photothermal properties of hexagonal gold nanoparticles are investigated in this work, including the absorption peak wavelength and light-heat conversion rate, using both experimental and simulation methods. Furthermore, the ability to use these nanostructures in axonal neural stimulation and cardiac stimulation by measuring temperature changes of gold nano-hexagons under 532 nm laser irradiation is studied. In addition, their thermal effect on neural responses is investigated by modeling small-diameter unmyelinated axons and heart pacemaker cells. The results show that the increase in temperature caused by these nano-hexagons can successfully stimulate the small diameter axon and produce an action potential. Experiments have also demonstrated that the heat created by gold nano-hexagons affects toad cardiac rhythm and increases T wave amplitude. An increase in T wave amplitude on toad heart rhythm shows the thermal effect of nano hexagons heat on heart pacemaker cells and intracellular ion flows. This work demonstrates the feasibility of utilizing these nanostructures to create portable and compact medical devices, such as optical pacemakers or cardiac stimulation.

Wavelength and pulse energy optimization for detecting hypoxia in photoacoustic imaging of the neonatal brain: a simulation study.

Cerebral hypoxia is a severe injury caused by oxygen deprivation to the brain. Hypoxia in the neonatal period increases the risk for the development of neurological disorders, including hypoxic-ischemic encephalopathy, cerebral palsy, periventricular leukomalacia, and hydrocephalus. It is crucial to recognize hypoxia as soon as possible because early intervention improves outcomes. Photoacoustic imaging, using at least two wavelengths, through a spectroscopic analysis, can measure brain oxygen saturation. Due to the spectral coloring effect arising from the dependency of optical properties of biological tissues to the wavelength of light, choosing the right wavelength-pair for efficient and most accurate oxygen saturation measurement and consequently quantifying hypoxia at a specific depth is critical. Using a realistic neonate head model and Monte Carlo simulations, we found practical wavelength-pairs that quantified regions with hypoxia most accurately at different depths down to 22 mm into the cortex neighboring the lateral ventricle. We also demonstrated, for the first time, that the accuracy of the sO2 measurement can be increased by adjusting the level of light energy for each wavelength-pair. Considering the growing interest in photoacoustic imaging of the brain, this work will assist in a more accurate use of photoacoustic spectroscopy and help in the clinical translation of this promising imaging modality. Please note that explaining the effect of acoustic aberration of the skull is not in the scope of this study.

Improving vascular imaging with co-planar mutually guided photoacoustic and diffuse optical tomography: a simulation study.

Diffuse optical tomography (DOT) and photoacoustic tomography (PAT) are functional imaging modalities that provide absorption coefficient maps of the tissue. Spatial resolution of DOT is relatively low due to light scattering characteristics of the tissue. On the other hand, although PAT can resolve regions of different absorptions with a high spatial resolution, measuring the absolute value of optical absorptions using PAT is challenging due to unknown light fluence distribution in the tissue. Development of image guidance techniques using a priori information of imaging target structure has been shown to increase the accuracy of DOT. PAT is one such method that can be used as a complementary modality to serve as a guide for DOT image reconstruction. On the other hand, estimated fluence map provided by DOT can be used to quantitatively correct PAT images. In this study we introduce a mutually-guided imaging system for fast and simultaneous optical and photoacoustic measurements of tissue absorption map, where DOT is guided by the PAT image and vice versa. Using the obtained absorption map of the tissue, we then estimate the tissue scattering map. We conducted this study using a series of simulations on digital phantoms and demonstrated the effectiveness of the proposed method.

In vivo detection of human cutaneous beta-carotene using computational optical clearing.

