Rutin-coated ultrasmall manganese oxide nanoparticles for targeted magnetic resonance imaging and photothermal therapy of malignant tumors.

Manganese oxide nanoparticles (MONs)-based contrast agents have attracted increasing attention for magnetic resonance imaging (MRI), attributed to their good biocompatibility and advantageous paramagnetism. However, conventional MONs have poor imaging performance due to low T1 relaxivity. Additionally, their lack of tumor-targeting theranostics capabilities and complex synthesis pathways have impeded clinical applications. Rutin (Ru) is an ideal tumor-targeted ligand that targets glucose transporters (GLUTs) overexpressed in various malignant tumors, and exhibits photothermal effects upon chelation with metal ions. Herein, a series of Ru-coated MONs (Ru/MnO2) were synthesized using a straightforward, rapid one-step process. Specifically, Ru/MnO2-5, with the smallest crystal size of approximately 4 nm, exhibits the highest T1 relaxivity (33.3 mM-1s-1 at 1.5 T, surpassing prior MONs) along with notable stability, photothermal efficacy, and tumor-targeting ability. Furthermore, Ru/MnO2-5 shows promise in MRI and photothermal therapy of H22 tumors owing to its superior GLUTs-mediated tumor-targeting capability.

Porphyrin-Based Self-Assembled Nanoparticles for PET/MR Imaging of Sentinel Lymph Node Metastasis.

Diagnosing of lymph node metastasis is challenging sometimes, and multimodal imaging offers a promising method to improve the accuracy. This work developed porphyrin-based nanoparticles (68Ga-F127-TAPP/TCPP(Mn) NPs) as PET/MR dual-modal probes for lymph node metastasis imaging by a simple self-assembly method. Compared with F127-TCPP(Mn) NPs, F127-TAPP/TCPP(Mn) NPs synthesized by amino-porphyrins (TAPP) doping can not only construct PET/MR bimodal probes but also improve the T1 relaxivity (up to 456%). Moreover, T1 relaxivity can be adjusted by altering the molar ratio of TAPP/TCPP(Mn) and the concentration of F127. However, a similar increase in T1 relaxivity was not observed in the F127-TCPP/TCPP(Mn) NPs, which were synthesized using carboxy-porphyrins (TCPP) doping. In a breast cancer lymph node metastasis mice model, subcutaneous injection of 68Ga-F127-TAPP/TCPP(Mn) NPs through the hind foot pad, the normal lymph nodes and metastatic lymph nodes were successfully distinguished based on the difference of PET standard uptake values and MR signal intensities. Furthermore, the dark brown F127-TAPP/TCPP(Mn) NPs demonstrated the potential for staining and mapping lymph nodes. This study provides valuable insights into developing and applying PET/MR probes for lymph node metastasis imaging.

Facile Synthesis of Rigid Binuclear Manganese Complexes for Magnetic Resonance Angiography and SLC39A14-Mediated Hepatic Imaging.

Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn2-PhDTA2) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn2-TPA-PhDTA2) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn2-PhDTA2 is lower than that of Mn2-TPA-PhDTA2, their T1 relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn2-PhDTA2 was slightly lower than that of Mn2-TPA-PhDTA2, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn2-PhDTA2 has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature 17O NMR study, both Mn-PhDTA and Mn2-PhDTA2 demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn2-PhDTA2 demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn2-PhDTA2 mediated by SLC39A14 was validated in cellular uptake studies.

Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging.

Effective vascular and hepatic enhancement and better safety are the key drivers for exploring gadolinium-free hepatobiliary contrast agents. Herein, a facile strategy proposes that the high lipophilicity may be favorable to enhancing sequentially vascular and hepatobiliary signal intensity based on the structure-activity relationship that both hepatic uptake and interaction with serum albumins partly depend on lipophilicity. Therefore, 11 newly synthesized derivatives of manganese o-phenylenediamine-N,N,N',N'-tetraacetic acid (MnLs) were evaluated as vascular and hepatobiliary agents. The maximum signal intensities of the heart, liver, and kidneys were strongly correlated with log P, a key indicator of lipophilicity. The most lipophilic agent, MnL6, showed favorable relaxivity when binding with serum albumin, good vascular enhancement, rapid excretion, and reliable hepatobiliary phases comparable to a classic hepatobiliary agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for in vivo liver tumor imaging. Inhibition experiments confirmed the hepatic targeting of MnL6 is mediated by organic anion-transporting polypeptides.

