Visualization of photothermal therapy by semiconducting polymer dots mediated photoacoustic detection in NIR II.

Visualization of photothermal therapy mediated by photothermal transduction agents (PTAs) is important to promote individual treatment of patients with low side effects. Photoacoustic detection has emerged as a promising noninvasive method for the visualization of PTAs distribution but still has limitations in temperature measurement, including poor measurement accuracy and low tissue penetration depth. In this study, we developed biocompatible semiconducting polymer dots (SPD) for in situ coupling of photothermal and photoacoustic detection in the near-infrared II window. SPD has dual photostability under pulsed laser and continuous-wave laser irradiation with a photothermal conversion efficiency of 42.77%. Meanwhile, a strong correlation between the photoacoustic signal and the actual temperature of SPD can be observed. The standard deviation of SPD-mediated photoacoustic thermometry can reach 0.13 °C when the penetration depth of gelatin phantom is 9.49 mm. Preliminary experimental results in vivo show that SPD-mediated photoacoustic signal has a high signal-to-noise ratio, as well as good performance in temperature response and tumor enrichment. Such a study not only offers a new nanomaterial for the visualization of photothermal therapy but will also promote the theranostic platform for clinical applications.

Handheld interventional ultrasound/photoacoustic puncture needle navigation based on deep learning segmentation.

Interventional ultrasound (US) has challenges in accurate localization of the puncture needle due to intrinsic acoustic interferences, which lead to blurred, indistinct, and even invisible needles in handheld linear array transducer-based US navigation, especially the incorrect needle tip positioning. Photoacoustic (PA) imaging can provide complementary image contrast, without additional data acquisition. Herein, we proposed an internal illumination to solely light up the needle tip in PA imaging. Then deep-learning-based feature segmentation alleviates acoustic interferences, enhancing the needle shaft-tip visibility. Further, needle shaft-tip compensation aligned the needle shaft in US image and the needle tip in the PA image. The experiments on phantom, ex vivo chicken breast, preclinical radiofrequency ablation and in vivo biopsy of sentinel lymph nodes were piloted. The target registration error can reach the submillimeter level, achieving precise puncture needle tracking ability with in-plane US/PA navigation.

Dynamic Speed of Sound Adaptive Transmission-Reflection Ultrasound Computed Tomography.

Ultrasound computed tomography (USCT) can visualize a target with multiple imaging contrasts, which were demonstrated individually previously. Here, to improve the imaging quality, the dynamic speed of sound (SoS) map derived from the transmission USCT will be adapted for the correction of the acoustic speed variation in the reflection USCT. The variable SoS map was firstly restored via the optimized simultaneous algebraic reconstruction technique with the time of flights selected from the transmitted ultrasonic signals. Then, the multi-stencils fast marching method was used to calculate the delay time from each element to the grids in the imaging field of view. Finally, the delay time in conventional constant-speed-assumed delay and sum (DAS) beamforming would be replaced by the practical computed delay time to achieve higher delay accuracy in the reflection USCT. The results from the numerical, phantom, and in vivo experiments show that our approach enables multi-modality imaging, accurate target localization, and precise boundary detection with the full-view fast imaging performance. The proposed method and its implementation are of great value for accurate, fast, and multi-modality USCT imaging, particularly suitable for highly acoustic heterogeneous medium.

Magnetomotive Ultrasound Shear Wave Elastography (MMUS-SWE): A Validation Study From Simulations to Experiments.

Ultrasound elastography is a functional imaging method that enables the measurement of soft tissue elasticity, which is associated with the pathological process of many diseases. However, the measurement area of the conventional elastography method is subjectively selected. Inspired by the targeted imaging technology, we propose a method of magnetomotive ultrasound shear wave elastography (MMUS-SWE). This method utilizes the magnetic force between the magnetic nanoparticles (MNPs) and the external magnetic field to generate shear waves. Then, it can detect the distribution of MNPs and the elasticity of the tissue around the MNPs. As MNPs have been widely used for targeted labeling, the strategy to induce local vibration by MNPs will be more specific than that of the conventional SWE. In this study, the theoretical feasibility was verified by the finite element simulation model. Then, an experimental system was built, and the experimental feasibility of the method was demonstrated through phantom experiments, in vitro tissue experiments, and in vivo experiments. The results show that the distribution of the MNPs and the elastic information of tissues surrounding the MNPs can be detected simultaneously. This technology is expected to realize targeted elasticity measurement based on the MNPs and has potential applications for disease diagnosis.