The content of dermal beta-carotene can be a good indicator showing the body health. Because, it is involved in production of vitamin A maintaining healthy skin and mucous membranes. Also, it reduces the risk of cardiovascular diseases and its antioxidant capacity prevents the formation of cancerous cells. In this work, we use Raman spectroscopy and a low-cost diffuse reflectance spectroscopy (DRS) to detect the dermal beta-carotene spectra. We apply computational optical clearing (OC) method to in vivo evaluation the concentration of this chromophore. The results show that Raman spectroscopy is a good tool for in vitro detection of carotenoids but is not able to clearly discriminate the individual carotenoids in skin tissue in vivo. The results also show that using OC enhances the ability of low-cost diffuse reflection spectroscopy for in vivo detection of dermal beta-carotene in humans. This method can be used as a low-cost and portable device to screening the concentration of chromophores such as melanin and carotenoid molecules for oncological studies.

Blind Localization of Heating in Neural Tissues Induced by a Train of the Infrared Pulse Laser.

Introduction: Recently, infrared lasers (wavelengths larger than 1100 nm) have been applied to stimulate neural tissues. Infrared neural stimulation (INS) has some advantages over conventional electric stimulation, including contact-free delivery, spatial precision, and lack of stimulation artifacts. In this study and based on a photothermal mechanism, we applied the heat diffusion equation to study temperature variation of a biological phantom during INS. In addition, the impact of laser parameters on spatially localized heating induced by 2 different infrared wavelengths were studied. Methods: We studied the localization of INS inside a phantom similar to cortical neural tissue. First, we analytically solved the heat diffusion equation to study the distribution of temperature inside this phantom. Then, the accuracy of analytical results was verified by heating the phantom using amplitude-modulated infrared lasers (lambda= 1450 and 1500 nm, the energy between 2 and 5 mJ and pulse duration up to 20 ms). The laser light was directed to sample by a multimode optical fiber (NA=0.22, core size= 200 microns). Finally, the impacts of laser properties on the spatial resolution of infrared heating were discerned. Results: In order to verify analytical results, we measured the maximum temperatures of the phantom during illumination of lasers and compared them with analytical results. The analytical results were in agreement with the experimental results. The effects of laser beam properties such as pulse duration, energy and repetition rate frequency on the spatial resolution were investigated. The results indicated that the spatial resolution of INS can be smaller than one millimeter. Conclusion: Here, the influences of laser properties on the localization of INS inside a biological phantom were studied. These results can be applied to improve the spatial selectivity of the peripheral nerve interface.

Head model based on the shape of the subject's head for optical brain imaging.

Optical imaging methods such as near-infrared spectroscopy and diffuse optical tomography rely on models to solve the inverse problem. Imaging an adult human head also requires a head model. Using a model, which makes describing the structure of the head better, leads to acquiring a more accurate absorption map. Here, by combining the key features of layered slab models and head atlases, we introduce a new two-layered head model that is based on the surface geometry of the subject's head with variable thickness of the superficial layer. Using the Monte Carlo approach, we assess the performance of our model for fitting the optical properties from simulated time-resolved data of the adult head in a null distance source-detector configuration. Using our model, we observed improved results at 70 percent of the locations on the head and an overall 20 percent reduction in relative error compared to layered slab model.

Influence of radiant exposure and repetition rate in infrared neural stimulation with near-infrared lasers.

In this study, we combine heat diffusion equation and modified Hodgkin-Huxley axonal model to investigate how an action potential is generated during infrared neural stimulation. The effects of temporal and spatial distribution of heat induced by infrared pulsed lasers on variation of electrical membrane capacitance are investigated. These variations can lead to depolarize the membrane and generate an action potential. We estimate the threshold values of laser light parameters such as energy density, pulse duration, and repetition rate are needed to trigger an action potential. In order to do it, we present an analytic solution to heat diffusion equation. Then, the analytic results are verified by experimental results. Furthermore, the modified Hodgkin-Huxley axonal model is applied to simulate the generation of action potential during infrared neural stimulation by taking into account the temperature dependence of electrical membrane capacitance. Results show that the threshold temperature increase induced by a train infrared pulse laser can be smaller if repetition rate is higher. These results also indicate that temperature rise time and axon diameter influence on threshold temperature increase. To verify threshold values estimated by the presented method, we use a train infrared pulsed laser (λ = 1450 nm with repetition rate of 3.8 Hz, pulse duration of 18 ms and energy density of 5 J/cm2) to optically pace an adult rat heart, and we are able to successfully pace the rat heart during an open-heart surgery. The presented method can be used to estimate threshold values of laser parameters required for generating an action potential, and it can provide an insight to how the temperature changes lead to neural stimulation during INS.

