Photoacoustic Signal Enhancement Research Articles

Effect of interfacial thermal resistance on the near-field photoacoustic signal from gold nanorod in water: a numerical study.

The near-field photoacoustics of gold nanoparticle in water has received much attention for its biomedical applications and is strongly affected by the gold-water interfacial thermal resistance. However, the effect of interfacial thermal resistance on near-field photoacoustics has been very little studied. Here we present the numerical simulations of near-field photoacoustic signal generation from a single gold nanorod in water by considering different thermal resistances at the gold-water interface. It is shown that, different from the reported reduction of far-field photoacoustic signals by interfacial thermal resistance, enhancement of near-field photoacoustic signals is obtained with the typical gold-water interfacial thermal resistance. Further analysis reveals that the higher rate of net heat transfer to the surrounding water at the typical interfacial thermal resistance, which corresponds to faster thermal expansion of the surrounding water, accounts for such enhancement of near-field photoacoustic signal and that the enhancement of near-field photoacoustic amplitude is mainly present at a distance within thermal diffusion length.

A dual‐resonance enhanced photoacoustic spectroscopy gas sensor based on a fiber optic cantilever beam microphone and a spherical photoacoustic cell

AbstractWe propose a novel high‐performance dual‐resonance enhanced photoacoustic spectroscopy (DRE‐PAS) gas sensor based on a highly sensitive fiber optic cantilever beam microphone and a high‐Q spherical photoacoustic cell (PAC). The first‐order resonant frequency (FORF) of the spherical PAC is analyzed by finite element analysis to match the FORF of the cantilever microphone for the double resonance enhancement of the photoacoustic signal. The photoacoustic spectroscopy (PAS) system, including the DRE‐PAS sensor, a 1532.8 nm distributed feedback laser, and a high‐speed spectrometer, has been successfully exploited for trace acetylene (C2H2) detection. The experimental results show that the limit of detection (LOD) is 106.8 parts‐per‐billion (ppb) with an integral time of 1 s, and the LOD can be further reduced to 11.03 ppb by Allan‐Werle deviation for 100 s integral time. The normalized noise equivalent absorption coefficient can be obtained as 2.44 × 10−8 cm−1 WHz−1/2. The reported DRE‐PAS gas sensor has the superior characteristics of photoacoustic signal enhancement, high sensitivity, and strong antielectromagnetic interference capability, which can provide a new solution for PAS development.

Preparation of near-infrared photoacoustic imaging and photothermal treatment agent for cancer using a modifiable acid-triggered molecular platform.

Ratiometric near-infrared fluorescent pH probes with various pKa values were innovatively designed and synthesized based on cyanine with a diamine moiety. The photochemical properties of these probes were thoroughly evaluated. Among the series, IR-PHA exhibited an optimal pKa value of approximately 6.40, closely matching the pH of cancerous tissues. This feature is particularly valuable for real-time pH monitoring in both living cells and living mice. Moreover, when administered intravenously to tumor-bearing mice, IR-PHA demonstrated rapid and significant enhancement of near-infrared fluorescence and photoacoustic signals within the tumor region. This outcome underscores the probe's exceptional capability for dual-modal cancer imaging utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) modalities. Concurrently, the application of a continuous-wave near-infrared laser efficiently ablated cancer cells in vivo, attributed to the photothermal effect induced by IR-PHA. The results strongly indicate that IR-PHA is well-suited for NIRF/PA dual-modality imaging and photothermal therapy of tumors. This makes it a promising candidate for theranostic applications involving small molecules.

Differential integrating sphere-based photoacoustic spectroscopy gas sensing.

In this Letter, a differential integrating sphere-based photoacoustic spectroscopy (PAS) gas sensor is proposed for the first time to our knowledge. The differential integrating sphere system consists of two integrating spheres and a tube. Based on differential characteristics, the photoacoustic signal of the designed differential integrating sphere was doubly enhanced and the noise was suppressed. Compared with a single channel integrating sphere, the differential integrating sphere sensing system had a 1.86 times improvement in signal level. An erbium-doped fiber amplifier (EDFA) was adopted to amplify the output of diode laser to enhance the optical excitation. The second harmonic (2f) signal of differential integrating sphere-based acetylene (C2H2) PAS sensor with an amplified 1000 mW optical output power was 104.67 mV, which was 22.80 times improved compared to the sensing system without EDFA. When the integration time was 100 s, the minimum detection limit (MDL) of the differential integrating sphere-based C2H2 PAS sensor was 416.7 ppb. The differential integrating sphere provides a new method, to the best of our knowledge, for the development of PAS sensor, which has the advantages of photoacoustic signal enhancement, strong noise immunity, and no need for optical adjustment.

