This phase I clinical trial evaluated the safety and clinical efficacy of adipose‐derived stromal cells (ASCs) in osteoarthritis. Eighteen patients with severe knee osteoarthritis were treated with a single intra‐articular injection of autologous ASCs at low (2 × 106 cells), medium (10 × 106), or high (50 × 106) doses (n = 6 each). After 6 months, no serious adverse events were reported, and patients treated with low‐dose ASCs significantly improved in pain and function.

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Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intra-myocardial injection of BMCs from distinct donor individuals that are healthy, unlike autologous BMCs used for clinical trials that are from post-MI individuals. Using BMCs from post-MI donor mice, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to post-MI donor mice prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments, and suggest potential strategies to improve the success of clinical autologous BMC therapy.

BackgroundDuring the last years, 19F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent based MRI methodology to track cells and to visualize inflammation. We applied this new modality to visualize deep tissue abscesses during acute and chronic phase of inflammation caused by Staphylococcus aureus infection.Methodology and Principal FindingsIn this study, a murine thigh infection model was used to induce abscess formation and PFC or CLIO (cross linked ironoxides) was administered during acute or chronic phase of inflammation. 24 h after inoculation, the contrast agent accumulation was imaged at the site of infection by MRI. Measurements revealed a strong accumulation of PFC at the abscess rim at acute and chronic phase of infection. The pattern was similar to CLIO accumulation at chronic phase and formed a hollow sphere around the edema area. Histology revealed strong influx of neutrophils at the site of infection and to a smaller extend macrophages during acute phase and strong influx of macrophages at chronic phase of inflammation.Conclusion and SignificanceWe introduce 19F-MRI in combination with PFC nanoemulsions as a new platform to visualize abscess formation in a murine thigh infection model of S. aureus. The possibility to track immune cells in vivo by this modality offers new opportunities to investigate host immune response, the efficacy of antibacterial therapies and the influence of virulence factors for pathogenesis.

Marking and identification of materials is becoming increasingly important due to complex global resource and supply chains. Luminescent particle‐based markers have come to the forefront due to their small dimensions and their ability to be integrated in diverse materials. However, light‐absorbing materials can hardly be marked by these particles, thus leading to insufficient recycling rates of, e.g., black plastics. In this work, microparticles with a unique magnetic fingerprint are tailored by modification of their nanoparticle building blocks. This fingerprint tailoring is achieved either by combination of magnetic building blocks with nonmagnetic ones in the supraparticles or, alternatively, by surface modification of the building blocks. An easy‐to‐use device, based on the principle of magnetic particle spectroscopy (MPS), is established to resolve the magnetic fingerprint information. This facilitates the employment of magnetic supraparticles as markers for product tracking and identification. As a proof of concept, it is shown that such particles enable the marking of black plastic.

Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 ± 5.4 vs. 14.2 ± 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 ± 2.9 vs. 7.6 ± 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 ± 5.3/122.7 ± 6.4 vs. 203.8 ± 1.9/143.7 ± 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 ± 0.4 vs. 3.2 ± 1.0 mmHg · min · l(-1) for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 ± 1.7%, day 0) to a level (13.0 ± 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension.

BackgroundRecent studies have shown that human ferritin can be used as a reporter of gene expression for magnetic resonance imaging (MRI). Bacteria also encode three classes of ferritin-type molecules with iron accumulation properties.Methods and FindingsHere, we investigated whether these bacterial ferritins can also be used as MRI reporter genes and which of the bacterial ferritins is the most suitable reporter. Bacterial ferritins were overexpressed in probiotic E. coli Nissle 1917. Cultures of these bacteria were analyzed and those generating highest MRI contrast were further investigated in tumor bearing mice. Among members of three classes of bacterial ferritin tested, bacterioferritin showed the most promise as a reporter gene. Although all three proteins accumulated similar amounts of iron when overexpressed individually, bacterioferritin showed the highest contrast change. By site-directed mutagenesis we also show that the heme iron, a unique part of the bacterioferritin molecule, is not critical for MRI contrast change. Tumor-specific induction of bacterioferritin-expression in colonized tumors resulted in contrast changes within the bacteria-colonized tumors.ConclusionsOur data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast changes.

Magnetic particle spectroscopy (MPS) is used in this work to obtain a magnetic fingerprint signal from anisotropic supraparticles, i.e., microrods assembled from superparamagnetic iron oxide nanoparticles. Exceeding its intended purpose of nanoparticle characterization for biomedical magnetic particle imaging, it is shown that MPS is capable of resolving structural differences between the anisotropic alignment of individual nanoparticles and its isotropic counterpart. Additionally, orientation-dependent MPS signal variations of anisotropic supraparticles are identifiable. This finding enables the detection of cold-chain breaches (for instance, during delivery of a product that needs to be cooled all of the time) by recording the initial and final MPS signals of microrod samples integrated into the container of a frozen product.