Multi-Scale Photoacoustic Assessment of Wound Healing Using Chitosan-Graphene Oxide Hemostatic Sponge.

Hemostasis is vital to save lives, reducing risks of organ failure and hemorrhagic shock. Exploring novel hemostatic materials and precise monitoring of the hemostatic status is of great importance for efficient hemostasis. We present the development of chitosan-graphene oxide-based hemostatic composite and multi-scale photoacoustic evaluation of the hemostatic performance. The hemostatic sponge can quickly and efficiently absorb the blood with its porous cavity and specific surficial property. We inspect the hemostatic performance via an in vitro blood absorption test and in vivo mouse bleeding injury experiments. Results show that the synthesized hemostatic sponge can not only absorb plasma in blood fast with its interior porous structure but also stimulate the interfacial reaction with erythrocytes and platelets. The superiority of multi-scale photoacoustic imaging for guiding, monitoring, and evaluating the hemostatic stages of sponges is demonstrated with high spatial resolution and great sensitivity at depths. Photoacoustic evaluation of a chitosan-graphene oxide-based hemostatic sponge has the potential to be transferred toward the clinical assessment of wound healing.

NIR-II Absorbing Semiconducting Polymer-Triggered Gene-Directed Enzyme Prodrug Therapy for Cancer Treatment.

Exploration of facile strategies for precise regulation of target gene expression remains highly challenging in the development of gene therapies. Especially, a stimuli-responsive nanocarrier integrated with ability of noninvasive remote control for treating wide types of cancers is rarely developed. Herein, a NIR-II absorbing semiconducting polymer (PBDTQ) is employed to remotely activate the heat-inducible heat-shock protein 70 (HSP70) promoter under laser irradiation, further realizing regulation of gene-directed enzyme prodrug therapy (GDEPT) for cancer treatment in mild hyperthermia. In this multifunctional nanocomposite, the PBDTQ and double suicide gene plasmid (pSG) based on HSP70 promoter are incorporated into a lipid complex. Upon NIR-II laser excitation, the mild photothermal effect (≈43 °C) generated from PBDTQ can cause the release of pSG and activation of HSP70 promoter, and then upregulate suicide gene expression triggered by the HSP70 promoter which can further convert the nontoxic prodrug into its cytotoxic metabolites. Therefore, this work demonstrates a universal NIR-II laser-triggered GDEPT using semiconducting polymers as the photothermal generator for cancer treatment with minimized collateral damage and nontargeted side effects.

An Ester-Substituted Semiconducting Polymer with Efficient Nonradiative Decay Enhances NIR-II Photoacoustic Performance for Monitoring of Tumor Growth.

Photoacoustic agents have been of vital importance for improving the imaging contrast and reliability against self-interference from endogenous substances. Herein, we synthesized a series of thiadiazoloquinoxaline (TQ)-based semiconducting polymers (SPs) with a broad absorption covering from NIR-I to NIR-II regions. Among them, the excited s-BDT-TQE, a repeating unit of SPs, shows a large dihedral angle and narrow adiabatic energy as well as low radiative decay, attributing to its strongly electron-deficient ester-substituted TQ-segment. In addition, its more vigorous molecular motions trigger a higher reorganization energy that further yields an efficient photoinduced nonradiative decay, which has been carefully examined and understood by theoretical calculation. Thus, BDT-TQE SP-cored nanoparticles with twisted intramolecular charge transfer (TICT) feature exhibit a high NIR-II photothermal conversion efficiency (61.6 %) and preferable PA tracking of in situ hepatic tumor growth for more than 20 days. This study highlights a unique strategy for constructing efficient NIR-II photoacoustic agents via TICT-enhanced PNRD effect, advancing their applications for in vivo bioimaging.

Development of a molecular K+ probe for colorimetric/fluorescent/photoacoustic detection of K.