High Contrast Detection of Carotid Neothrombus with Strong Near-Infrared Absorption Selenium Nanosphere Enhanced Photoacoustic Imaging.

Carotid artery thrombosis is the leading cause of stroke. Since there are no apparent symptoms in the early stages of carotid atherosclerosis onset, it causes a more significant clinical diagnosis. Photoacoustic (PA) imaging provides high contrast and good depth information, which has been used for the early detection and diagnosis of many diseases. We investigated thrombus formation by using 20% ferric chloride (FeCl3) in the carotid arteries of KM mice for the thrombosis model. The near-infrared selenium/polypyrrole (Se@PPy) nanomaterials are easy to synthesize and have excellent optical absorption in vivo, which can be used as PA contrast agents to obtain thrombosis information. In vitro experiments showed that Se@PPy nanocomposites have fulfilling PA ability in the 700 nm to 900 nm wavelength range. In the carotid atherosclerosis model, maximum PA signal enhancement up to 3.44, 4.04, and 5.07 times was observed by injection of Se@PPy nanomaterials, which helped to diagnose the severity of carotid atherosclerosis. The superior PA signal of Se@PPy nanomaterials can identify the extent of atherosclerotic carotid lesions, demonstrating the feasibility of PA imaging technology in diagnosing carotid thrombosis lesion formation. This study demonstrates nanocomposites and PA techniques for imaging and diagnosing carotid thrombosis in vivo.

Biomimetic Approach to Promote Cellular Uptake and Enhance Photoacoustic Properties of Tumor-Seeking Dyes.

The attachment of glucose to drugs and imaging agents enables cancer cell targeting via interactions with GLUT1 overexpressed on the cell surface. While an added benefit of this modification is the solubilizing effect of carbohydrates, in the context of imaging agents, aqueous solubility does not guarantee decreased π-stacking or aggregation. The resulting broadening of the absorbance spectrum is a detriment to photoacoustic (PA) imaging since the signal intensity, accuracy, and image quality all rely on reliable spectral unmixing. To address this major limitation and further enhance the tumor-targeting ability of imaging agents, we have taken a biomimetic approach to design a multivalent glucose moiety (mvGlu). We showcase the utility of this new group by developing aza-BODIPY-based contrast agents boasting a significant PA signal enhancement greater than 11-fold after spectral unmixing. Moreover, when applied to targeting cancer cells, effective staining could be achieved with ultra-low dye concentrations (50 nM) and compared to a non-targeted analogue, the signal intensity was >1000-fold higher. Lastly, we employed the mvGlu technology to develop a logic-gated acoustogenic probe to detect intratumoral copper (i.e., Cu(I)), which is an emerging cancer biomarker, in a murine model of breast cancer. This exciting application was not possible using other acoustogenic probes previously developed for copper sensing.

Photoacoustic signal enhancement in dual-contrast gastrin-releasing peptide receptor-targeted nanobubbles.

Translatable imaging agents are a crucial element of successful molecular imaging. Photoacoustic molecular imaging relies on optical absorbing materials to generate a sufficient signal. However, few materials approved for human use can generate adequate photoacoustic responses. Here we report a new nanoengineering approach to further improve photoacoustic response from biocompatible materials. Our study shows that when optical absorbers are incorporated into the shell of a gaseous nanobubble, their photoacoustic signal can be significantly enhanced compared to the original form. As an example, we constructed nanobubbles using biocompatible indocyanine green (ICG) and biodegradable poly(lactic-co-glycolic acid) (PLGA). We demonstrated that these ICG nanobubbles generate a strong ultrasound signal and almost four-fold photoacoustic signal compared to the same concentration of ICG solution; our theoretical calculations corroborate this effect and elucidate the origin of the photoacoustic enhancement. To demonstrate their molecular imaging performance, we conjugated gastrin-releasing peptide receptor (GRPR) targeting ligands with the ICG nanobubbles. Our dual photoacoustic/ultrasound molecular imaging shows a more than three-fold enhancement in targeting specificity of the GRPR-targeted ICG nanobubbles, compared to untargeted nanobubbles or prostate cancer cells not expressing GRPR, in a prostate cancer xenograft mouse model in vivo.

