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Nanodiamonds (ND) hold great potential for diverse applications due to their biocompatibility, non-toxicity, and versatile functionalization. Direct visualization of ND by means of non-invasive imaging techniques will open new venues for labeling and tracking, offering unprecedented and unambiguous detection of labeled cells or nanodiamond-based drug carrier systems. The structural defects in diamonds, such as vacancies, can have paramagnetic properties and potentially act as contrast agents in magnetic resonance imaging (MRI). The smallest nanoscale diamond particles, detonation ND, are reported to effectively reduce longitudinal relaxation time T 1 and provide signal enhancement in MRI. Using in vivo, chicken embryos, direct visualization of ND is demonstrated as a bright signal with high contrast to noise ratio. At 24 h following intravascular application marked signal enhancement is noticed in the liver and the kidneys, suggesting uptake by the phagocytic cells of the reticuloendothelial system (RES), and in vivo labeling of these cells. This is confirmed by visualization of nanodiamond-labeled macrophages as positive (bright) signal, in vitro. Macrophage cell labeling is not associated with significant increase in pro-inflammatory cytokines or marked cytotoxicity. These results indicate nanodiamond as a novel gadolinium-free contrast-enhancing agent with potential for cell labeling and tracking and over periods of time., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

While a majority of wireless microrobots have shown multi-responsiveness to implement complex biomedical functions, their functional executions are strongly dependent on the range of stimulus inputs, which curtails their functional diversity. Furthermore, their responsive functions are coupled to each other, which results in the overlap of the task operations. Here, a 3D-printed multifunctional microrobot inspired by pollen grains with three hydrogel components is demonstrated: iron platinum (FePt) nanoparticle-embedded pentaerythritol triacrylate (PETA), poly N-isopropylacrylamide (pNIPAM), and poly N-isopropylacrylamide acrylic acid (pNIPAM-AAc) structures. Each of these structures exhibits their respective targeted functions: responding to magnetic fields for torque-driven surface rolling and steering, exhibiting temperature responsiveness for on-demand surface attachment (anchoring), and pH-responsive cargo release. The versatile multifunctional pollen grain-inspired robots conceptualized here pave the way for various future medical microrobots to improve their projected performance and functional diversity., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Building medical microrobots from the body's own cells may circumvent the biocompatibility concern and hence presents more potential in clinical applications to improve the possibility of escaping from the host defense mechanism. More importantly, live cells can enable therapeutically relevant functions with significantly higher efficiency than synthetic systems. Here, live immune cell-derived microrobots from macrophages, i.e., immunobots, which can be remotely steered with externally applied magnetic fields and directed toward anti-tumorigenic (M1) phenotypes, are presented. Macrophages engulf the engineered magnetic decoy bacteria, composed of 0.5 µm diameter silica Janus particles with one side coated with anisotropic FePt magnetic nanofilm and the other side coated with bacterial lipopolysaccharide (LPS). This study demonstrates the torque-based surface rolling locomotion of the immunobots along assigned trajectories inside blood plasma, over a layer of endothelial cells, and under physiologically relevant flow rates. The immunobots secrete signature M1 cytokines, IL-12 p40, TNF-α, and IL-6, and M1 cell markers, CD80 and iNOS, via toll-like receptor 4 (TLR4)-mediated stimulation with bacterial LPS. The immunobots exhibit anticancer activity against urinary bladder cancer cells. This study further demonstrates such immunobots from freshly isolated primary bone marrow-derived macrophages since patient-derivable macrophages may have a strong clinical potential for future cell therapies in cancer., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)

Microcatheters have enabled diverse minimally invasive endovascular operations and notable health benefits compared with open surgeries. However, with tortuous routes far from the arterial puncture site, the distal vascular regions remain challenging for safe catheter access. Therefore, we propose a wireless stent-shaped magnetic soft robot to be deployed, actively navigated, used for medical functions, and retrieved in the example M4 segment of the middle cerebral artery. We investigate shape-adaptively controlled locomotion in phantoms emulating the physiological conditions here, where the lumen diameter shrinks from 1.5 mm to 1 mm, the radius of curvature of the tortuous lumen gets as small as 3 mm, the lumen bifurcation angle goes up to 120 ° , and the pulsatile flow speed reaches up to 26 cm/s. The robot can also withstand the flow when the magnetic actuation is turned off. These locomotion capabilities are confirmed in porcine arteries ex vivo. Furthermore, variants of the robot could release the tissue plasminogen activator on-demand locally for thrombolysis and function as flow diverters, initiating promising therapies towards acute ischemic stroke, aneurysm, arteriovenous malformation, dural arteriovenous fistulas, and brain tumors. These functions should facilitate the robot's usage in new distal endovascular operations., (© 2022. The Author(s).)

