Ultrabright Renal-Clearable Cyanine-Protein Nanoprobes for High-Quality NIR-II Angiography and Lymphography.

The renal-clearable aspect of imaging agent with minimum toxicity issues and side effects is essential for clinical translation, yet clinical near-infrared-I/II (NIR-I/II) fluorophores with timely renal-clearance pathways are very limited. Herein, we rationally develop the cyanine-protein composite strategy through covalent bonding of ß-lactoglobulin (ß-LG) and chloride-cyanine dye to produce a brilliant and stable NIR-I/II fluorophore (e.g., ß-LG@IR-780). The ß-LG acts as a protecting shell with small molecular weight (18.4 kDa) and ultrasmall size (<5 nm), thus endowing the ß-LG@IR-780 with excellent biocompatibility and renal excretion. Our ß-LG@IR-780 probe enables noninvasive and precise NIR-II visualization of the physiological and pathological conditions of the vascular and lymphatic drainage system, facilitating intraoperative imaging-guided surgery and postoperative noninvasive monitoring. The minimum accumulation of our probes in the main organs improves the overall biosafety. This study provides a facile methodology for new-generation NIR-II fluorophores and largely improves the brightness and pharmacokinetics of small molecular dyes.

The bright future of nanotechnology in lymphatic system imaging and imaging-guided surgery.

Lymphatic system is identified the second vascular system after the blood circulation in mammalian species, however the research on lymphatic system has long been hampered by the lack of comprehensive imaging modality. Nanomaterials have shown the potential to enhance the quality of lymphatic imaging due to the unparalleled advantages such as the specific passive targeting and efficient co-delivery of cocktail to peripheral lymphatic system, ease molecular engineering for precise active targeting and prolonged retention in the lymphatic system of interest. Multimodal lymphatic imaging based on nanotechnology provides a complementary means to understand the kinetics of lymphoid tissues and quantify its function. In this review, we introduce the established approaches of lymphatic imaging used in clinic and summarize their strengths and weaknesses, and list the critical influence factors on lymphatic imaging. Meanwhile, the recent developments in the field of pre-clinical lymphatic imaging are discussed to shed new lights on the design of new imaging agents, the improvement of delivery methods and imaging-guided surgery strategies.

A Meta-analysis of 37 Studies on the Effectiveness of Microsurgical Techniques for Lymphedema.

BACKGROUND: Microsurgery is a new technique for lymphedema treatment. Its advantages and disadvantages remain controversial. This study is sought to collect clinical data from patients who underwent lymphovenous bypass and vascularized lymph node transplantation to explore whether surgical procedures can effectively treat lymphedema. METHODS: We performed a meta-analysis of the effectiveness of lymphatic microsurgery. We searched the databases of literature for articles in Chinese and English. These articles were graded for quality. Report details and outcomes were recorded. Data extraction, systematic review, and meta-analysis were performed. RESULTS: Thirty-seven studies were included. Patients who underwent microsurgery had a significantly better chance of achieving an excellent result than patients who received conservative treatment (odds ratio = 7.07). The affected limb circumference was reduced by approximately, 44.68% after the microsurgery. After the microsurgery, 63% of the patients did not need physiotherapy, and 96% were free from painful skin infections. Lymphography showed that lymphatic transport capacity was enhanced. Moreover, 12% of the patients reported that edema reappeared in the long-term, 26% required reoperation for unsatisfactory results, and 32% experienced lymphatic leakage. CONCLUSIONS: A vast majority of patients derive more benefit from lymphatic microsurgery than from conventional treatment. The advantages of lymphatic microsurgery outweigh the disadvantages for patients in the early and middle stages of chronic secondary lymphedema and patients in whom conventional treatment failed.

Arrangement of Indocyanine Green in a 1.5-Nanometer Channel to Achieve High-Efficiency Imaging of the Intestinal Lymphatic System.