Correction: Maternal separation blunted spatial memory formation independent of peripheral and hippocampal insulin content in young adult male rats.

[This corrects the article DOI: 10.1371/journal.pone.0204731.].

The Temporal Confounding Effects of Extra-cerebral Contamination Factors on the Hemodynamic Signal Measured by Functional Near-Infrared Spectroscopy.

Introduction: Functional near-infrared spectroscopy (fNIRS) has been broadly applied for optical brain imaging. This method is hemodynamic-based functional brain imaging relying on the measurement of the neurovascular coupling to detect changes in cerebral neuronal activities. The extra-cerebral hemodynamic changes are important contaminating factors in fNIRS measurements. This error signal can be misinterpreted as cerebral activities during fNIRS studies. Recently, it was assumed that temporal changes in deoxygenated hemoglobin concentration [HHb] was hardly affected by superficial blood flow, and it was proposed that the activation maps could be determined from [HHb] at large source-detector separation. Methods: In the current study, we measured the temporal changes in [HHb] using a continueswave fNIRS device at large source-detector separation, while superficial blood flow was stimulated by infrared lasers. A mesh-based Monte Carlo code was applied to estimate fNIRS sensitivity to superficial hemodynamic changes in a realistic 3D MRI-based brain phantom. Results: First, we simulated photon migration in a four-layered human-head slab model to calculate PPLs and fNIRS sensitivity. Then, the localization of the infrared laser inside a realistic brain model was studied using the Monte Carlo method. Finally, the changes in [HHb] over the prefrontal cortex of six adult males were measured by fNIRS at a source-detector separation of 3 cm. The results demonstrated that the relation between fNIRS sensitivity and an increase in S-D separation was nonlinear and a correlation between shallow and deep signals was observed. Conclusion: The presented results demonstrated that the temporal changes in the superficial blood flow could strongly affect HHb measurement at large source-detector separation. Hence, the cerebral activity map extracted from the [HHb] signal was mainly contaminated by superficial blood flow.

Maternal separation blunted spatial memory formation independent of peripheral and hippocampal insulin content in young adult male rats.

This study explores the effects of maternal separation as a chronic early life stress (ELS) on pancreatic islets insulin content and secretion, and their potential relationship with the hippocampus insulin content and spatial memory in young adulthood. Male rat offspring were divided into two groups: stress (STR) and non-stress (non-STR) groups. The animals of the STR group were separated from their mothers during postnatal days (PND) 1 to 21. During the weaning time, that is, PND-0 to PND-21, the body weight and length of the pups were measured. Blood samples were collected on PND-1, 21, 29 and 34 and during young adulthood (53±2 days) to determine plasma corticosterone and insulin levels. The young adult animals were also tested for spatial memory. One day after the memory test, the animals were decapitated and their pancreases were removed to measure the islets insulin content and secretion. Finally, the animals' hippocampi were isolated to determine their insulin content and insulin receptor protein amounts. During the period of weaning, the body weight and length of pups belonging to the STR group were significantly lower as compared to those in the non-STR group. Maternal separation did not change the plasma levels of insulin but increased plasma corticosterone levels from PND-21 to young adulthood and also reduced the islets insulin content but did not affect insulin secretion and the hippocampus insulin content and insulin receptor protein amount. Although, at the end of the memory tests, rats of the STR group reached the escape box at almost the same time and distance and with the same errors as rats of the non-STR group, the distance traveled to reach the escape box showed a steep reduction in the non-STR group as compared to the STR group after the first trial. Moreover, as compared to the STR group, the non-STR group showed an increasing trend for direct strategy to find the escape box. The islets insulin content and secretion, and the plasma insulin concentration were not significantly correlated with the hippocampus insulin content. From the results of the present study, it appears that the main behavioral effect of the maternal separation stress in the spatial memory task was to impair the strategy used by the animals to reach the escape box. This may indicate that maternal separation stress affects brain regions other than the hippocampus. Moreover, due to the reduction of the body weight and length of offspring belonging to the STR group, it should be further considered that both maternal separation and early life malnutrition are directly (and mechanistically) linked to cognitive alterations later in life in ways that are not dependent on peripheral and hippocampal insulin content.