Relaxivity Enhancement of Hybrid Micelles via Modulation of Water Coordination Numbers for Magnetic Resonance Lymphography.

Considerable efforts have been made to develop nanoparticle-based magnetic resonance contrast agents (CAs) with high relaxivity. The prolonged rotational correlation time (τR) induced relaxivity enhancement is commonly recognized, while the effect of the water coordination numbers (q) on the relaxivity of nanoparticle-based CAs gets less attention. Herein, we first investigated the relationship between T1 relaxivity (r1) and q in manganese-based hybrid micellar CAs and proposed a strategy to enhance the relaxivity by increasing q. Hybrid micelles with different ratios of amphiphilic manganese complex (MnL) and DSPE-PEG2000 were prepared, whose q values were evaluated by Oxygen-17-NMR spectroscopy. Micelles with lower manganese doping density exhibit increased q and enhanced relaxivity, corroborating the conception. In vivo sentinel lymph node (SLN) imaging demonstrates that DSPE-PEG/MnL micelles could differentiate metastatic SLN from inflammatory LN. Our strategy makes it feasible for relaxivity enhancement by modulating q, providing new approaches for the structural design of high-performance hybrid micellar CAs.

Ultra-small superparamagnetic iron oxide nanoparticles for intra-articular targeting of cartilage in early osteoarthritis.

Early diagnosis of osteoarthritis (OA) is critical for effective cartilage repair. However, lack of blood vessels in articular cartilage poses a barrier to contrast agent delivery and subsequent diagnostic imaging. To address this challenge, we proposed to develop ultra-small superparamagnetic iron oxide nanoparticles (SPIONs, 4 nm) that can penetrate into the matrix of articular cartilage, and further modified with the peptide ligand WYRGRL (particle size, 5.9 nm), which allows SPIONs to bind to type II collagen in the cartilage matrix and increase the retention of probes. Type II collagen in the cartilage matrix is gradually lost with the progression of OA, consequently, the binding of peptide-modified ultra-small SPIONs to type II collagen in the OA cartilage matrix is less, thus presenting different magnetic resonance (MR) signals in OA group from the normal ones. By introducing the AND logical operation, damaged cartilage can be differentiated from the surrounding normal tissue on T1 and T2 AND logical map of MR images, and this was also verified in histology studies. Overall, this work provides an effective strategy for delivering nanosized imaging agents to articular cartilage, which could potentially be used to diagnosis joint-related diseases such as osteoarthritis.

Kinetically inert manganese (II)-based hybrid micellar complexes for magnetic resonance imaging of lymph node metastasis.

The localization and differential diagnosis of the sentinel lymph nodes (SLNs) are particularly important for tumor staging, surgical planning and prognosis. In this work, kinetically inert manganese (II)-based hybrid micellar complexes (MnCs) for magnetic resonance imaging (MRI) were developed using an amphiphilic manganese-based chelate (C18-PhDTA-Mn) with reliable kinetic stability and self-assembled with a series of amphiphilic PEG-C18 polymers of different molecular weights (C18En, n = 10, 20, 50). Among them, the probes composed by 1:10 mass ratio of manganese chelate/C18En had slightly different hydrodynamic particle sizes with similar surface charges as well as considerable relaxivities (∼13 mM-1 s-1 at 1.5 T). In vivo lymph node imaging in mice revealed that the MnC MnC-20 formed by C18E20 with C18-PhDTA-Mn at a hydrodynamic particle size of 5.5 nm had significant signal intensity brightening effect and shortened T1 relaxation time. At an imaging probe dosage of 125 µg Mn/kg, lymph nodes still had significant signal enhancement in 2 h, while there is no obvious signal intensity alteration in non-lymphoid regions. In 4T1 tumor metastatic mice model, SLNs showed less signal enhancement and smaller T1 relaxation time variation at 30 min post-injection, when compared with normal lymph nodes. This was favorable to differentiate normal lymph nodes from SLN under a 3.0-T clinical MRI scanner. In conclusion, the strategy of developing manganese-based MR nanoprobes was useful in lymph node imaging.

Ultra-small manganese dioxide nanoparticles with high T1 relaxivity for magnetic resonance angiography.

