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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. Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose‐escalation protocol of intra‐articular injected adipose‐derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra‐articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 106 cells), medium dose (10 × 106), and high dose (50 × 106). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow‐up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low‐dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra‐articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo‐controlled double‐blind phase IIb study is being initiated to assess clinical and structural efficacy. Significance Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose‐derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long‐term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.

In order to treat degenerative diseases, the importance of advanced therapy medicinal products has increased in recent years. The newly developed treatment strategies require a rethinking of the appropriate analytical methods. Current standards are missing the complete and sterile analysis of the product of interest to make the drug manufacturing effort worthwhile. They only consider partial areas of the sample or product while also irreversibly damaging the investigated specimen. Two-dimensional T 1 / T 2 MR relaxometry meets these requirements and is therefore a promising in-process control during the manufacturing and classification process of cell-based treatments. In this study a tabletop MR scanner was used to perform two-dimensional MR relaxometry. Throughput was increased by developing an automation platform based on a low-cost robotic arm, resulting in the acquisition of a large dataset of cell-based measurements. Two-dimensional inverse Laplace transformation was used for post-processing, followed by data classification performed with support vector machines (SVM) as well as optimized artificial neural networks (ANN). The trained networks were able to distinguish non-differentiated from differentiated MSCs with a prediction accuracy of 85%. To increase versatility, an ANN was trained on 354 independent, biological replicates distributed across ten different cell lines, resulting in a prediction accuracy of up to 98% depending on data composition. The present study provides a proof of principle for the application of T 1 / T 2 relaxometry as a non-destructive cell classification method. It does not require labeling of cells and can perform whole mount analysis of each sample. Since all measurements can be performed under sterile conditions, it can be used as an in-process control for cellular differentiation. This distinguishes it from other characterization techniques, as most are destructive or require some type of cell labeling. These advantages highlight the technique’s potential for preclinical screening of patient-specific cell-based transplants and drugs.

Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.

Recent 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. Here, 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. Our data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast changes.

New multifunctional nanoparticles (NPs) that can be used as contrast agents (CA) in different imaging techniques, such as photoluminescence (PL) microscopy and magnetic resonance imaging (MRI), open new possibilities for medical imaging, e.g., in the fields of diagnostics or tissue characterization in regenerative medicine. The focus of this study is on the synthesis and characterization of CaF 2 :(Tb 3+ ,Gd 3+ ) NPs. Fabricated in a wet-chemical procedure, the spherical NPs with a diameter of 5–10 nm show a crystalline structure. Simultaneous doping of the NPs with different lanthanide ions, leading to paramagnetism and fluorescence, makes them suitable for MR and PL imaging. Owing to the Gd 3+ ions on the surface, the NPs reduce the MR T 1 relaxation time constant as a function of their concentration. Thus, the NPs can be used as a MRI CA with a mean relaxivity of about r = 0.471 mL·mg −1 ·s −1 . Repeated MRI examinations of four different batches prove the reproducibility of the NP synthesis and determine the long-term stability of the CAs. No cytotoxicity of NP concentrations between 0.5 and 1 mg·mL −1 was observed after exposure to human dermal fibroblasts over 24 h. Overall this study shows, that the CaF 2 :(Tb 3+ ,Gd 3+ ) NPs are suitable for medical imaging.

During the last years, (19)F-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. In 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. We introduce (19)F-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.