Photoacoustic signal enhancement of Al- and Si-Phthalocyanines caused by photoinduced cleavage of water-soluble axial ligand

Aluminum and silicon phthalocyanines bearing water-soluble poly(ethylene glycol) as axial ligands which formed vesicles in water enhanced photoacoustic (PA) signal intensities under continuous photoirradiation. The photoinduced cleavage of axial ligands in water-soluble phthalocyanines is a key step to produce phthalocyanine aggregates which generate strong photoacoustic wave.

Multi-mechanism collaboration enhanced photoacoustic analyzer for trace H2S detection

To realize the real-time highly sensitive detection of SF6 decomposition product H2S, a multi-mechanism collaboration enhancement photoacoustic spectroscopy analyzer (MCEPA) based on acoustic resonance enhancement, cantilever enhancement and excitation light enhancement is proposed. An SF6 background gas-induced photoacoustic cell (PAC) was used for acoustic resonance (AR) enhancement of the photoacoustic signals. A fiber-optic acoustic sensor based on a silicon cantilever is optimized and fabricated. The narrow-band acoustic signal enhancement based on cantilever mechanical resonance (MR) is realized in the optimal working frequency band of the PAC. A fiber-coupled DFB cascaded an Erbium-doped fiber amplifier (EDFA) realized the light power enhancement (LPE) of the photoacoustic signals excitation source. Experimental results show that the MR of the fiber-optic silicon cantilever acoustic sensor (FSCAS) is matched with the AR of the PAC and combined with the LPE, which realizes the multi-mechanism collaboration enhancement of weak photoacoustic signals. The Allan-Werle deviation evaluation showed that the minimum detection limit of H2S in the SF6 background is 10.96 ppb when the average time is 200 s. Benefiting from the all-optimization of photoacoustic excitation and detection, the MCEPA has near-field high-sensitivity gas detection capability immune to electromagnetic interference.

An activatable photoacoustic probe for imaging upregulation of hydrogen sulfide in inflammation

Inflammation is a response to traumatic, infectious, toxic, or autoimmune injury, and uncontrolled inflammation can lead to diseases such as cardiovascular and cerebrovascular disease, fibrosis, and cancer. Hydrogen sulfide (H2S) acts as an extremely important mediator of inflammation. As photoacoustic (PA) imaging can conduct high spatial resolution imaging while maintaining high contrast of optical imaging, it has shown great potential for clinical applications in disease microenvironment imaging, tumor imaging, and real-time drug imaging. However, the activatable PA probes for imaging of H2S levels in mice to detect inflammatory mediators have not yet developed. Herein, we have designed a novel activatable near-infrared (NIR) photoacoustic probe (PAP-H2S) with a specific response H2S, where the PA signal is turned on at 715 nm and the absorption wavelength is redshifted up to 165 nm. Meanwhile, it could be observed that PAP-H2S shows a 9.2-fold PA signal enhancement after being activated by H2S. Significantly, PAP-H2S was the first probe to monitor H2S levels in a mouse air pouch inflammation model by PA imaging technology. We expect PAP-H2S to become an effective tool for the diagnosis and monitoring of related diseases due to the development of inflammation in vivo.

Enhanced photoacoustic imaging in tissue-mimicking phantoms using polydopamine-shelled perfluorocarbon emulsion droplets

The current work features process parameters for the ultrasound (25 kHz)-assisted fabrication of polydopamine-shelled perfluorocarbon (PDA/PFC) emulsion droplets with bimodal (modes at 100–600 nm and 1–6 µm) and unimodal (200–600 nm) size distributions. Initial screening of these materials revealed that only PDA/PFC emulsion droplets with bimodal distributions showed photoacoustic signal enhancement due to large size of their optically absorbing PDA shells. Performance of this particular type of emulsion droplets as photoacoustic agents were evaluated in Intralipid®–India ink media, mimicking the optical scattering and absorbanceof various tissuetypes. From these measurements, it was observed that PDA/PFC droplets with bimodal size distributions can enhance the photoacoustic signal of blood-mimicking phantom by up to five folds in various tissue-mimicking phantoms with absorption coefficients from 0.1 to 1.0 cm−1. Furthermore, using the information from enhanced photoacoustic images at 750 nm, the ultimate imaging depth was explored for polydopamine-shelled, perfluorohexane (PDA/PFH) emulsion droplets by photon trajectory simulations in 3D using a Monte Carlo approach. Based on these simulations, maximal tissue imaging depths for PDA/PFH emulsion droplets range from 10 to 40 mm, depending on the tissue type. These results demonstrate for the first time that ultrasonically fabricated PDA/PFC emulsion droplets have great potential as photoacoustic imaging agents that can be complemented with other reported characteristics of PDA/PFC emulsion droplets for extended applications in theranostics and other imaging modalities.