Gadolinium (Gd)-based contrast agents (CAs) for clinical magnetic resonance imaging are facing the problems of low longitudinal relaxivity (r1) and toxicity caused by gadolinium deposition. Manganese-based small molecule complexes and manganese oxide nanoparticles (MONs) are considered as potential alternatives to Gd-based CAs due to their better biocompatibility, but their relatively low r1 values and complicated synthesis routes slow down their clinical translation. Herein, we presented a facile one-step co-precipitation method to prepare MONs using poly(acrylic acid) (PAA) as a coating agent (MnO2/PAA NPs), which exhibited good biocompatibility and high r1 values. A series of MnO2/PAA NPs with different particle sizes were prepared and the relationship between the particle size and r1 was studied, revealing that the MnO2/PAA NPs with a particle size of 4.9 nm exhibited higher r1. The finally obtained MnO2/PAA NPs had a high r1 value (29.0 Mn mM-1 s-1) and a low r2/r1 ratio (1.8) at 1.5 T, resulting in a strong T1 contrast enhancement. In vivo magnetic resonance angiography with Sprague-Dawley (SD) rats further proved that the MnO2/PAA NPs showed better angiographic performance at low-dosage administration than commercial Gadovist® (Gd-DO3A-Butrol). Moreover, the MnO2/PAA NPs could be rapidly cleared out after imaging, which effectively minimized the toxic side effects. The MnO2/PAA NPs are promising candidates for MR imaging of vascular diseases.

Collagen-based injectable and self-healing hydrogel with multifunction for regenerative repairment of infected wounds.

At present, the development trend of dressing materials is being multifunctional for convenient and long-term nursing care process of some complicated wounds. Here, basing on the theory of wound moist healing, an injectable and self-healing hydrogel comprising of collagen (COL), chitosan (CS) and oxidation modified Konjac glucomannan (OKGM), which acts as a macromolecular cross-linker to construct dynamic Schiff-base bonds was smartly designed. The strategy of introducing the silver nanoparticles (Ag NPs) into the COL-CS-OKGM hydrogel matrix achieved a markedly enhanced antibacterial activity derived from the synergistical effect between the Ag+ and the mild photothermal efficacy of Ag NPs, which also improved the local capillary blood circulation of the wound area to further facilitate wound healing process. The excellent syringeability and self-healing behaviors endowed the COL-CS-OKGM-Ag hydrogel with self-adapting ability for the wounds with irregular and large area needing frequent applying and changing without secondary injuries. In vitro and in vivo evaluations verified that so-designed COL-CS-OKGM-Ag hydrogel also with hemostatic performance is a promising multifunctional dressing for the treatments of infected wound with not only good biocompatibility and convenient use, but also with desired regenerative healing prognoses benefited from hydrogel moist environment and physiotherapy.

Multi-feature Fusion and Damage Identification of Large Generator Stator Insulation Based on Lamb Wave Detection and SVM Method.

Due to the merits of Lamb wave to Structural Health Monitoring (SHM) of composite, the Lamb wave-based damage detection and identification technology show a potential solution for the insulation condition evaluation of large generator stator. This was performed in order to overcome the problem that it is difficult to effectively identify the stator insulation damage the using single feature of Lamb wave. In this paper, a damage identification method of stator insulation based on Lamb wave multi-feature fusion is presented. Firstly, the different damage features were extracted from time domain, frequency domain, and fractal dimension of lamb wave signals, respectively. The features of Lamb wave signals were extracted by Hilbert transform (HT), power spectral density (PSD), fast Fourier transform (FFT), and wavelet fractal dimension (WFD). Then, a machine learning method based on support vector machine (SVM) was used to fuse and reconstruct the multi-features of Lamb wave and furtherly identify damage type of stator insulation. Finally, the effect of typical stator insulation damage identification is verified by simulation and experiment.

Effect of Hydroxyapatite Surface on BMP-2 Biological Properties by Docking and Molecular Simulation Approaches.

