Towards compliant small-diameter vascular grafts: Predictive analytical model and experiments.

The search for novel, more compliant vascular grafts for the replacement of blood vessels is ongoing, and predictive tools are needed to identify the most promising biomaterials. A simple analytical model was designed that enables the calculation of the ratio between the ultimate stress (σult) and the elastic modulus (E). To reach both the compliance of small-diameter coronary arteries (0.0725%/mmHg) and a burst pressure of 2031 mmHg, a material with a minimum σult/E ratio of 1.78 is required. Based on this result and on data from the literature, random electrospun Polyurethane/Polycaprolactone (PU/PCL) tubular scaffolds were fabricated and compared to commercial ePTFE prostheses. PU/PCL grafts showed mechanical properties close to those of native arteries, with a circumferential elastic modulus of 4.8 MPa and a compliance of 0.036%/mmHg at physiological pressure range (80-120 mmHg) for a 145 µm-thick prosthesis. In contrast, commercial expanded polytetrafluoroethylene (ePTFE) grafts presented a high Young's modulus (17.4 MPa) and poor compliance of 0.0034%/mmHg. The electrospun PU/PCL did not however reach the target values as its σult/E ratio was lower than expected, at 1.54, well below the calculated threshold (1.78). The model tended to overestimate both the compliance and burst pressure, with the differences between the analytical and experimental results ranging between 13 and 34%, depending on the pressure range tested. This can be explained by the anisotropy of random electrospun PU/PCL and its slightly non-linear elastic behavior, in contrast to the hypotheses of our model. Impermeability tests showed that the electrospun scaffolds were impermeable to blood for all thicknesses above 50 µm. In conclusion, this analytical model allows to select materials with suitable mechanical properties for the design of small-diameter vascular grafts. The novel electrospun PU/PCL tubular scaffolds showed strongly improved compliance as compared to commercial ePTFE prostheses.

Sodium Transporters Are Involved in Lithium Influx in Brain Endothelial Cells.

Variability in drug response to lithium (Li+) is poorly understood and significant, as only 40% of patients with bipolar disorder highly respond to Li+. Li+ can be transported by sodium (Na+) transporters in kidney tubules or red blood cells, but its transport has not been investigated at the blood-brain barrier (BBB). Inhibition and/or transcriptomic strategies for Na+ transporters such as NHE (SLC9), NBC (SLC4), and NKCC (SLC12) were used to assess their role on Li+ transport in human brain endothelial cells. Na+-free buffer was also used to examine Na+/Li+ countertransport (NLCT) activity. The BBB permeability of Li+ evaluated in the rat was 2% that of diazepam, a high passive diffusion lipophilic compound. Gene expression of several Na+ transporters was determined in hCMEC/D3 cells, human hematopoietic stem-cell-derived BBB models (HBLEC), and human primary brain microvascular endothelial cells (hPBMECs) and showed the following rank order with close expression profile: NHE1 > NKCC1 > NHE5 > NBCn1, while NHE2-4, NBCn2, and NBCe1-2 were barely detected. Li+ influx in hCMEC/D3 cells was increased in Na+-free buffer by 3.3-fold, while depletion of chloride or bicarbonate had no effect. DMA (NHE inhibitor), DIDS (anionic carriers inhibitor), and bumetanide (NKCC inhibitor) decreased Li+ uptake significantly in hCMEC/D3 by 52, 51, and 47%, respectively, while S0859 (NBC inhibitor) increased Li+ influx 2.3-fold. Zoniporide (NHE1 inhibitor) and siRNA against NHE1 had no effect on Li+ influx in hCMEC/D3 cells. Our study shows that NHE1 and/or NHE5, NBCn1, and NKCC1 may play a significant role in the transport of Li+ through the plasma membrane of brain endothelial cells.