Probe-based confocal laser endomicroscopy (pCLE) enables in vivo optical biopsy with cellular resolution, but its limited field of view makes large-area tissue inspection difficult and necessitates image stitching. Under clinically relevant probe motion, variable-speed acquisition introduces nonlinear scanning distortion and severe inter-frame deformation, making stable registration and globally consistent stitching difficult. Here, we propose an incremental pCLE image stitching framework whose core is a non-rigid registration method, termed probe motion space-based mismatch rejection (PMS-MR). The main innovation is a motion consistency constraint for robust mismatch rejection and deformation estimation. To achieve this, the point scanning mechanism for confocal imaging is exploited to map feature correspondences into the probe motion space (PMS). Experimental results show that, compared with state-of-the-art registration methods, the proposed method achieves competitive pairwise registration and more reliable stitching, keeps the cumulative error on a standard target within 4 pixels, and supports large-area mosaic reconstruction over 400 frames for clear visualization of lesion boundaries. These results indicate that the proposed method supports stable, globally consistent extension of the field of view and facilitates more flexible probe manipulation in clinical practice.

Background The spinal trigeminal nucleus caudalis (SPVC) is a key central relay in the trigeminal circuit that processes orofacial nociceptive and somatosensory information. However, its long-range connectivity patterns remain poorly characterized. Methods Using viral tracing and fluorescence micro-optical sectioning tomography (fMOST), we obtained three-dimensional datasets of long-range input-output circuits of the SPVC in adult male C57BL/6J mice. An orofacial pain model was established by injecting formalin into the whisker pad of adult male C57BL/6J mice, followed by pain behavior assays and cfos immunohistochemical staining. Using adult male Fos-CreER mice combined with viral tracing and fMOST imaging, we mapped the projection patterns of pain-activated neurons in the SPVC. Results We systematically mapped the long-range connectivity patterns of SPVC in adult male mice. High-resolution, three-dimensional whole-head imaging with the fMOST system revealed substantial neuronal input to the SPVC from the trigeminal ganglion (TG) neurons innervating the facial skin and vomeronasal glands. Cortical input neurons exhibited clear subregional preferences. Whole-brain and spinal cord continuous imaging further demonstrated that the SPVC projects centrally via two distinct circuits that target the thalamus and the parabrachial nucleus (PB), respectively. The thalamic projections were further subdivided into dorsal and ventral circuits and exhibited clear subregional specificity within the thalamus. Additionally, the SPVC extended to the spinal cord through three major projection circuits, reaching as far as the lumbar segments. Along the whole-brain and spinal projection circuits, synaptic connections were identified in major target regions, including the submedial nucleus of the thalamus (SMT), ventral posteromedial nucleus of the thalamus (VPM), PB, and the C1 segment of the cervical spinal cord. Furthermore, tracing of SPVC pain-activated neurons revealed that they do not project to cerebellar crus 2 of the ansiform lobule (ANcr2) and paraflocculus (PFL). Conclusions High-resolution 3D imaging reveals the SPVC long-range connectome across head, brain, and spinal cord. Together, these findings establish a comprehensive connectivity framework for understanding the neural mechanisms underlying orofacial pain and provide a foundation for advances in basic sensory research and disease prevention and treatment.

Supervised learning's reliance on high-fidelity labeled data limits its application in fluorescence diffusion tomography (FDT). Here, we propose a multi-operator-based model-driven self-supervised learning (MMSL) for FDT to eliminate the need for labeled data. Our approach exploits geometrically disjoint source-detector configurations to derive two forward operators from the photon transport model while integrating the operators as dual constraints into an unrolled network architecture: one enforces output-space consistency, and the other directs network parameter optimization. Experimental results on our custom-built line-illumination FDT system demonstrate that MMSL achieves reconstruction quality comparable to supervised methods while exhibiting superior recovery of morphological features. This advancement significantly expands the practical utility of deep learning in experimental FDT scenarios lacking labeled data.

