No abstract

The placenta is a dynamic and complex organ that plays an essential role in the health and development of the fetus. Placental disorders can affect the health of both the mother and the fetus. There is currently an unmet clinical need to develop nanoparticle-based therapies to target and treat placental disorders. However, little is known about the interaction of nanoparticles (NPs) with the human placenta under biomimetic conditions. Specifically, the impact of shear stress exerted on the trophoblasts (placental epithelial cells) by the maternal blood flow, the gradual fusion of the trophoblasts along the gestation period (syncytialization), and the impact of microvilli formation on the cell uptake of NPs is not known. To this end, we designed dynamic placenta-on-achip models using BeWo cells to recapitulate the micro-physiological environment, and we induced different degrees of syncytialization via chemical induction with forskolin. We characterized the degree of syncytialization quantitatively by measuring beta human chorionic gonadotropin (β-hCG) secretion, as well as qualitatively by immunostaining the tight junction protein, ZO-1, and counter nuclear staining. We also characterized microvilli formation under static and dynamic conditions via F-actin staining. We used these models to measure the cell uptake of chondroitin sulfate a binding protein (CSA) conjugated and control liposomes using confocal microscopy, followed by image analysis. Interestingly, exposure of the cells to a dynamic flow of media intrinsically induced syncytialization and microvilli formation compared to static controls. Under dynamic conditions, BeWo cells produced more β-hCG in conditions that increased the cell exposure time to forskolin (p < 0.005). Our cell uptake results clearly show a combined effect of the exerted shear stress and forskolin treatment on the cell uptake of liposomes as uptake increased in forskolin exposed conditions (p < 0.05). Overall, the difference in the extent of cell uptake of liposomes among the different conditions clearly displays a need for the development of dynamic models of the placenta that consider the changes in the placental cell phenotype along the gestation period, including syncytialization, microvilli formation, and the expression of different transport and uptake receptors. Knowledge generated from this work will inform future research aiming at developing drug delivery systems targeting the placenta.

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We have evaluated the 'two minute walking distance' in children with cystic fibrosis as an objective measurement of exercise tolerance. There was a strong correlation between walking distance and height in 89 normal children (r=072). Fifty children with cystic fibrosis showed a similar correlation (r=0-56) with a mean result of 94% of that expected for height compared with the normal children. There was a training effect in the normal children with the second walk being significantly better than the first, but this was not evident in children with cystic fibrosis. The test was reproducible with no significant change in 12 children retested after one to three months. Sixteen children with cystic fibrosis admitted for treatment of chest disease showed a significant improvement in walking distance with treatment. Children as young as 5 years old can perform a walking distance test. It seems to be an objective way of assessing exercise tolerance and can help in evaluating response to treatment.

Thirty-one Cystic Fibrosis patients were investigated for clinical and biochemical evidence of Vitamin A deficiency. All had been prescribed oral pancreatic enzyme replacements and twice the recommended daily requirement of Vitamin A (5000IU). None were aware of any ocular symptoms, but 3 out of 31 (10 per cent) were found to have frank conjunctival xerosis and six (19 per cent) to have abnormal dark adaptation. There was no correlation between the above findings and abnormal liver function or clinical disease severity. All patients with cystic fibrosis should have regular Vitamin A estimations with ophthalmological assessment if serum levels fall below 30 microgram/dl.