The structural design parameters of a medical microrobot, such as the morphology and surface chemistry, should aim to minimize any physical interactions with the cells of the immune system. However, the same surface-borne design parameters are also critical for the locomotion performance of the microrobots. Understanding the interplay of such parameters targeting high locomotion performance and low immunogenicity at the same time is of paramount importance yet has so far been overlooked. Here, we investigated the interactions of magnetically steerable double-helical microswimmers with mouse macrophage cell lines and splenocytes, freshly harvested from mouse spleens, by systematically changing their helical morphology. We found that the macrophages and splenocytes can recognize and differentially elicit an immune response to helix turn numbers of the microswimmers that otherwise have the same size, bulk physical properties, and surface chemistries. Our findings suggest that the structural optimization of medical microrobots for the locomotion performance and interactions with the immune cells should be considered simultaneously because they are highly entangled and can demand a substantial design compromise from one another. Furthermore, we show that morphology-dependent interactions between macrophages and microswimmers can further present engineering opportunities for biohybrid microrobot designs. We demonstrate immunobots that can combine the steerable mobility of synthetic microswimmers and the immunoregulatory capability of macrophages for potential targeted immunotherapeutic applications., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Nanotoxicology and nanosafety has been a topic of intensive research for about more than 20 years. Nearly 10 000 research papers have been published on the topic, yet there exists a gap in terms of understanding and ways to harmonize nanorisk assessment. In this review, we revisit critically ignored parameters of nanoscale materials (e.g. band gap factor, phase instability and silver leaching problem, defect and instability plasmonic versus inorganic particles) versus their biological counterparts (cell batch-to-batch heterogeneity, biological barrier model design, cellular functional characteristics) which yield variability and nonuniformity in results. We also emphasize system biology approaches to integrate the high throughput screening methods coupled with in vivo and in silico modeling to ensure quality in nanosafety research. We emphasize and highlight the recommendation regarding bridging the mechanistic gaps in fundamental research and predictive biological response in nanotoxicology. The research community has to develop visions to predict the unforeseen problems that do not exist yet in context with nanotoxicity and public health hazards due to the burgeoning use of nanomaterial in consumer's product.

Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog 177 Lu-DOTA-PP-F11N ( 177 Lu-DOTA-(dGlu) 6 -Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH 2 ) performs better than reference analogs with varying in vivo stability, namely 177 Lu-DOTA-MG11 ( 177 Lu-DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ) and 177 Lu-DOTA-PP-F11 ( 177 Lu-DOTA-(dGlu) 6 -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ), and whether the use of protease inhibitors further improves CCKR2 targeting. First human data on 177 Lu-DOTA-PP-F11N are also reported. Methods: In vitro stability of all analogs was assessed against a panel of extra- and intracellular endoproteases, whereas their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon and thiorphan was assessed 4 h after injection in MZ-CRC-1 and A431-CCK2R(+) dual xenografts. Autoradiography of 177 Lu-DOTA-PP-F11N (without and with phosphoramidon) and NanoSPECT/CT were performed. SPECT/CT images of 177 Lu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. Results: nat Lu-DOTA-PP-F11N is less of a substrate for neprilysins than the other analogs, whereas intracellular cysteine proteases, such as cathepsin-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors than in A431-CCK2R(+), apparently because of the higher number of binding sites on MZ-CRC-1 cells. 177 Lu-DOTA-PP-F11N had the same biodistribution as 177 Lu-DOTA-PP-F11; however, uptake in the MZ-CRC-1 tumors was almost double (20.7 ± 1.71 vs. 11.2 ± 2.94 %IA [percentage injected activity]/g, P = 0.0002). Coadministration of phosphoramidon or thiorphan increases 177 Lu-DOTA-MG11 uptake significantly in the CCK2R(+) tumors and stomach. Less profound was the effect on 177 Lu-DOTA-PP-F11, whereas no influence or even reduction was observed for 177 Lu-DOTA-PP-F11N (20.7 ± 1.71 vs. 15.6 ± 3.80 [with phosphoramidon] %IA/g, P < 0.05 in MZ-CRC-1 tumors). The first clinical data show high 177 Lu-DOTA-PP-F11N accumulation in tumors, stomach, kidneys, and colon. Conclusion: The performance of 177 Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance of 177 Lu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight the stomach as a potential dose-limiting organ besides the kidneys., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Here, we describe immuno-Cerenkov luminescence imaging (immuno-CLI) with a specific monoclonal antibody-based tracer for the detection of prostate tumors, which is used in preclinical positron emission tomography (PET) imaging. As PET isotopes generate a continuous spectrum of light in the ultraviolet/visible (UV/vis) wavelength range (Cerenkov luminescence, CL) in dielectric materials and consequently inside living tissues, these isotopes can also be detected by luminescence imaging performed with optical imaging (OI) systems. Imaging tumors with tracers that are specifically binding to a tumor-associated antigen can increase diagnostic accuracy, enables monitoring of treatment efficacy, and can be advantageous compared to radiolabeled small molecules used in PET-oncology such as 2-deoxy-2-[ 18 F]-fluoro-D-glucose ([ 18 F]FDG; glucose metabolism) or [ 11 C]choline (membrane synthesis) which was used to image prostate cancer. In this study, we compared on three consecutive days immuno-CLI and -PET of the applied 64 Cu-labeled and well described monoclonal antibody 3/F11 in prostate-specific membrane antigen (PSMA)-positive (C4-2, PSMA + ) and -negative (DU 145, PSMA - ) prostate tumor xenografts, inoculated in SCID mice. In vivo immuno-CLI and -PET measurements demonstrated linear correlation of both modalities, in line with ex vivo analysis performed with CLI and γ-counting. As CLI is also able to trace radioisotopes used for theranostic approaches, immuno-CLI could be an interesting, low-cost imaging alternative to immuno-PET., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The human commensal yeast Candida is the fourth most common cause of hospital-acquired bloodstream infections, with Candida albicans accounting for the majority of the >400,000 life-threatening infections annually. Diagnosis of invasive candidiasis (IC), a disease encompassing candidemia (blood-borne yeast infection) and deep-seated organ infections, is a major challenge since clinical manifestations of the disease are indistinguishable from viral, bacterial and other fungal diseases, and diagnostic tests for biomarkers in the bloodstream such as PCR, ELISA, and pan-fungal β-D-glucan lack either standardization, sensitivity, or specificity. Blood culture remains the gold standard for diagnosis, but test sensitivity is poor and turn-around time slow. Furthermore, cultures can only be obtained when the yeast resides in the bloodstream, with samples recovered from hematogenous infections often yielding negative results. Consequently, there is a pressing need for a diagnostic test that allows the identification of metastatic foci in deep-seated Candida infections, without the need for invasive biopsy. Here, we report the development of a highly specific mouse IgG3 monoclonal antibody (MC3) that binds to a putative β-1,2-mannan epitope present in high molecular weight mannoproteins and phospholipomannans on the surface of yeast and hyphal morphotypes of C. albicans , and its use as a [ 64 Cu]NODAGA-labeled tracer for whole-body pre-clinical imaging of deep-seated C. albicans infections using antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI). When used in a mouse intravenous (i.v.) challenge model that faithfully mimics disseminated C. albicans infections in humans, the [ 64 Cu]NODAGA-MC3 tracer accurately detects infections of the kidney, the principal site of blood-borne candidiasis in this model. Using a strain of the emerging human pathogen Candida auris that reacts with MC3 in vitro , but which is non-infective in i.v. challenged mice, we demonstrate the accuracy of the tracer in diagnosing invasive infections in vivo . This pre-clinical study demonstrates the principle of using antibody-guided molecular imaging for detection of deep organ infections in IC, without the need for invasive tissue biopsy.

Cytostatic drugs used in cancer therapy were evaluated for their capacity to inhibit Echinococcus multilocularis metacestode growth and proliferation. Metacestode tissues were exposed in vitro to docetaxel, doxorubicin, navelbine, paclitaxel, and vorinostat for 1 week, then incubated in drug-free culture, and thereafter metacestodes were injected into the peritoneum of Meriones unguiculatus . Magnetic resonance imaging (MRI) and simultaneous positron emission tomography (PET) were applied to monitor in vivo growth of drug-exposed E. multilocularis in Meriones . At 3 month p.i., docetaxel (at 10 μM, 5 μM and 2 μM) inhibited in vivo growth and proliferation of E. multilocularis , and at 5 months p.i., only in the 2 μM docetaxel exposure group 0.3 cm 3 of parasite tissue was found. With paclitaxel and navelbine the in vivo growth of metacestodes was suppressed until 3 months p.i., thereafter, parasite tissues enlarged up to 3 cm 3 in both groups. E. multilocularis tissues of more than 10 g developed in Meriones injected with metacestodes which were previously exposed in vitro to doxorubicin, navelbine, paclitaxel or vorinostat. In Meriones infected with metacestodes previously exposed to docetaxel, the in vivo grown parasite tissues weighted 0.2 g. In vitro cultured E. multilocularis metacestodes exposed to docetaxel did not produce vesicles until 7 weeks post drug exposure, while metacestodes exposed to doxorubicin, navelbine and vorinostat proliferated continuously. In summary, docetaxel, and less efficaciously paclitaxel, inhibited in vivo and in vitro parasite growth and proliferation, and these observations suggest further experimental studies with selected drug combinations which may translate into new treatment options against alveolar echinococcosis., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.