Successful treatment of prosthetic pulmonary valve thrombosis with reteplase: a case report.

Pulmonary prosthetic valve thrombosis is a serious and rare complication with high mortality. Using reteplase for treatment of prosthesis thrombosis is rarely reported. We report the first case in Iran of a thrombosed pulmonary valve in a patient who had undergone repair of tetralogy of Fallot, which was successfully treated twice with intravenous thrombolytic therapy with reteplase.

Is echocardiographic epicardial fat thickness increased in patients with coronary artery disease? A systematic review and meta-analysis.

BACKGROUND: The relation of epicardial fat thickness (EFT) to coronary artery disease (CAD) has recently been reported in multiple studies. Echocardiography is a safe and relatively inexpensive and accessible approach to assess regional EFT, which can be performed easily in many centers. OBJECTIVE: To determine the association between echocardiographic EFT and the presence or the absence of CAD. METHODS: This was a systematic review and meta-analysis conducted on literature available in electronic databases up to March 2018. The articles measuring EFT by echocardiography in the right ventricular (RV) free wall were included in the study. The quality of the enrolled items was assessed using the Methodological Index for Non-Randomized Studies (MINORS) checklist. The analyses were performed using the Comprehensive Meta-Analysis version 2 software. Cochran's Q test and I2 index were used to evaluate heterogeneity. RESULTS: This meta-analysis was performed on 13 studies involving 2,436 patients (1,622 with CAD, and 814 without CAD). The maximum EFT reported by echocardiography was 12.9±2.7 mm in the CAD group and 8.4±2.5 mm in the non-CAD group. The minimum EFT reported by echocardiography was 2.2±1.8 mm in the CAD group and 1.8±1.4 mm in the non-CAD group. The heterogeneity was found among the researched studies (I2=91.8%, p=0.000, Q-value=146.43, df [Q] =12) using the random effect model. The patients with CAD had a significantly higher echocardiographic EFT than those without CAD (SMD=1.03, 95% CI= 0.70-1.37, p=0.000). CONCLUSION: According to the findings of this meta-analysis, the echocardiographic EFT in the subjects with CAD was significantly higher than that of those without CAD. The measurement of echocardiographic EFT seems to be an acceptable strategy for risk stratification of heart diseases considering ease of use, cost-effectiveness and non-exposure characteristics, compared to other imaging interventions.

Combination of analytical and experimental optical clearing of rodent specimen for detecting beta-carotene: phantom study.

Recently, compression optical clearing (OC) was applied to detect dermal carotenoid using reflection spectroscopy. To enhance the precision and accuracy of reflection spectroscopy to better detect the spectral absorption of beta-carotene inside biological phantom, here, we simultaneously use compression and immersion OC using dimethyl sulfoxide. In addition, we analytically extract the absorption coefficient of beta-carotene using diffuse reflectance spectroscopy (as an analytical OC). Our results show that the presented analytical OC can be applied alone as a noninvasive method to measure cutaneous chromophores at deep tissues. Finally, we also improve the ability of the analytical clearing method mediated with experimental OC. Our result demonstrates that the combination of analytical and experimental clearing methods enhance the ability of diffuse reflection spectroscopy for extracting the absorption coefficient of beta-carotene as one of the chromospheres inside biological phantom.

Factors Affecting In-stent Restenosis in Patients Undergoing Percutaneous Coronary Angioplasty.