The potassium ion (K+) plays significant roles in many biological processes. To date, great efforts have been devoted to the development of K+ sensors for colorimetric, fluorescent, and photoacoustic detection of K+ separately. However, the development of molecular K+ probes for colorimetric detection of urinary K+, monitoring K+ fluxes in living cells by fluorescence imaging, and photoacoustic imaging of K+ dynamics in deep tissues still remains an open challenge. Herein, we report the first molecular K+ probe (NK2) for colorimetric, fluorescent, and photoacoustic detection of K+. NK2 is composed of 2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF) as the chromophore and phenylazacrown-6-lariat ether (ACLE) as the K+ recognition unit. Predominate features of NK2 include a short synthetic procedure, high K+ selectivity, large detection range (5-200 mM), and triple-channel detection manner. NK2 shows good response to K+ with obvious color changes, fluorescence enhancements (about threefold), and photoacoustic intensity changes. The existence of other metal ions (including Na+, Mg2+, Ca2+, Fe2+) and pH changes (6.5-9.0) have no obvious influence on K+ sensing of NK2. Portable test strips stained by NK2 can be used to qualitatively detect urinary K+ by color changes for self-diagnosis of diseases induced by high levels of K+. NK2 can be utilized to monitor K+ fluxes in living cells by fluorescent imaging. We also find its excellent performance in photoacoustic imaging of different K+ concentrations in the mouse ear. NK2 is the first molecular K+ probe for colorimetric, fluorescent, and photoacoustic detection of K+ in urine, in living cells, and in the mouse ear. The development of NK2 will broaden K+ probes' design and extend their applications to different fields. Graphical abstract.

I-BET726 suppresses human skin squamous cell carcinoma cell growth in vitro and in vivo.

Bromodomain-containing protein 4 (BRD4) is a potential therapeutic target of skin squamous cell carcinoma (SCC). I-BET726 is a novel BRD4 inhibitor. Its potential effect in skin SCC cells was tested in the present study. We show that I-BET726 potently inhibited survival, proliferation, cell cycle progression, and migration in established (A431/SCC-9/SCC-12/SCC-13 lines) and primary human skin SCC cells. I-BET726 induced significant apoptosis activation in skin SCC cells. It was more efficient in inhibiting skin SCC cells than known BRD4 inhibitors (JQ1, CPI203, and AZD5153). I-BET726 not only downregulated BRD4-regulated proteins (c-Myc, Bcl-2, and cyclin D1), but also inhibited sphingosine kinase 1 (SphK1) and Akt signalings in SCC cells. Restoring Akt activation, by a constitutively active S473D mutant Akt1 ("caAkt1"), partially inhibited I-BET726-induced cytotoxicity in A431 cells. In vivo, I-BET726 oral administration potently inhibited A431 xenograft growth in severe combined immunodeficient mice. Downregulation of BRD4-regulated proteins and inhibition of the SphK1-Akt signaling were detected in I-BET726-treated A431 xenograft tumor tissues. Together, I-BET726 inhibits skin SCC cell growth in vitro and in vivo.

A Photoinduced Nonadiabatic Decay-Guided Molecular Motor Triggers Effective Photothermal Conversion for Cancer Therapy.

It remains highly challenging to identify small molecule-based photothermal agents with a high photothermal conversion efficiency (PTCE). Herein, we adopt a double bond-based molecular motor concept to develop a new class of small photothermal agents to break the current design bottleneck. As the double-bond is twisted by strong twisted intramolecular charge transfer (TICT) upon irradiation, the excited agents can deactivate non-radiatively through the conical intersection (CI) of internal conversion, which is called photoinduced nonadiabatic decay. Such agents possess a high PTCE of 90.0 %, facilitating low-temperature photothermal therapy in the presence of a heat shock protein 70 inhibitor. In addition, the behavior and mechanism of NIR laser-triggered molecular motions for generating heat through the CI pathway have been further understood through theoretical and experimental evidence, providing a design principle for highly efficient photothermal and photoacoustic agents.

Dual-Polarized Fiber Laser Sensor for Photoacoustic Microscopy.

Optical resolution photoacoustic microscopy (OR-PAM) provides high-resolution, label-free and non-invasive functional imaging for broad biomedical applications. Dual-polarized fiber laser sensors have high sensitivity, low noise, a miniature size, and excellent stability; thus, they have been used in acoustic detection in OR-PAM. Here, we review recent progress in fiber-laser-based ultrasound sensors for photoacoustic microscopy, especially the dual-polarized fiber laser sensor with high sensitivity. The principle, characterization and sensitivity optimization of this type of sensor are presented. In vivo experiments demonstrate its excellent performance in the detection of photoacoustic (PA) signals in OR-PAM. This review summarizes representative applications of fiber laser sensors in OR-PAM and discusses their further improvements.

Photostable, hydrophilic, and near infrared quaterrylene-based dyes for photoacoustic imaging.