The complications of inflammatory bowel diseases (IBDs) seriously endanger people's health, such as bleeding, polyp hyperplasia, and even cancer. Although the precise pathophysiology of IBD is unknown, alterations in the intestinal lymphatic network, such as lymphangiogenesis and lymphatic vessel dysfunction, are well-established features. Therefore, the development of a reliable technology is urgently required, with a stereoscopic, deep, and high-resolution technology for IBD lymphatic targeting imaging in clinical practice. However, indocyanine green, the only clinically approved imaging agent by the Food and Drug Administration, can easily cause self-aggregation or be interfered with by microenvironments, causing fluorescence quenching, which seriously affects the imaging and detective capabilities. Herein, indocyanine green molecules are arranged in a 1.5-nanometer one-dimensional channel (TpPa-1@ICG). Based on this specified structure, the fluorescence enhancement effect is observed in the TpPa-1@ICG resultant, and the fluorescence intensity is enhanced by 27%. In addition, the ICG-incorporated porous solid reveals outstanding solvent (dichloromethane, tetrahydrofuran, etc.) and thermal (>300 °C) stability. After modifying the target molecules, TpPa-1@ICG showed excellent imaging ability for intestinal lymphatic vessels, providing a new imaging tool for IBDs research.

A Facile and Highly Efficient Approach to Obtain a Fluorescent Chromogenic Porous Organic Polymer for Lymphatic Targeting Imaging.

Porous organic polymers have an open architecture, excellent stability, and tunable structural components, revealing great application potential in the field of fluorescence imaging, but this part of the research is still in its infancy. In this study, we aimed to tailor the physical and chemical characteristics of indocyanine green using sulfonic acid groups and conjugated fragments, and prepared amino-grafted porous polymers. The resulting material had excellent solvent and thermal stability, and possessed a relatively large pore structure with a size of 3.4 nm. Based on the synergistic effect of electrostatic bonding and π-π interactions, the fluorescent chromogenic agent, indocyanine green, was tightly incorporated into the pore cavity of POP solids through a one-step immersion method. Accordingly, the fluorescent chromogenic POP demonstrated excellent imaging capabilities in biological experiments. This preparation of fluorescent chromogenic porous organic polymer illustrates a promising application of POP-based solids in both fluorescence imaging and biomedicine applications.

A novel ratiometric fluorescent probe for differential detection of HSO3- and ClO- and application in cell imaging and tumor recognition.

By connecting 1,8-naphthalimide and indole sulfonate, a ratio fluorescent probe capable of differential detection of hydrogen sulfite and hypochlorite was synthesized for the first time. It was able to achieve the qualitative detection of HSO3- and ClO- with high sensitivity and selectivity, respectively. It provides a multi-purpose probe and is based on different emission channels without mutual interference. The probe has the advantages of larger Stokes shift (ClO-: 115 nm, HSO3-: 88 nm), longer λem (ClO-: 515 nm, HSO3-: 548 nm) and better water solubility (DMF/PBS = 1:99, v/v). In addition, the probe is a ratio fluorescence probe, which can detect fluorescence intensity with two different emission waves. It provides internal self-calibration, reduces interference from the background and increases detection accuracy. In vitro cytotoxicity and imaging experiments show that the probe can effectively perform the detection of exogenous HSO3- and ClO- in cells. It can also achieve the detection of HSO3- and ClO- in the plasma environment. Because the probe can detect endogenous ClO-, it also has a good prospect for biological application in identifying tumor cells. Graphical abstract.

LncRNA MEG3 inhibits HMEC-1 cells growth, migration and tube formation via sponging miR-147.

Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been identified as a regulatory molecule in angiogenesis. The goal of this study was to illustrate how MEG3 affects the angiogenesis of vascular endothelial cells. Expression of MEG3, miR-147 and intracellular cell adhesion molecule-1 (ICAM-1) in human microvascular endothelial cell line (HMEC-1) was altered by transfection, then cell viability, apoptosis, migration, tube formation, as well as the correlation among MEG3, miR-147 and ICAM-1 were explored. MEG3 was down-regulated during tube formation of HMEC-1 cells. MEG3 expression suppressed cells viability, migration and tube formation, while it induced apoptosis. MEG3 could bind with miR-147 and repress miR-147 expression. MiR-147 induced ICAM-1 expression, and contained ICAM-1 target sequences. The anti-atherogenic actions of MEG3 were inhibited by miR-147, and the anti-atherogenic actions of miR-147 suppression were also inhibited when ICAM-1 was overexpressed. Further, ICAM-1 overexpression showed activated roles in Wnt/ß-catenin and Jak/Stat signaling pathways. In low-density lipoprotein receptor (Ldlr)-/- mice, MEG3 overexpression reduced CD68+, CD3+ and ICAM-1 areas in lesions and increased collagen content. MEG3 inhibited HMEC-1 cell growth, migration and tube formation. The anti-atherogenic actions of MEG3 might be mediated via sponging miR-147, and thereby repressing the expression of ICAM-1.

Water-soluble fluorescent probe for simultaneous detection of cyanide, hypochlorite and bisulfite at different emission wavelengths.

A fluorescent probe that responds at distinct wavelengths upon exposure to cyanide, hypochlorite, and bisulfite was synthesized. As a result, an easy to apply analytical methodology was developed for the detection of these ions. The feasibility of this method was evaluated by theoretical calculations. The probe exhibited excellent solubility in the test solution (H2O: DMF = 99: 1, v: v) with low detection limits for cyanide, hypochlorite and bisulfite (4.5 × 10 -8 M, 4.9 × 10 -7 M and 4.3 × 10 -8 M respectively) showing distinct emission wavelengths for each ion without interference in practical application. Furthermore, the probe had low toxicity and was applied for the imaging experiments of cyanide, hypochlorite and bisulfite in living HeLa and MDCK cells.

Fibrinogen, Neutrophil-to-Lymphocyte Rate and Platelet-to-Neutrophil Rate as Novel Acute Phase Indicators in Patients with Thromboangiitis Obliterans.

BACKGROUND/OBJECTIVES: The acute exacerbations and progressive deterioration seen in thromboangiitis obliterans (TAO) have been related to poor clinical outcomes. Here, we have studied the association of laboratory biomarkers with the acute phase of TAO (AP-TAO). METHODS/RESULTS: We conducted a retrospective case-control study on 112 patients with TAO and 98 healthy controls; comparing the neutrophil-to-lymphocyte rate (NLR), lymphocyte-to-monocyte rate (LMR), platelet-to-neutrophil rate (PNR), fibrinogen (FIB), and apolipoprotein A-I (ApoA-I). Significantly higher NLR level, as well as lower LMR, PNR, and ApoA-I levels were observed in patients with TAO, particularly the acute phase. Significantly increased FIB was only observed in AP-TAO. A positive correlation was found between NLR and with C-reactive protein (CRP) in the acute phase (r = 0.817, P < 0.001). Moreover, NLR, PNR, and FIB levels of 3.38, 45.12, and 3.69 were shown to be the predictive cut-off values for the AP-TAO (sensitivity 72.5, 82,4, and 66,7%, specificity 92.2, 78.4, and 96.1%; area under the curve [AUC] 0.875, 0.855, and 0.872), respectively. The FIB level was independently associated with the AP-TAO (OR = 11.420, P = 0.007). CONCLUSIONS: NLR, PNR, and FIB may be useful markers for the identification of inflammation and the AP-TAO. FIB may be an independent risk factor for the acute phase.

Association between SORL1 polymorphisms and the risk of Alzheimer's disease.

A meta-analysis was performed to identify empirical data assessing the effects of a single nucleotide polymorphisms of sortilin related receptor on Alzheimer's disease based on 14 studies involving 37941 cases and 49727 control studies. Analysis showed, (i) Increased risk between the single nucleotidepolymorphisms (rs641120, rs1010159) and Alzheimer's disease susceptibility inAsian populations, (ii) Single nucleotide polymorphism rs689021 was associatedwith decreased risk in Caucasians, and (iii) Single nucleotide polymorphismrs641120 was detected as a decreased risk in both populations. Given thesedata, crucial evidence is provided to demonstrate that a significantrelationship exists between SORL1 polymorphisms and susceptibility to Alzheimer's disease.