The interactions between osteogenic proteins and the biomaterial surface are crucial to the application of biomaterials, in which the conformational or orientational change of the adsorbed protein on the solid surfaces is one of the most important interactions other than the protein adsorption. Although some progress has been made in the mechanism of protein adsorption on the surface of hydroxyapatite (HAP) in recent years, there is still insufficient atomistic/molecular information about the conformation and orientation of proteins upon adsorbing on solid surfaces. In this study, different orientations and conformations of bone morphological protein-2 (BMP-2) adsorbed on the surface of HAP were calculated through the protein-solid surface docking approach; the relationship between optimal adsorption and biological activity of BMP-2 was investigated by applying a combination of molecular dynamic simulation (MD) and steered molecular dynamic simulation (SMD). Two optimal adsorption conformers were screened out according to the docking results on the basis of orientations of BMP-2 with different epitopes. Subsequent MD and SMD results showed that the knuckle epitope of BMP-2 was easier to adsorb on the surface of HAP(100) than the wrist epitope accompanying certain conformational changes. Such an absorption mode led to the wrist epitope of BMP-2 being exposed to the environment and then being identified/interacted with type I receptors on the stem cell membrane, which further induces the differentiation of stem cells into osteoblasts. Current simulation provided a theoretical high-throughput screening method for the protein-biomaterial adsorption states. It can be extended to more research on different protein adsorptions on the surface of different materials. The simulation results provided more information at the molecular and atomic levels to further interpret the mechanism of osteoinductivity from the perspective of growth factor adsorption. Meanwhile, we believe that it should be a meaningful attempt to screen biomaterial key factors by the high-throughput method, which might become a promising way to develop or optimize new biomaterials.

[Clinical analysis on arthroscopic debridement for the treatment of early infection after total knee replacement].

OBJECTIVE: To compare the clinical effects of arthroscopic debridement versus open debridement on controlling and treatment of infection after total knee replacement. METHODS: From October 2009 to September 2016 in three hospitals, 11 patients with 11 joints which were infected after total knee replacement were randomly divided into two groups:5 cases in arthroscopy group and 6 cases in routine group. Patients in arthroscopy group were treated with arthroscopic debridement to remove the necrotic tissues, then closed-type irrigation with sensitive antibiotics by using two sebific ducts were performed continuously for 2 or 3 weeks until the flushing fluid became clear for 3 or 5 days;other 6 patients in routine group were treated with open surgical debridement and the following procedures in keeping with those in the arthroscopy group. Operation time, blood loss and incision length were recorded during the operation, and pain scores were recorded on the 1st, 3rd and 7th day after the operation. The curative effects were evaluated according to the Hospital for Special Surgery score system. RESULTS: The local and general symptoms of the 11 patients disappeared, and the test outcomes of biochemistry, blood and synovial fluid were normal. All patients were followed up, and the duration ranged from 6 to 18 months. Infection recurrences were observed in 1 case of arthroscopy group and 2 cases of routine group 3 months later after operation, and all these patients who underwent the second time operation with arthroscopic debridement were cured. According to the Hospital for Special Surgery score system, 3 cases obtained excellent result, 2 good, no poor and bad cases in arthroscopy group;3 cases obtained excellent result, 1 good, 1 poor and 1 bad in routine group. CONCLUSIONS: If the sensitive antibiotics can be found for the infected joints without obvious destruction of bone and no prosthesis loosening, it has a better therapeutic effect by using arthroscopic debridement combined with continuous drainage and irrigation. The method has a better curative effect with smaller trauma.

[A retrospective study of Schatzker III tibial plateau--fracture using minimally invasive fixation and bone grafting through medial side].

OBJECTIVE: To investigate clinical effects of minimally invasive fixation and bone grafting througn medial side for the treatment of Schatzker III tibial plateau fracture. METHODS: From April 2009 to August 2011, 18 patients with Schatzker III tibial plateau fracture were treated with minimally invasive fixation and bone grafting through medial side. There were 15 males and 3 females ranging in age from 64 to 73 years, with an average of (69.75 ± 1.22) years. Sixteen patients were caused by falling down, 2 cases were caused by traffic accident. Operative time and length of incision were be recorded. Clinical and radiological follow-up was performed after operation. Hospital for Special Surgery (HSS) score and Kellgren-Lawrence score were used to evaluate clinical effects. RESULTS: The mean operative time was (45.32 ± 1.58) min, and the mean length of incision was (5.21 ± 0.65) cm. Postoperative X-ray showed excellent reduction. Eighteen patients were followed up for 10 to 13 months with an average of (11.5 ± 1.35) months. The mean HSS score was 86.51 ± 2.71, 12 cases got excellent results,4 good and 2 fair. Three patients were developed mild osteoarthritis according to the Kellgren-Lawrence system. CONCLUSION: Minimally invasive fixation and bone grafting through medial side, not only could reduce surgical invasive, but also guarantee early function activities. It has advantages of keeping well after reduction. So it has the favorable future in clinic.