A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles.

Mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs) show therapeutic potential in multiple disease models, including kidney injury. Clinical translation of sEVs requires further preclinical and regulatory developments, including elucidation of the biodistribution and mode of action (MoA). Biodistribution can be determined using labelled sEVs in animal models which come with ethical concerns, are time-consuming and expensive, and may not well represent human physiology. We hypothesised that, based on developments in microfluidics and human organoid technology, in vitro multi-organ-on-a-chip (MOC) models allow us to study effects of sEVs in modelled human organs like kidney and liver in a semi-systemic manner. Human kidney- and liver organoids combined by microfluidic channels maintained physiological functions, and a kidney injury model was established using hydrogenperoxide. MSC-sEVs were isolated, and their size, density and potential contamination were analysed. These sEVs stimulated recovery of the renal epithelium after injury. Microscopic analysis shows increased accumulation of PKH67-labelled sEVs not only in injured kidney cells, but also in the unharmed liver organoids, compared to healthy control conditions. In conclusion, this new MOC model recapitulates therapeutic efficacy and biodistribution of MSC-sEVs as observed in animal models. Its human background allows for in-depth analysis of the MoA and identification of potential side effects.

Estimation of changes in maternal mortality in a rural district of northern Tanzania during the last 50 years.

OBJECTIVE: Maternal mortality remains a major challenge worldwide. Reliable information concerning ratios and trends is essential for resource mobilization and assessment of progress towards the Millennium Development Goals. DESIGN: Assessment of levels and trends in maternal mortality during the last 50 years. SETTING: Sengerema district, rural North Tanzania. POPULATION: Number of deliveries, births, admissions, maternal deaths and causes of maternal mortality in the only hospital in the area. METHODS: We compiled a database from the annual hospital reports for the period of 1962-2011 to obtain estimated maternal mortality ratio for each decade. MAIN OUTCOME MEASURES: Maternal mortality ratio for each decade and classification of maternal deaths. RESULTS: Of 629 maternal deaths, 490 (77.9%) could be classified as either direct or indirect and causes of mortality ascertained. Of the 361 direct causes (73.7%), hemorrhage (29.8%) and sepsis (20.4%) were the leading causes. Of the 129 indirect causes (26.3%), anemia during pregnancy (6.5%), meningitis (4.1%), HIV-AIDS (3.5%), malaria (2.9%), heart diseases (2.4%) and relapsing fever (2.0%) were most often diagnosed. Since 1962, a 63% decrease in maternal mortality ratio has been achieved. The hospital-based maternal mortality ratio decreased from 770/100,000 to 282/100,000 in the last decade (95% confidence interval 244/100,000, 320/100,000). The yearly decline since 1962 was 1.3%. CONCLUSIONS: During the last 50 years we have witnessed a reduction of maternal mortality and improvements in maternal health. Progress has been made towards improving Millennium Development Goal 5, although only a prospective population-based survey will provide the ultimate answer.