Activatable Nanoprobe with Aggregation-Induced Dual Fluorescence and Photoacoustic Signal Enhancement for Tumor Precision Imaging and Radiotherapy.

Owing to the high sensitivity and high spatial resolution, fluorescence (FL) imaging has been widely applied for visualizing biological processes. To gain insight into molecular events on deeper tissues, photoacoustic (PA) imaging with better deep-tissue imaging capability can be incorporated to provide complementary visualization and quantitative information on the pathological status. However, the development of activatable imaging probes to achieve both FL and PA signal amplification remains challenging because the enhancement of light absorption in PA imaging often caused the quenching of FL signal. Herein, we first developed a caspase-3 enzyme activatable nanoprobe of a nanogapped gold nanoparticle coated with AIE molecule INT20 and DEVD peptides (AuNNP@DEVD-INT20) for tumor FL and PA imaging and subsequent imaging-guided radiotherapy. The nanoprobe could interact with GSH and caspase-3 enzyme to liberate INT20 molecules, leading to AIE. Simultaneously, the in situ self-assembly of AuNPs was achieved through the cross-linking reaction between the sulfhydryl and the maleimide, resulting in ratiometric PA imaging in tumor. Remarkably, the nanoprobe can generate richful ROS for cancer radiotherapy under X-ray irradiation. The platform not only achieves the aggregation-induced FL and PA signal enhancement but also provides a general strategy for imaging of various biomarkers, eventually benefiting precise cancer therapy.

DNA-Templated ultrasmall bismuth sulfide nanoparticles for photoacoustic imaging of myocardial infarction

Photoacoustic imaging (PAI) has shown great clinical potential in diagnosing various diseases due to its noninvasive, cost-effective, and real-time imaging properties but is limited by the lack of contrast agents with high sensitivity for deep tissue imaging. Here, DNA-templated ultrasmall bismuth sulfide (Bi2S3) nanoparticles (NPs) were reported as a photoacoustic (PA) probe for imaging myocardial infarction. We present a simple synthesis strategy of ultrasmall NPs via self-assembly of single-stranded DNA (ssDNA)/metal ion complexes. The in vivo imaging results showed a dramatically enhanced PA signal in the region of myocardial infarction after intravenous injection of DNA-Bi2S3 NPs in the myocardial ischaemia/reperfusion (I/R) mouse model. Further near infrared fluorescence imaging indicated that Bi2S3 NPs mainly accumulated in the infarcted area, leading to enhancement of PA signals. Moreover, such hybrid NPs possess a well-defined nanostructure, superior photobleaching resistance, excellent water dispersibility and negligible acute toxicity. These results not only demonstrate that ultrasmall DNA-Bi2S3 NPs are a potent PA probe for imaging the infarcted region but also provide a new avenue for preparing ultrasmall-sized PA probes by using ssDNA as a template.

Photoacoustic Signal Enhancement of Al- and Si-Phthalocyanines Caused by Photoinduced Cleavage of Water-Soluble Axial Ligand

Photoacoustic Signal Enhancement of Al- and Si-Phthalocyanines Caused by Photoinduced Cleavage of Water-Soluble Axial Ligand

Copper‐Catalyzed Covalent Dimerization of Near‐Infrared Fluorescent Cyanine Dyes: Synergistic Enhancement of Photoacoustic Signals for Molecular Imaging of Tumors

AbstractInvited for this month's cover is the group of Prof. Samuel Achilefu at the Washington University School of Medicine and colleagues at the Pohang University of Science and Technology. The cover picture shows copper (the hammer) catalyzing the assembly of monomeric near‐infrared fluorescent dye molecules, cypate (yellow glow), into covalently‐linked dimeric molecules (merged red balls). More information can be found in the Communication at 10.1002/anse.202100045.

Front Cover: Copper‐Catalyzed Covalent Dimerization of Near‐Infrared Fluorescent Cyanine Dyes: Synergistic Enhancement of Photoacoustic Signals for Molecular Imaging of Tumors (Anal. Sens. 1/2022)

The cover picture shows copper (hammer)-catalyzes the assembly of monomeric near-infrared fluorescent dye molecules, cypate (yellow glow), into covalently-linked dimeric molecules (merged red balls). Dimerization induces fluorescence quenching due to enhanced photothermal dissipation (red hot flashes), which generates acoustic waves. Decorating the dimers with a tumor-targeting agent, LS301, facilitates selective tumor uptake of the probes, which are detectable in vivo by photoacoustic imaging. More information can be found in the Communication by Samuel Achilefu, Chulhong Kim and co-workers.