Percutaneous coronary angioplasty (PCI) and stent implantation are the most common therapeutic strategies for coronary artery stenosis; however, in-stent restenosis (ISR) is one of its important challenges. Although in some studies, coronary artery disease (CAD) factors are deemed to be the causes of ISR, in some others, the relationship between CAD factors and ISR are not observed. Over the past ten years, there has been no review article on factors affecting the ISR. This article aimed to review the possible factors affecting ISR in patients undergoing PCI. This narrative review study was conducted on PubMed, Web of Science, Scopus, and Google Scholar databases between 1 January 1990 and 30 July 2017. After initial screening of 1728 retrieved articles, 1401 articles were excluded to due irrelevancy to the review; and finally, 39 papers were selected for data collection. Our study results showed that the site and length of implanted stent, hypertension and diabetes are the most probable factors affecting ISR. Further studies are required for evaluation of the effect of other possible risk factors such as genetic sequencing, obesity, chronic infections and hemoglobin A1C levels.

Development of low-cost photoacoustic imaging systems using very low-energy pulsed laser diodes.

With the growing application of photoacoustic imaging (PAI) in medical fields, there is a need to make them more compact, portable, and affordable. Therefore, we designed very low-cost PAI systems by replacing the expensive and sophisticated laser with a very low-energy laser diode. We implemented photoacoustic (PA) microscopy, both reflection and transmission modes, as well as PA computed tomography systems. The images obtained from tissue-mimicking phantoms and biological samples determine the feasibility of using a very low-energy laser diode in these configurations.

Diffuse optical tomography: image reconstruction and verification.

INTRODUCTION: In this study, we intend to use diffuse optical Tomography (DOT) as a noninvasive, safe and low cost technique that can be considered as a functional imaging method and mention the importance of image reconstruction in accuracy and procession of image. One of the most important and fastest methods in image reconstruction is the boundary element method (BEM). This method is introduced and employed in our works. METHOD: Generally, to image a biological tissue we must obtain its optical properties. In order to reach this goal we benefit from diffusion equation because tissue is highly scattering medium. Diffusion equation is solved by boundary element equation (BEM) in our research. First, we assume a double layer phantom with different scattering and absorption coefficients to simulate and verify precession and accuracy of image reconstruction by BEM. Light absorption can be affected by volume fraction of blood in skin. For a specific skin species the volume fraction is calculated and then the results are compared with the reconstructed values obtained by BEM. Since the depth of tissue is important in light absorption a two layer phantom with known values is made and the depths of layers are reconstructed by BEM then they are compared with the expected values. A homogenous phantom with known scattering and absorption coefficients was made and then these coefficients were reconstructed by BEM. Finally, an inhomogeneous phantom (phantom with defect) whose defect was in a known position was made and the absorption and scattering coefficients were reconstructed and compared with real values. RESULTS: Comparison between real or simulated values and reconstructed values of scattering and absorption coefficients, volume fraction of blood and thickness of phantom layers by BEM shows maximum errors of 24%, 7% and 35%, respectively. CONCLUSION: Comparison between BEM data and real or simulated values shows an acceptabl eagreement. Consequently, we can rely on BEM as a beneficial method in diffuse optical tomography image reconstruction.

Study of the effect of mechanical pressure on determination of position and size of tumor in biological phantoms.

Diffuse optical tomography (DOT) is an emerging oncological imaging modality that is based on a near-infrared optical technique. DOT provides the spatial volume and depth of tumors by determination of optical properties of biological tissues, such as the absorption and scattering coefficients. During a DOT, the optical fibers are kept in contact with biological tissues that introduce a certain amount of pressure on the local biological tissue. Due to this pressure, the shape of the organ, for instance a breast, deforms. Moreover, this pressure could influence the intrinsic characteristics of the biological tissue. Therefore, pressure can be an important parameter in DOT. In this paper, the effects of pressure on the determination of the size and position of a tumor in biological phantoms are studied. To do so, tissue-like phantoms that are made of intralipid, Indian ink, and agar are constructed. Defects with optical properties similar to those of tumors are placed inside the phantoms. Then various values of pressure are applied to the phantoms. Subsequently, the optical properties of phantoms as well as the position and size of the tumor are reconstructed by inverse models based on the boundary integral method. The variations of reconstructed data induced by pressure are studied. The results demonstrate that pressure causes an increase in the scattering coefficient.