Recent literature suggests that the use of sugammadex for the reversal of neuromuscular blocking agents (NMBAs) reduces the risk of postoperative myasthenic crisis (MC) in patients with myasthenia gravis (MG), particularly after thymectomy, but studies are lacking on emergency surgeries. We achieved successful intraoperative reversal of neuromuscular blockade (NMB) using a combination of sugammadex and neostigmine (with glycopyrrolate). However, MC was not avoided and reintubation was required on postoperative day 1.A 65-year-old male with a longstanding history of MG presented to the emergency department with complaints of abdominal pain, diarrhea, vomiting, chills, and fatigue for three days. A computed tomography (CT) scan of the abdomen showed acute appendicitis, for which he underwent a laparoscopic appendectomy on hospital day 1. The patient received successful general anesthesia with a rapid sequence induction using a smaller than average dose of rocuronium, given his history of MG. At the conclusion of the case, sugammadex followed by neostigmine/glycopyrrolate and a subsequent dose of sugammadex were given, with reversal of NMB. The patient was successfully extubated but required reintubation on postoperative day 1 for hypercapnic respiratory failure.Our case report on this patient with MG yields two topics that have not been extensively examined. First, dual therapy with sugammadex and neostigmine/glycopyrrolate may provide significant clinical benefit over individual therapy for NMBA reversal, given that their mechanisms of action are different and particularly when sugammadex is given prior to neostigmine/glycopyrrolate. Second, anesthesia literature is lacking on MG patients undergoing emergency surgeries. While sugammadex has been promising in medically optimized non-emergent surgeries, we discuss here a case where sugammadex failed to prevent MC in the emergency surgery setting and a look into what may provide patients with the best chance for avoiding postoperative MC.

Pulmonary embolism, peripartum cardiomyopathy, acute myocardial infarction, aortic dissection, anxiety, and gastroesophageal reflux disease are known causes of chest pain during the peripartum period. A cardiac tumor is a rare cause of chest pain during this time period. While cardiac myxomas during pregnancy have been reported, cardiac hemangiomas are exceptionally rare. To the best of our knowledge, there are no existing case reports regarding cardiac hemangiomas in either pregnant or postpartum patients. Here, we present a 23-year-old female who presented with visual changes, headache, and midsternal pain and was subsequently found to have a cardiac hemangioma.

Serenoa repens (saw palmetto) berries are one of the most consumed medicinal herbs in the United States and the wild green variety is used in the initial therapy of benign prostatic hyperplasia (BPH), globally. Use of saw palmetto is approved by the German Commission E, and several clinical trials are underway for evaluation of its efficacy. Exploitation of its habitats and over foraging imperil this plant, which only grows in the wild. This is the first study, to propose the use of the S . repens forma glauca (silver variety) as a qualitative substitute for the wild variety, to support its conservation. We compared tissue microstructures and lipid and water distribution through spatial imaging and examined metabolite distribution of three tissue domains and whole berries. This combined approach of 3D imaging and metabolomics provides a new strategy for studying phenotypic traits and metabolite synthesis of closely related plant varieties.

Adipose tissue-derived stromal cells (ASCs) represent a capable source for cell-based therapeutic approaches. For monitoring a cell-based application in vivo, magnetic resonance imaging (MRI) of cells labeled with iron oxide particles is a common method. It is the aim of the present study to analyze potential DNA damage, cytotoxicity and impairment of functional properties of human (h)ASCs after labeling with citrate-coated very small superparamagnetic iron oxide particles (VSOPs). Cytotoxic as well as genotoxic effects of the labeling procedure were measured in labeled and unlabeled hASCs using the MTT assay, comet assay and chromosomal aberration test. Trilineage differentiation was performed to evaluate an impairment of the differentiation potential due to the particles. Proliferation as well as migration capability were analyzed after the labeling procedure. Furthermore, the labeling of the hASCs was confirmed by Prussian blue staining, transmission electron microscopy (TEM) and high-resolution MRI. Below the concentration of 0.6 mM, which was used for the procedure, no evidence of genotoxic effects was found. At 0.6 mM, 1 mM as well as 1.5 mM, an increase in the number of chromosomal aberrations was determined. Cytotoxic effects were not observed at any concentration. Proliferation, migration capability and differentiation potential were also not affected by the procedure. Labeling with VSOPs is a useful labeling method for hASCs that does not affect their proliferation, migration and differentiation potential. Despite the absence of cytotoxicity, however, indications of genotoxic effects have been demonstrated.