Comparison of Pathogenic Mechanisms Underlying Single and Recurrent Venous Thromboembolism Based on Gene Expression Profiling.

BACKGROUND: Unprovoked venous thromboembolism (VTE), generally divided into single and recurrent categories, is a common leading cause of morbidity and mortality in a real-world population. This study was aimed to explore the similarities and differences in the mechanisms of single and recurrent VTE. METHODS: Gene expression data (GSE19151) generated from 63 healthy controls, 32 single, and 38 recurrent VTE patients were analyzed. Differentially expressed genes (DEGs) were screened by Affy package and Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis were performed using database for annotation, visualization, and integrated discovery. Based on the Search Tool for the Retrieval of Interacting Genes/Proteins database, protein-protein interaction network was visualized by Cytoscape, and modules were identified by CFinder. Finally, transcription factor regulatory networks were constructed. RESULTS: Totally, 559 and 294 DEGs were obtained from recurrent and single VTE, respectively. There were 202 upregulated and 58 downregulated genes overlapped between them. Terms of regulation of actin cytoskeleton enriched by downregulated genes and oxidative phosphorylation enriched by upregulated genes were found in 2 types of VTE. Leukocyte transendothelial migration and Jak-STAT signaling pathway were found related with recurrent VTE. In addition, genes including signal transducer and activator of transcription 3 (STAT3) involving in the Jak-STAT signaling pathway were highly connected nodes. CONCLUSIONS: Actin cytoskeleton and oxidative phosphorylation may be involved in the common mechanisms of recurrent VTE and single VTE. Leukocyte migration and Jak-STAT signaling pathway and their related genes may be important for the development and recurrence of VTE.

Synthesis of oxidant prone nanosilver to develop H2O2 responsive drug delivery system.

Our immune system uses toxicity of hydrogen peroxide to kill off bacterial invaders. In this contribution, we intended to integrate ROS producing capability of immune system with oxidant-sensitive nature of antibacterial silver nanoparticles (Ag NPs) to develop an oxidant drug delivery system. Prior to execute this strategy, we have developed an efficient one-pot synthetic protocol to produce ultrasmall (5 nm), water-stable, and oxidant-prone Ag NPs. Notably, the yield of as-synthesized Ag NPs is 10-fold higher than standard citrate reduction route. The resulting therapeutically active and well-dispersed Ag NPs are used as nanolids to cap the drug loaded nanochannels of porous silica. Upon exposing to H2O2, dissolution-accompanied aggregation of Ag nanolids unleashes the encapsulated therapeutic entities from channels of nanocarrier. Combination of antibacterial and anti-inflammatory drugs in single nanocarriers can potentially augment the effectiveness of various therapies.

Hyaluronic acid modified indocyanine green nanoparticles: a novel targeted strategy for NIR-II fluorescence lymphatic imaging.

The lymphatic system, alongside blood circulation, is crucial for maintaining bodily equilibrium and immune surveillance. Despite its importance, lymphatic imaging techniques lag behind those for blood circulation. Fluorescence imaging, particularly in the near-infrared-II (NIR-II) region, offers promising capabilities with centimeter-scale tissue penetration and micron-scale spatial resolution, sparking interest in visualizing the lymphatic system. Although indocyanine green (ICG) has been approved by the Food and Drug Administration (FDA) for use as a near-infrared-I (NIR-I) region fluorescent dye, its limitations include shallow penetration depth and low signal-to-noise ratio. Research suggests that ICG's fluorescence emission tail in the second near-infrared window holds potential for high-quality NIR-II imaging. However, challenges like short circulation half-life and concentration-dependent aggregation hinder its wider application. Here we developed HA@ICG nanoparticles (NPs), a superior ICG-based NIR-II fluorescent probe with excellent biocompatibility, prolonging in vivo imaging, and enhancing photostability compared to ICG alone. Leveraging LYVE-1, a prominent lymphatic endothelial cell receptor that binds specifically to hyaluronic acid (HA), our nanoprobes exhibit exceptional performance in targeting lymphatic system imaging. Moreover, our findings demonstrate the capability of HA@ICG NPs for capillary imaging, offering a means to assess local microcirculatory blood supply. These compelling results underscore the promising potential of HA@ICG NPs for achieving high-resolution bioimaging of nanomedicines in the NIR-II window.