Novel near-infrared contrast agents based on the quaterrylene structure were strategically developed and tested for high photo-stability. Both a dendrimeric quaterrylene molecule, QR-G2-COOH, and a small molecule cationic quaterrylene dye, QR-4PyC4, remain optically stable and continue to generate a competitive photoacoustic response when irradiated by short near-infrared laser pulses for a relatively long time in an in-vitro cell study, unlike indocyanine green that rapidly decreases photoacoustic signal amplitude. The small molecule dye, QR-4PyC4 exhibits not only significantly higher cellular uptake rate than QR-G2-COOH and indocyanine green, but also low toxicity at a concentration of up to 10 µM. The dendrimeric dye, QR-G2-COOH that has surface functional groups available for conjugation with targeting and therapeutic agents shows the highest photoacoustic amplitude with high optical stability. Therefore, QR-4PyC4 can be a promising universal, sensitive and reliable photoacoustic contrast agent and QR-G2-COOH has great potential as a nano-platform with stable photoacoustic imaging capability.

Highly Sensitive Fluorescence and Photoacoustic Detection of Metastatic Breast Cancer in Mice Using Dual-Modal Nanoprobes.

The biomedical imaging of metastatic breast cancer, especially in lymphatic and lung metastasis, is highly significant in cancer staging as it helps assess disease prognosis and treatment. Using an albumin-indocyanine green dual-modal nanoprobe developed in our laboratory, in vivo fluorescence imaging and photoacoustic imaging of metastatic breast cancer tumors were performed separately. Fluorescence imaging at the near-infrared window features high imaging sensitivity but is generally limited by a low imaging depth. Thus, tumors can only be observed in situ whereas tumor cells in the lymph nodes and lung cannot be imaged in a precise manner. In contrast, photoacoustic imaging often helps overcome the limitations of imaging depth with high acoustic spatial resolution, which could provide complementary information for imaging cancer metastases. Ex vivo fluorescence and photoacoustic imaging were also performed to verify the tumor metastatic route. This study may not only provide insights into the design of dual-modal nanoprobes for breast cancer diagnosis but may also demonstrate the superiority of combined fluorescence imaging and photoacoustic imaging for guiding, monitoring, and evaluating lymphatic and lung metastatic stages of breast cancer with a high imaging specificity as well as sensitivity.

Dual-foci detection in photoacoustic computed tomography with coplanar light illumination and acoustic detection: a phantom study.

A dual-foci transducer with coplanar light illumination and acoustic detection was applied for the first time. It overcame the small directivity angle, low-sensitivity, and large datasets in conventional circular scanning or array-based photoacoustic computed tomography (PACT). The custom-designed transducer is focused on both the scanning plane with virtual-point detection and the elevation direction for large field of view (FOV) cross-sectional imaging. Moreover, a coplanar light illumination and acoustic detection configuration can provide ring-shaped light irradiation with highly efficient acoustic detection, which in principle has a better adaptability when imaging samples of irregular surfaces. Phantom experiments showed that our PACT system can achieve high resolution (∼0.5 mm), enhanced signal-to-noise ratio (16-dB improvement), and a more complete structure in a greater FOV with an equal number of sampling points compared with the results from a flat aperture transducer. This study provides the proof of concept for the fabrication of a sparse array with the dual-foci property and large aperture size for high-quality, low-cost, and high-speed photoacoustic imaging.

Acellular Dermal Matrix Combined with Autologous Skin Grafts for Closure of Chronic Wounds after Reconstruction of Skull Defects with Titanium Mesh.

Objective The closure of chronic wounds after skull defect reconstruction with titanium mesh is one of the most challenging problems for plastic and reconstructive surgeons. Current approaches are disappointing. Methods In 10 patients, we explored the role of acellular dermal matrix (ADM) in combination with autologous skin grafts (ASGs) for closure of chronic wounds after skull reconstruction with titanium. Results ADM and ASG survived in all patients. Grade A healing (healing well without defect) was achieved. The average operating time was 30 to 45 minutes, and the average blood loss 30 to 50 mL. After 3 months, the wound was still closed in all patients. Conclusion The combination of ADM plus ASG obtained a high wound closure rate. ADM plus ASG allows avoiding other procedures such as rotational flaps and free flaps that require more operating time, special equipment, and adequate training.

[Effect of laparoscopic proctectomy and open proctectomy on plasma levels of vascular endothelial growth factor].