Cyclophilin A (CyPA) is involved in the pathophysiology of several inflammatory and cardiovascular diseases. To our knowledge, there is no specific inhibitor targeting extracellular CyPA without affecting other extracellular cyclophilins or intracellular CyPA functions. In this study, we developed an antibody-based inhibitor of extracellular CyPA and analysed its effects in vitro and in vivo . To generate a specific antibody, mice and rats were immunized with a peptide containing the extracellular matrix metalloproteinase inducer binding site and various antibody clones were selected and purified. At first, antibodies were tested for their binding capacity to recombinant CyPA and their functional activity. The clone 8H7-mAb was chosen for further experiments. 8H7-mAb reduced the CyPA-induced migration of inflammatory cells in vitro and in vivo . Furthermore, 8H7-mAb revealed strong antithrombotic effects by inhibiting CyPA-dependent activation of platelets and thrombus formation in vitro and in vivo . Surprisingly, 8H7-mAb did not influence in vivo tail bleeding time or in vitro whole blood coagulation parameters. Our study provides first evidence that antibody-based inhibition of extracellular CyPA inhibits thrombosis and thromboinflammation without affecting blood homeostasis. Thus, 8H7-mAb may be a promising compound for thrombi modulation in inflammatory diseases to prevent organ dysfunction., Competing Interests: Disclosure: None., (Schattauer GmbH Stuttgart.)

The clinical selection of volunteers for blood donation is essential to reduce the risk of viral transmission by blood transfusion. The aim of this study was to evaluate a new questionnaire for a pre-donation medical interview. This questionnaire was developed by transfusion practitioners, epidemiologists and professional investigators, and focused on risk behaviors of blood donors and their partners. Five blood banks in the French Ile-de-France region (around Paris), participated in the study from May 1995 to January 1996. All participating doctors were specifically trained by professional investigators. The sex and the age of donors, the type of collection, the duration of interviews and the reasons for exclusion from donation were recorded. The results were compared to those of a prior study dealing with a sample of 15,000 donors presenting the same characteristics, whose blood was taken of at the same collection sites in 1993. Of the 1,527 volunteers donating blood, 14% were interviewed in fixed centers and 86% by moving teams (38% in firms, 22% in towns, 13% in civil service facilities, 13% in school or academic centers). For 15.9% of the volunteers, this was the first donation (range: 7.3% in fixed centers to 41.5% in school and academic centers). The mean duration of the interview was 11 min (10 min for volunteers included, 14 min for donors excluded from donation). It decreased from 14 min at the beginning of the study to 10 min by the end of the study. The percentage of donors excluded for risk behavior (3.7% in 1995-96 vs 1.5% in 1993, P < 0.001), or medical reasons (12.2% in 1995-96 vs 8.4%, in 1993, P < 0.001) was significantly greater in 1995-96 than in 1993 (15.9% vs 9.9%, P < 0.001). In 1995-96, 35.0% of exclusions for risk behavior were related to male homosexuality, multiple partners or the risk behavior of the partner vs 12% in 1993 (P < 0.001). The risk of exclusion was 5.5 times higher for donors not living in a couple. The results obtained demonstrated the value of this new approach to the medical interview.

The prevalence of different hepatitis C virus (HCV) genotypes in HCV infected individuals and the relation between the HCV genotypes and the source of the infection are controversial. The aim of this study was to determine the HCV genotypes in French blood donors. Fifty-one anti-HCV positive blood donors were studied with detectable serum HCV RNA by nested polymerase chain reaction (PCR) using primers derived from the 5' non-coding region. For genotyping HCV, we used a method based on analysis of the restriction fragment length polymorphisms (RFLP) after amplification by PCR of the HCV non-structural 5 (NS5) genome domain. Using this technique, the genotypes of 39 of the 51 blood donors (76%) were determined. Three previously described genotypes were found: 19 blood donors were infected by HCV genotype I (37%), 14 were infected by HCV genotype II (27%), 3 were infected by HCV genotype III (6%), and 3 were coinfected by two genotypes (6%). All three blood donors infected with two different genotypes were intravenous drug abusers. A past history of intravenous drug abuse was more frequent in blood donors with HCV genotype I. However, there was no difference in alanine transaminase (ALT) levels, histological lesions, and RIBA-2 patterns in blood donors infected with either HCV genotype I or HCV genotype II. These findings indicate that most HCV genotypes isolated from French blood donors belong to HCV genotype I and HCV genotype II, and that risk factors for HCV infection may differ for different genotypes of HCV.