Repurposing ICG enables MR/PA imaging signal amplification and iron depletion for iron-overload disorders.

Precise and noninvasive theranostic methods to quantify and deplete focal iron are of crucial importance for iron-overload disorders. Here, we developed an indocyanine green (ICG)–based imaging platform to reveal Fe3+ in vitro and in vivo. The high sensitivity and specificity of ICG-Fe interaction facilitated MR images with a marked correlation between T1 signal intensity ratio (T1SIR) changes and Fe3+ concentration in rodent models and humans. On the basis of these findings, a rational design for coordination-driven self-assembly ICG-Lecithin (ICG/Leci) was proposed to determine Fe3+. The enhancement of photoacoustic signal at 890 nm with increasing Fe3+ concentration showed an over 600% higher linear slope than that of T1SIR changes in animal models. ICG/Leci also promoted a 100% increase in iron depletion in the liver compared with deferoxamine. The high MR sensitivity and superior photoacoustic contrast, combined with enhanced iron depletion, demonstrate that ICG/Leci is a promising theranostic agent for simultaneous detection and treatment of iron-overload disorders.

Cathespin B‐Initiated Cypate Nanoparticle Formation for Tumor Photoacoustic Imaging

AbstractCathepsin B (CTSB) is a lysosomal protease that is overexpressed in the early stage of many cancer types. Precise evaluation of CTSB expression in vivo may provide a promising method for the early diagnosis of cancers. By virtue of the high‐resolution PA imaging modality, a “smart” photoacoustic (PA) probe Cypate‐CBT, which can self‐assemble to cypate‐containing nanoparticles in response to abundant GSH and CTSB inside tumor cells, was developed for the sensitive and specific detection of CTSB activity. Compared with unmodified Cypate, our probe Cypate‐CBT exhibited a 4.9‐fold or 4.7‐fold PA signal enhancement in CTSB‐overexpressing MDA‐MB‐231 cancer cells or tumors, respectively, revealing intracellular accumulation of the probe after CTSB‐initiated self‐assembly. We expect Cypate‐CBT to be employed as an effective PA imaging agent for clinical diagnosis of cancer at early stages.

Cathespin B-Initiated Cypate Nanoparticle Formation for Tumor Photoacoustic Imaging.

Cathepsin B (CTSB) is a lysosomal protease that is overexpressed in the early stage of many cancer types. Precise evaluation of CTSB expression in vivo may provide a promising method for the early diagnosis of cancers. By virtue of the high-resolution PA imaging modality, a "smart" photoacoustic (PA) probe Cypate-CBT, which can self-assemble to cypate-containing nanoparticles in response to abundant GSH and CTSB inside tumor cells, was developed for the sensitive and specific detection of CTSB activity. Compared with unmodified Cypate, our probe Cypate-CBT exhibited a 4.9-fold or 4.7-fold PA signal enhancement in CTSB-overexpressing MDA-MB-231 cancer cells or tumors, respectively, revealing intracellular accumulation of the probe after CTSB-initiated self-assembly. We expect Cypate-CBT to be employed as an effective PA imaging agent for clinical diagnosis of cancer at early stages.

Hydrophobically Modified Silica-Coated Gold Nanorods for Generating Nonlinear Photoacoustic Signals.

In this work, we report that gold nanorods coated with hydrophobically-modified mesoporous silica shells not only enhance photoacoustic (PA) signal over unmodified mesoporous silica coated gold nanorods, but that the relationship between PA amplitude and input laser fluence is strongly nonlinear. Mesoporous silica shells of ~14 nm thickness and with ~3 nm pores were grown on gold nanorods showing near infrared absorption. The silica was rendered hydrophobic with addition of dodecyltrichlorosilane, then re-suspended in aqueous media with a lipid monolayer. Analysis of the PA signal revealed not only an enhancement of PA signal compared to mesoporous silica coated gold nanorods at lower laser fluences, but also a nonlinear relationship between PA signal and laser fluence. We attribute each effect to the entrapment of solvent vapor in the mesopores: the vapor has both a larger expansion coefficient and thermal resistance than silica that enhances conversion to acoustic energy, and the hydrophobic porous surface is able to promote phase transition at the surface, leading to a nonlinear PA response even at fluences as low as 5 mJ cm-2. At 21 mJ cm-2, the highest laser fluence tested, the PA enhancement was >12-fold over mesoporous silica coated gold nanorods.