Accurate three-dimensional (3D) localization and sensing of intravital fluorescent probes are indispensable for elucidating neural circuit mechanisms and evaluating tumor dynamics. Fluorescence diffusion tomography in reflection geometry (rFDT) offers a powerful tool for circumventing object size limitations and enables volumetric functional imaging in deep tissues. However, due to its spatially nonuniform detection sensitivity in reflection geometry, imperfect photon transport models, and tissue heterogeneity, the photon diffusion paths are highly susceptible to unexpected perturbations. Here, we present multierror-learning-enhanced rFDT (MEL-rFDT) for precise 3D localization and sensing of intravital fluorescent probes at subcentimeter depths. By embedding physical priors derived from photon transport models and spatial attention into the deep network, MEL-rFDT adaptively compensates for various errors and depth-dependent detection sensitivity, thus enabling the high-fidelity reconstruction of intravital fluorescent probes trained with only hundreds of in silico samples. Ex vivo brain tumor and in vivo subcutaneous tumor imaging in mice demonstrated MEL-rFDT's unprecedented 3D localization and sensing accuracy, as well as its volumetric and functional generalization across samples, facilitating intraoperative pathology, dynamic imaging, and reliable healthcare decision-making.

BACKGROUND:Engineered extracellular vesicles (EVs) are emerging as a highly potential platform for targeted drug delivery in cancer therapy. Although intravenous injection is commonly used in EV treatment, there is growing interest in using microneedles (MNs) for transdermal EV delivery; however, comprehensive studies comparing the tissue distribution, safety and antitumour efficacy of these two approaches for delivering engineered EVs remain scarce. METHODS:We used EVs derived from umbilical cord mesenchymal stem cells, modified with phospholipid‒polyethylene glycol‒N-hydroxysuccinimide and conjugated with CD38 peptides (CD38-EVs), to target myeloma cells that highly express CD38 antigen, and tested their safety and antitumour efficacy in mice with subcutaneous plasmacytoma, administrated via dissolvable transdermal MNs or intravenous injection. Flow cytometry, immunofluorescence and fluorescence molecular projection imaging analysis were employed to evaluate the distribution of CD38-EVs at the cellular level and within living systems. Additionally, histopathological analysis and biochemical analyses were conducted to assess the antitumour effects and safety of CD38-EVs loaded with doxorubicin (CD38-EVs-Dox). RESULTS:Compared to standard EVs, CD38-EVs exhibited enhanced uptake by CD38high tumour cells and reduced uptake by CD38-negative non-tumour cells in vitro. In plasmacytoma NOD/SCID mouse models, CD38-EVs encapsulated within MNs (CD38-EVsMNs) effectively targeted the tumour cells much more than the standard EVs encapsulated within MNs (EVsMNs) and CD38-EVs intravenously administrated (CD38-EVsi.v), with reduced distribution to the lungs and spleen. Additionally, CD38-EVs-Dox induced significantly greater cytotoxicity against the tumour cells than EVs-Dox in vitro, and CD38-EVs-DoxMNs significantly reduced tumour burden compared to both EVs-DoxMNs and CD38-EVs-Doxi.v, while maintaining favourable safety profiles. CONCLUSIONS:CD38-EVs-DoxMNs have superior efficacy and safety in treating plasmacytoma mice, compared to CD38-EVs-Doxi.v, providing novel insights into the potential of MNs as a platform for delivering targeted engineered EVs in tumour therapy. HIGHLIGHTS:Enhanced tumor targeting: CD38-modified EVs (CD38-EVs) showed increased uptake by CD38high tumor cells while reducing uptake by CD38-negative non-tumor cells. Optimized delivery: MN-loaded CD38-EVs targeted tumors more effectively than MN-loaded EVs and intravenously injected CD38-EVs, with lower lung and spleen accumulation. Superior antitumor efficacy: MN-delivered CD38-EVs-Dox significantly suppressed tumor growth, outperforming intravenous CD38-EVs-Dox and MN-delivered EVs-Dox.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Double integrating sphere measurements obtained from thin ex vivo tissues provides more spectral information and hence allows full estimation of all basic optical properties (OPs) theoretically. However, the ill-conditioned nature of the OP determination increases excessively with the reduction in tissue thickness. Therefore, it is crucial to develop a model for thin ex vivo tissues that is robust to noise. Herein, we present a deep learning solution to precisely extract four basic OPs in real-time from thin ex vivo tissues, leveraging a dedicated cascade forward neural network (CFNN) for each OP with an additional introduced input of the refractive index of the cuvette holder. The results show that the CFNN-based model enables accurate and fast evaluation of OPs, as well as robustness to noise. Our proposed method overcomes the highly ill-conditioned restriction of OP evaluation and can distinguish the effects of slight changes in measurable quantities without any a priori knowledge.