An innovative fluorescent probe based on dicyanoisoflurone derivatives for differential detection of Hg2+ and Cu2+ and its applications in bacteria, cell imaging and food analysis.

BACKGROUND: Heavy metal pollution has become one of the world's most important environmental pollution, especially Hg2+ is enriched, it is easy to enter the human body through the food chain, bind to the sulfhydryl group in the protein, cause mercury poisoning. Traditional methods for detecting Hg2+ have obvious drawbacks, such as poor selectivity and long detection time. Fluorescence detection has attracted attention because of its good sensitivity and specificity detection ability. In previously reported probes for detecting Hg2+, Cu2+ often interferes. Therefore, it is of great practical significance to synthesize a fluorescent probe that can distinguish between Hg2+ and Cu2+. RESULTS: We have successfully synthesized the probe DFS, a fluorescent probe that can differentially detect Hg2+ and Cu2+, and the probe DFS has good selectivity and anti-interference ability for Hg2+ and Cu2+. The fluorescence intensity at 530 nm increased rapidly when Hg2+ was detected; during the Cu2+ detection, the fluorescence intensity at 636 nm gradually decreased, fluorescence quenching occurred, and the detection limits of Hg2+ and Cu2+ were 7.29 × 10-9 M and 2.13 × 10-9 M, respectively. Through biological experiments, it was found that probe DFS can complete the fluorescence imaging of Hg2+ and Cu2+ in Staphylococcus aureus and HUVEC cells, which has certain research value in the field of environmental monitoring and microbiology, and the probe DFS has low cytotoxicity, so it also has broad application prospects in the field of biological imaging. In addition, the probe DFS also has good applicability for Hg2+ and Cu2+ detection in actual samples. SIGNIFICANCE AND NOVELTY: This is a fluorescent probe that can distinguish between Hg2+ and Cu2+, the fluorescence emission peak appears at 530 nm when Hg2+ is detected; when detecting Cu2+, fluorescence quenching occurs at 636 nm, the fluorescence emission peak distance between Hg2+ and Cu2+ differs by 106 nm. This reduces mutual interference between Hg2+ and Cu2+ during detection, it provides a new idea for the detection of Hg2+ and Cu2+.

An innovative near-infrared fluorescent probe with FRET effect for the continuous detection of Zn2+ and PPi with high sensitivity and selectivity, and its application in bioimaging.

As the second most abundant transition metal element in the human body, zinc ions play an important role in the normal growth and development of the human body. We have successfully synthesized a near-infrared fluorescent probe with FRET effect for the detection of Zn2+. Probe DR6G has good selectivity and anti-interference ability for Zn2+. When Zn2+ is added to the probe DR6G solution, it responds completely within seconds, releasing red fluorescence with a detection limit of 2.02 × 10-8 M. As the main product of ATP hydrolysis, PPi is indispensable in various metabolic activities in cells and the human body. Due to the strong binding ability of Zn2+ and PPi, it is easy to form ZnPPi precipitation, so we added PPi to the solution to complete the Zn2+ detection, and realized the continuous detection of PPi, and the detection limit was 2.06 × 10-8 M. Since Zn2+ and PPi play an important role in vivo, it is of great practical significance to design and synthesize a fluorescent probe that can continuously detect Zn2+ and PPi. Biological experiments have shown that the probe DR6G has low cytotoxicity and can complete the detection of exogenous Zn2+ and PPi in cells and living mice in vitro. Bacterial experiments have shown that the DR6G probe also has certain research value in the field of environmental monitoring and microbiology. Due to the constant variation of the fluorescence signals of Zn2+ and PPi during detection, we designed the logic gate program. In practical applications, the probe DR6G can quantitatively detect Zn2+ in zinc-containing oral liquids and qualitatively detect PPi in toothpaste.