The detection of serum HCV-RNA needs to be standardized. The aim of this study was to assess the effectiveness of the branched DNA amplification method in detecting and quantitating serum HCV-RNA in 54 blood donors, 33 with and 21 without increased serum alanine aminotransferase levels and with detectable serum HCV-RNA by polymerase chain reaction. HCV-RNA was detected by branched DNA signal amplification in 42/54 (77%) of the blood donors. Positivity rates were not different among the 21 blood donors with normal and the 33 blood donors with increased serum alanine aminotransferase levels (86% and 76%, respectively). Median serum HCV-RNA levels were not different among donors with or without increased serum alanine aminotransferase levels (28.6 x 10(5) Eq/ml and 14.7 x 10(5) Eq/ml, respectively). There was no significant correlation between serum alanine aminotransferase levels and serum HCV-RNA levels. These findings show that branched DNA signal amplification identifies most of the donors with true hepatitis C virus viremia and that the level of hepatitis C virus replication is not correlated to serum alanine aminotransferase levels.

We describe the case of a 39-year-old man who was accidentally shot in the back by a rivet gun. This resulted in paraplegia and partial sensory loss. Magnetic resonance imaging (MRI) was helpful in the accurate localization of the foreign body and in the assessment of the spinal cord damage. MRI enabled accurate pre-operative localization of the rivet and provided information on the degree of damage to the spinal cord. The artefact produced on computed tomography plus the limited anatomical detail of the spinal cord in the absence of intrathecal contrast makes this technique unhelpful.

Three patients are described who were selected for stereotactic thalamotomy to alleviate the tremor and rigidity of Parkinson's disease but in whom these symptoms were abolished whilst attempting ventriculography. Discrete deep brain lesions were seen on post-operative CT scan and the basis for their relieving the patients' symptoms is discussed. Although the tremor and rigidity was abolished in these cases and a favourable result ensued, ventriculography is an invasive and potentially dangerous procedure and it is therefore recommended that CT-derived thalamic targets should be employed for functional stereotaxy.

The recent expansion in CT guided stereotactic biopsy has revealed deficiencies in biopsy instrumentation. In view of this, the authors have developed a versatile side-cutting cannula which has been used successfully in over eighty stereotactic biopsies as well as for the drainage of deep seated abscesses.

Two hundred consecutive stereotactic procedures were performed. These were 153 biopsies and 43 therapeutic procedures. The latter included aspiration of craniopharyngiomata, arachnoid cysts, deep-seated abscesses, and the destruction of colloid cysts. Cryogenesis was used to treat an arteriovenious malformation (AVM) in one case. In four cases, the system was used to locate lesions during open surgery. Leksell stereotactic systems were used throughout. The ages of the patients ranged between 12 months and 83 years. Overall, in 35% of biopsies the preoperative diagnosis was not confirmed. When the provisional diagnosis was glioma 70% were confirmed; 21% of them were benign, with 9% some other form of malignancy. Biopsy provided tissue on which a histological diagnosis could be made in 140 procedures. In eight cases the biopsy was repeated and in seven cases a positive diagnosis was subsequently made. Mortality was 1%; there was transient deterioration postoperatively in 5% and prolonged deterioration in 1%. These observations suggest that stereotactic surgery is far superior to freehand burr hole biopsy in the management of these lesions. No radiation treatment should be considered without histological confirmation.

A 31-year-old male presented with a 1 year history of left leg weakness and right leg sensory changes. Myelography revealed a probable intramedullary lesion at T4 and CT confirmed its intramedullary nature. At operation an almost black, firm mass was found projecting from the dorsal aspect of the cord and was totally excised. Histological examination revealed it to be a cavernous angioma.

Platelet functions studied in 163 unselected diabetics compared with 163 controls had the following characteristics: hyperagregation induced by ADP (1.2 muM and 0.6 muM), delayed platelet disagregation (ADP: 0.6 muM), normal agregation in the presence of collagen and thrombin. Platelet hyperagregation induced by ADP was marked in both sexes in cases of retinopathy and in women after the age of 50. By contrast, no correlation was demonstrated between the degree of hyperagregation and age, weight, the duration of diabetes, blood glucose control, lipid profile, vascular complications other than retinopathy and the nature of treatment.