Large-area in situ real-time imaging with cellular resolution is important in small animal imaging and clinical diagnoses. Laparoscopy is a commonly used technical tool in minimally invasive surgeries. However, laparo-scopies cannot achieve cellular resolution. Here we propose a handheld rigid confocal microendoscope with a high numerical aperture, large imaging field of view, and high-resolution laparoscopic confocal objective lens that provides cellular structural information equivalent to that provided by pathological biopsies in real time. With a field-of-view diameter of approximately 540 mu m and a lateral resolution of 1.95 mu m, which are sufficient for distinguishing cells, the system is both handheld and compatible with conventional laparoscopic trocar pins. Through ex vivo/in situ imaging experiments on various organs, including rat livers, kidneys, and spleens, the potential of this system in clinical applications is demonstrated.

We present a deep background-mismodeling-learned reconstruction framework for high-accuracy fluorescence diffuse optical tomography (FDOT). A learnable regularizer incorporating background mismodeling is formulated in the form of certain mathematical constraints. The regularizer is then learned to obtain the background mismodeling automatically using a physics-informed deep network implicitly. Here, a deep-unrolled FIST-Net for optimizing L1-FDOT is specially designed to obtain fewer learning parameters. Experiments show that the accuracy of FDOT is significantly improved via implicitly learning the background mismodeling, which proves the validity of the deep background-mismodeling-learned reconstruction. The proposed framework can also be used as a general method to improve a class of image modalities based on linear inverse problems with unknown background modeling errors.

In fluorescence diffuse optical tomography (fDOT), the quality of reconstruction is severely limited by mismodeling and ill-posedness of inverse problems. Although data-driven deep learning methods improve the quality of image reconstruction, the network architecture lacks interpretability and requires a lot of data for training. We propose an interpretable model-driven projected gradient descent network (MPGD-Net) to improve the quality of fDOT reconstruction using only a few training samples. MPGD-Net unfolds projected gradient descent into a novel deep network architecture that is naturally interpretable. Simulation and in vivo experiments show that MPGD-Net greatly improves the fDOT reconstruction quality with superior generalization ability.

Since manual hemolysis test methods are given priority with practical experience and its cost is high, the characteristics of hemolysis images are studied. A hemolysis image detection method based on generative adversarial networks (GANs) and convolutional neural networks (CNNs) with extreme learning machine (ELM) is proposed. First, the image enhancement and data enhancement are performed on a sample set, and GAN is used to expand the sample data volume. Second, CNN is used to extract the feature vectors of the processed images and label eigenvectors with one-hot encoding. Third, the feature matrix is input to the map in the ELM network to minimize the error and obtain the optimal weight by training. Finally, the image to be detected is input to the trained model, and the image with the greatest probability is selected as the final category. Through model comparison experiments, the results show that the hemolysis image detection method based on the GAN-CNN-ELM model is better than GAN-CNN, GAN-ELM, GAN-ELM-L1, GAN-SVM, GAN-CNN-SVM, and CNN-ELM in accuracy and speed, and the accuracy rate is 98.91%.

Phototherapy, including photodynamic and photothermal therapies, is a non-invasive photo-triggered tumor treatment. Combination therapy and new synergistic therapeutic reagents may hold promise for improving these treatments. Herein, we report an amphiphilic iridium-based photosensitizer (C14-IP2000) loaded with a hydrophobic photo-thermal drug (ZnPc) to form nano-micelles (ZNPs) for dual-light triggered tumor phototherapy. The C14-IP2000 was contained within ZNPs consisting of an iridium complex core decorated with hydrophilic polyethylene glycol chains to extend the time in blood circulation, and two hydrophobic carbon chains to enhance the loading capacity and the hydrophobic interaction with the loaded reagent. The designed ZNPs showed effective blood circulation, passive tumor targeting ability, remarkable photodynamic conversion ability, and good photothermal conversion capability, and therefore may be used for combined tumor ablation. Our results demonstrated that the amphipathic bionic structure of ZNPs not only enables self-assembled reagent fabrication with prolonged circulation time and favorable metabolic characteristics for tumor combination therapy, but also provides a nanostructure strategy for the modification of functionalized reagents.

The low magnetic saturation of iron oxide nanoparticles, which are developed primarily as contrast agents for magnetic resonance imaging, limits the sensitivity of their detection using magnetic particle imaging (MPI). Here, we show that FeCo nanoparticles that have a core diameter of 10 nm and bear a graphitic carbon shell decorated with poly(ethylene glycol) provide an MPI signal intensity that is sixfold and fifteenfold higher than the signals from the superparamagnetic iron oxide tracers VivoTrax and Feraheme, respectively, at the same molar concentration of iron. We also show that the nanoparticles have photothermal and magnetothermal properties and can therefore be used for tumour ablation in mice, and that they have high optical absorbance in a broad near-infrared region spectral range (wavelength, 700–1,200 nm), making them suitable as tracers for photoacoustic imaging. As sensitive multifunctional and multimodal imaging tracers, carbon-coated FeCo nanoparticles may confer advantages in cancer imaging and hyperthermia therapy. FeCo nanoparticles with a graphitic carbon shell decorated with poly(ethylene glycol) have photothermal and magnetothermal properties and are sensitive tracers for magnetic particle imaging, magnetic resonance imaging and photoacoustic imaging.