OBJECTIVE: To investigate the effect of laparoscopic and open proctectomy on plasma levels of vascular endothelial growth factor (VEGF). METHODS: From January 2011 to December 2012, 100 rectal cancer patients in Shantou Central Hospital were enrolled in the study. Patients were divided into laparoscopic (LR) group and open (OR) group based on the decision of the patients. There were 63 patients in the LR group (44 cases undergoing low anterior resection and 19 abdominoperineal resection) and 37 patients in the OR group(26 cases undergoing low anterior resection and 11 abdominoperineal resection). Double antibody sandwich enzyme-linked immunohistochemistry was used to detect the level of VEGF on 1-day before and 1-day, 3-day, 7-day after operation. RESULTS: In the LR group, the postoperative levels of VEGF increased slowly, and the level of VEGF was significantly higher than that before operation until the 7-day after operation(P<0.05) regardless of the procedure. In the OR group, all the postoperative levels of VEGF were significantly increased(P<0.05). There was no significant difference of the VEGF level on 1-day before and 1-day after operation between the two groups(all P>0.05). The VEGF level in the OR group was significantly higher than that in the LR group on the day 3 and day 7 after operation(P<0.05). CONCLUSION: Compared with open approach, laparoscopic proctectomy has smaller short-term impact on the plasma level of VEGF in rectal cancer patients.

Synthesis and application of lignin-based copolymer LSAA on controlling non-point source pollution resulted from surface runoff.

In this article, alkali lignin separated from paper pulp waste was grafted into a novel copolymer LSAA (a copolymer of lignin, starch, acrylamide, and acrylic acid). Its practical application effect and environmental safety were studied. The results of field simulation experiment indicated that the application of LSAA significantly affected the output of the runoff and pollutants. The runoff quantity was decreased by 16.67%-47.00% and the loads of total suspended solids (TSS), chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) were reduced by 17.78%-62.14%, 26.32%-59.91%, 15.25%-47.42%, and 22.18%-52.78%, respectively. The tests on its environmental safety showed that LSAA did no harm the soil. Compared with polyacrylamide (PAM), a dominant product in this field, LSAA exhibited similar effects and cheap cost. Thus, this study not only created a new product for controlling runoff water quality but also offered a beneficial application for industrial paper waste.

Anti-fouling ultrafiltration membrane prepared from polysulfone-graft-methyl acrylate copolymers by UV-induced grafting method.

Membrane fouling is one of the most important challenges faced in membrane ultrafiltration operations. The copolymers of polysulfone-graft-methyl acrylate were synthesized by homogeneous photo-initiated graft copolymerization. The variables affecting the degree of grafting, such as the time of UV (Ultraviolet-visible) irradiation and the concentrations of the methyl acrylate and photoinitiator, were investigated. The graft copolymer membranes were prepared by the phase inversion method. The chemical and morphological changes were characterized by attenuated total reflection-Fourier transform infrared spectroscopy (ATR/FT-IR), scanning electron microscopy, and water contact angles measurements. Results revealed that methyl acrylate groups were present on the membranes and the graft degree of methyl acrylate had remarkable effect on the performance of membranes. Pure water contact angle on the membrane surface decreases with the increase of methyl acrylate graft degree, which indicated that the hydrophilicity of graft copolymer membranes was improved. The permeation fluxes of pure water and bovine serum albumin solution were measured to evaluate the antifouling property of graft copolymer membranes, the results of which have shown an enhancement of antifouling property for graft copolymer membranes.

Ultravilolet-radiation-induced graft polymerization of acrylamide onto the melt-blown polypropylene filter element by dynamic method.

By dynamic method under UV irradiation, commercial melt-blown polypropylene (PPMB) filter element was modified with acrylamide (AAm) using benzophenone (BP) as initiator. Attenuated total reflection-Fourier transform infrared spectroscopy and scanning electron microscope verified that polyacrylamide chain was grafted on the fiber surface of PPMB filter element. Elemental content analysis with energy dispersive X-ray of fibers revealed that the polymerization content in the inner part of filter element was relatively higher than that in the outer. Degree of grafting changed with initiator concentration, monomer concentration, reaction temperature and reached 2.6% at the reaction condition: CBP=0.06 mol/L, CAAm=2.0 mol/L, irradiation time: 80 min, temperature: 600 degrees C. Relative water flux altered with the hydrophilicity and pore size of filter element. In the antifouling test, the modified filter gave greater flux recovery (approximately 70%) after filtration of the water extract of Liuweidihuang, suggesting that the fouling layer was more easily reversible due to the hydrophilic nature of the modified filter.