Albumin-based nanoparticle for dual-modality imaging of the lymphatic system.

The lymphatic system is a complex network of lymphatic vessels, lymph nodes, and lymphoid organs. The current understanding of the basic mechanism and framework of the lymphatic system is relatively limited and not ideal for exploring the function of the lymphatic system, diagnosing lymphatic system diseases, and controlling tumor metastasis. Imaging modalities for evaluating lymphatic system diseases mainly include lymphatic angiography, reactive dye lymphatic angiography, radionuclide lymphatic angiography, computed tomography, and ultrasonography. However, these are insufficient for clinical diagnosis. Some novel imaging methods, such as magnetic resonance imaging, positron emission computed tomography, single-photon emission computed tomography, contrast-enhanced ultrasonography, and near-infrared imaging with agents such as cyanine dyes, can reveal lymphatic system information more accurately and in detail. We fabricated an albumin-based fluorescent probe for dual-modality imaging of the lymphatic system. A near-infrared cyanine dye, IR-780, was absorbed into bovine serum albumin (BSA), which was covalently linked to a molecule of diethylenetriaminepentaacetic acid to chelate gadolinium Gd3+. The fabricated IR-780@BSA@Gd3+ nanocomposite demonstrates strong fluorescence and high near-infrared absorption and can be used as a T1 contrast agent for magnetic resonance imaging. In vivo dual-modality fluorescence and magnetic resonance imaging showed that IR-780@BSA@Gd3+ rapidly returned to the heart through the lymphatic circulation after it was injected into the toe webs of mice, facilitating good lymphatic imaging. The successful fabrication of the new IR-780@BSA@Gd3+ nanocomposite will facilitate the study of the mechanism and morphological structure of the lymphatic system.

Stromal cells in the tumor microenvironment: accomplices of tumor progression?

The tumor microenvironment (TME) is made up of cells and extracellular matrix (non-cellular component), and cellular components include cancer cells and non-malignant cells such as immune cells and stromal cells. These three types of cells establish complex signals in the body and further influence tumor genesis, development, metastasis and participate in resistance to anti-tumor therapy. It has attracted scholars to study immune cells in TME due to the significant efficacy of immune checkpoint inhibitors (ICI) and chimeric antigen receptor T (CAR-T) in solid tumors and hematologic tumors. After more than 10 years of efforts, the role of immune cells in TME and the strategy of treating tumors based on immune cells have developed rapidly. Moreover, ICI have been recommended by guidelines as first- or second-line treatment strategies in a variety of tumors. At the same time, stromal cells is another major class of cellular components in TME, which also play a very important role in tumor metabolism, growth, metastasis, immune evasion and treatment resistance. Stromal cells can be recruited from neighboring non-cancerous host stromal cells and can also be formed by transdifferentiation from stromal cells to stromal cells or from tumor cells to stromal cells. Moreover, they participate in tumor genesis, development and drug resistance by secreting various factors and exosomes, participating in tumor angiogenesis and tumor metabolism, regulating the immune response in TME and extracellular matrix. However, with the deepening understanding of stromal cells, people found that stromal cells not only have the effect of promoting tumor but also can inhibit tumor in some cases. In this review, we will introduce the origin of stromal cells in TME as well as the role and specific mechanism of stromal cells in tumorigenesis and tumor development and strategies for treatment of tumors based on stromal cells. We will focus on tumor-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), tumor-associated adipocytes (CAAs), tumor endothelial cells (TECs) and pericytes (PCs) in stromal cells.