Sorafenib, a multi-targeted kinase inhibitor, has been reported to elicit a limited therapeutic effect in hepatocellular carcinoma (HCC). Currently, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is emerging as a powerful modality for cancer therapy. However, few studies have been reported the effectiveness of the combination of sorafenib with PDT and PTT in HCC. Herein, we designed and synthesized bovine serum albumin (BSA) coated zinc phthalocyanine (ZnPc) and sorafenib (SFB) nanoparticle (ZnPc/SFB@BSA). The obtained ZnPc/SFB@BSA was able to trigger PDT, PTT, and chemotherapy. After irradiation by a 730 nm light, ZnPc/SFB@BSA significantly suppressed HCC cell proliferation and metastasis, while promoted cell apoptosis in vitro. Furthermore, intravenous injection of ZnPc/SFB@BSA led to dramatically reduced tumor growth in an orthotopic xenograft HCC model. More importantly, ZnPc/SFB@BSA presented low toxicity and adequate blood compatibility. Therefore, a combination of ZnPc with sorafenib via BSA-assembled nanoparticle can markedly suppress HCC growth, representing a promising strategy for HCC patients.

Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), reveals a limited therapeutic effect due to a lack of selectivity and evident drug resistance. In the present study, bismuth-based mesoporous nanomaterial (NBOF) is loaded with SOR and then coated with polyethylene glycol and folic acid conjugates (P-FA) to form an NBOF@SOR-P-FA nanocarrier system. The system achieves significantly enhanced anti-cancer efficacy by combining chemotherapy with radiotherapy. To evaluate the effect of synergistic treatment, cytotoxicity detection, Live/Dead staining, apoptotic assay, and Western blot analysis are performed. The results suggest that NBOF@SOR-P-FA significantly inhibits HCC cell proliferation and promotes cell apoptosis. Also, the NBOF@SOR-P-FA exhibits excellent biocompatibility by hemolysis and serum biochemical tests and produces a substantially enhanced contrast efficiency as compared to iohexol by computed tomography imaging. More importantly, the profound suppression of tumor growth and potentiation of apoptosis are observed in a mouse subcutaneous tumor model. Collectively, these results indicate that the bismuth-based nanotheranostic platform could enhance the therapeutic effect of sorafenib and serve as an innovative method for HCC treatment.

Objective:To investigate the effect of hepatitis B virus (HBV) infection in patients with hepatic alveolar echinococcoisis after surgical resection and determine the differences of liver function between patients with different HBV-DNA levels.Methods:Patients were selected from January 2014 to July 2018 in the Affiliated Hospital of Qinghai University. Twenty-eight patients with hepatitis B and hepatic alveolar echinococcoisis were included in the experimental group, and 20 patients with hepatic alveolar echinococcoisis but without hepatitis B virus were included in the control group. Based on HBV-DNA level, the experimental group was divided into low-level group (HBV-DNA level<200 IU/ml, n=6), intermediate-level group (HBV-DNA level 200-20 000 IU/ml, n=15) and high level group (HBV-DNA level>20 000 IU/ml, n=7). Comparison of complications and liver function after liver resection in two groups.Univariate and multivariate logistic regression were used to analyze the influential factors of postoperative complications in patients.Comparison of postoperative liver function indexes in patients with different HBV-DNA levels. Results:In the control group, postoperative total bilirubin 10.6(8.3, 16.9) μmol/L, direct bilirubin 5.3(3.4, 10.0) μmol/L, prothrombin time 13.6(13.0, 15.8)s, and the incidence of complications 25.0%(5/20), were better than the experimental group 12.6(8.4, 46.9) μmol/L, 6.7(3.1, 26.4) μmol/L, 15.4(13.5, 18.1)s, 78.6% (22/28), the differences were statistically significant significance (all P<0.05). Multivariate logistic analysis showed that patients with HBV infection ( OR=4.593, 95% CI: 1.128-18.708) and intraoperative blood loss ≥1 000 ml ( OR=2.200, 95% CI: 1.106-4.378) were the hepatic alveolar echinococcoisis independent risk factors for postoperative complications. There were no significant differences in total bilirubin and albumin between the three groups of patients with different HBV-DNA levels ( P>0.05). Conclusion:Patients with HBV and hepatic alveolar echinococcoisis have worse liver function and are more prone to complications after surgical resection, but there is no significant difference in liver function among patients with different HBV-DNA levels.

Fiber bundle coupler is a key part in a probe-based endomicroscope used to couple laser in each core of the fiber bundles precisely when the laser scan unit is performing a high speed confocal scanning. Common fiber connector is usually used in communication application with single fiber core. But for image transmitting, common connector such as SMA must be manually adjusted in 5 axes to locate all fiber cores of the bundle. A micron precision fiber bundle coupler is introduced in this article. This coupler is special designed for an endomicroscope. This coupler can locate the position of the fiber cores of a bundle in micro precision in all 3 dimensions with the help of the mechanical structure and focusing mechanism. The coupler has a plug and a socket component. A polished fiber bundle is installed in the center of the plug. A connection core is located in the center of the socket component to make sure the plug and the coupling objective can stay in a same axis, so that the fiber bundle can also located in the same axis. A number of arms distributed symmetrically can be pushed by the operating cover to apply a constant pressure on the plug through a spring to lock the plug. The coupling objective can move along the axis inside the connection core by a linear actuator. An image evaluation algorithm can help the actuator to find a proper location to achieve auto focus. The coupler can work smoothly and automatically. It is very easy for clinical use.

Photodynamic therapy (PDT) is one of effective cancer therapy methods. It is important to develop a PDT reagent with tumor-targeted ability, high phototoxicity and low dark toxicity. In this study, an iridium(III) complex (Irpy) can electrostatically self-assemble with hyaluronic acid (HA) to form nanostructured Irpy-HA, which exhibited stable spheroid structure and outstanding ability of singlet oxygen (1O2) generation. The photophysical property of Irpy has been well studied, which qualified green light absorption ability and could emit red phosphorescence. The nanostructure and stability of self-assembled Irpy-HA have been well investigated, which can keep its nanostructure at least 30 days. More importantly, Irpy-HA can target to a CD44 receptor in cancer cell membrane for enhancing internalization and selective disintegration. Then, Irpy can accumulate in mitochondria and generate 1O2 to realize PDT-induced cell apoptosis by green light irradiation. The Irpy-HA could be used as a nanophotosensitizer for effective photodynamic therapy.

Developing a multi-functional radiosensitizer with high efficiency and low toxicity remains challenging. Herein, we report a mesoporous heterostructure radiosensitizer (UCNP@NBOF-FePc-PFA) containing Lu-based upconversion nanophosphor (UCNP) and Bi-based nanomaterial loaded with iron phthalocyanine for X-ray and NIR light dual-triggered tri-modal tumor therapy. NaLuF4:Yb,Tm, a Lu-based UCNP, offers radiosensitization and upconversion luminescence for optical bio-imaging. However, Bi has a higher X-ray mass attenuation coefficient than Lu. Thus, after stepwise fabrication, Na0.2Bi0.8O0.35F1.91:Yb (NBOF) was assembled with the UCNP to form a mesoporous heterostructure composite. This enhanced the radiosensitization effect and drug load to realize multi-modal tumor therapy. After coating it with folate-conjugated amphiphilic PEG (PFA), UCNP@NBOF-FePc-PFA realized tumor photothermal/photodynamic/radio-therapy. The structure of UCNP@NBOF-FePc-PFA was well characterized. Different properties triggered by X-ray and NIR light were evaluated. Finally, a highly efficient tumor ablation effect was demonstrated in vitro and in vivo. Consequently, this kind of nanocomposite provides a unique strategy for designing a theranostic platform for oncotherapy. STATEMENT OF SIGNIFICANCE: The synergy of enhanced radiotherapy and photothermal/photodynamic therapy is found to improve tumor therapeutic efficacy. On that basis, a heterostructure nanohybrid containing Lu-based UCNP and Bi-based mesoporous material is synthesized. The heterostructure nanohybrid can be loaded with FePc and decorated with folate-modified amphiphilic PEG to form a multi-functional theranostic nano-platform. The platform exhibits upconversion luminescence capacity, X-ray attenuation property, photothermal effect, and X-ray and NIR dual-light triggered ROS generation capability. These features can not only enable upconversion luminescence/CT bioimaging of living beings but also be applied to the photothermal/photodynamic/radio- synergistic tumor ablation. To sum up, the nanomaterial offers a novel method for the construction of a new theranostic platform.