PSMA-Targeted Supramolecular Nanoparticles Prepared From Cucurbit[8]uril-Based Ternary Host-Guest Recognition for Prostate Cancer Therapy.

Nanomedicines play an important role in cancer therapy; however, some drawbacks including unsatisfactory efficacy and side effects arising from indiscriminate drug release retard their clinical applications. Although functionalization of nanomedicines through covalent interactions can improve the pharmacokinetics and efficacy of the loaded drugs, complicated and tedious synthesis greatly limits the exploration of multifunctional nanoparticles. Herein, we utilize a supramolecular strategy to design a nanomedicine for targeted drug delivery through cucurbit[8]uril-based host-guest ternary complexation and successfully prepare prostate-specific membrane antigen (PSMA)-targeted supramolecular nanoparticles encapsulating doxorubicin (DOX). In vitro studies exhibit targeted modification via noncovalent enhance anticancer efficiency of DOX due to the increased cell uptake on account of receptor-mediated endocytosis. This design provides a new strategy for the development of sophisticated drug delivery systems and holds perspective potentials in precise cancer treatments.

Preparation of the Biodegradable Lymphatic Targeting Imaging Agent Based on the Indocyanine Green Mesoporous Silicon System.

The lymphatic system plays a crucial role in the immune system's recognition and response to disease. Therefore, the imaging of the lymphatic system, especially lymphatic vessels, has emerged as a valuable tool for the diagnosis of metastasis. FDA-approved small-molecule dyes, namely, indocyanine green (ICG), have been widely applied to lymphatic vessels imaging. However, due to the small physical size, such molecule-based agents show no selectivity, and rapid clearance from lymph nodes. Herein, a biodegradable lymphatic targeting imaging agent based on the ICG-mesoporous silicon system (ICG@HMONs-HA) was obtained, which not only could target lymph vessels but also had a long residence time. The reported work provides a practical way for lymph vessel fluorescence imaging and paves the way for clinical translation of nanomaterial-based tracers.

Visual analysis of global research output of lymphedema based on bibliometrics.

Background: Globally, several generations of doctors in the field of lymphedema have created numerous publications. To date, no bibliometric analysis has been performed specifically on these publications. For the further promotion of research on lymphedema and to align with the international research frontiers, it is essential to understand the current state of Lymphedema research output. Objective: This study aims to statistically and visually analyze the characteristics of publications output, distribution of contributions and development process of lymphedema, enriching the knowledge base of Lymphedema, and then seek potential research topics and collaborators. Methods: Based on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of lymphedema, secondly profiled the publishing groups in terms of country, institution, author's publication and cooperation network, and finally sorted out and summarized the hot topics of research. Results: A total of 8569 papers were retrieved from 1900-2021. The top4 journals with the most publications were LYMPHOLOGY, LYMPHATIC RESEARCH AND BIOLOGY, PLASTIC AND RECONSTRUCTIVE SURGERY and ANNALS OF SURGICAL ONCOLOGY. The top 4 countries with the most publications were USA, Japan, UK, and China. The United States dominates the total number of publications and the international cooperation network. The most productive research institution is Harvard University, and the research institution with the most collaborating institutions is Memorial Sloan Kettering Cancer Center. Mortimer, Peter S contributes the most research in this field. The research achievements of Japanese scholars in this field are of great significance. The top 5 ranked keywords are "Breast Cancer", "Health-Related Quality Of Life", "Lymphscintigraphy", "Lymphovenous Anastomosis", and "Lymphangiogenesis". Conclusion: More and more scholars are devoted to the research of cancer-related Lymphedema. It is foreseeable that breast cancer-related lymphedema and lymphangiogenesis will remain a focus of future research. Advances in Lymphatic vessel imaging and the development of lymphatic microsurgery will further play a role in the clinical workup of lymphedema. Meanwhile, This study can help researchers identify potential collaborators and partner institutions and contribute to further research.