Figure 4.

Drug delivery strategies in BBB-chips. (a) BBB disruption after hyperosmolar mannitol treatment shown with cetuximab permeability spike and TEER drop [11^••]. (b) Continuous TEER responses to two doses of histamine exposure [14]. Barrier functions recover within 6 and 15 μin after 100 and 150 mM exposures, respectively. (c) Enhanced permeabilization of fluorescent sodium salt after electroporation via 10 pulses of 833 V/cm (reversible) and 90 pulses of 200 V/cm (irreversible) [18]. The dashed line indicates pulse application. (d, top) Sonoporation in vascular-chips demonstrates vessel permeability changes due to varying levels of ultrasound intensity and microbubble perfusion rates [43]. Red dashed line indicates the control. (d, bottom) Junctional opening comparison of untreated (CTRL), ultrasound irradiated (US), and microbubble injected ultrasound irradiated (USMB) samples [44]. (e, top) Improved transport of 100 nm polystyrene (PS) nanoparticles (NPs) after surface functionalization with gH625 [15]. (e, bottom) 16 CPPs tested for brain penetration using BBB spheroids [35^••]. Well-established BBB-penetrating CPPs are pointed out with arrows. (f) Higher apparent permeabilities of PS and polyurethane (PU) NPs when transferrin (Tf) is conjugated [33^•]. (g) Shuttling effects of angiopep-2-conjugation on liposomal and quantum dot NPs [11^••,16]. (h, top) Inhibition of efflux transporters P-gp and MRP1 shown with the increased permeabilities of their substrate rhodamine 123 [11^••]. Similar trends appear with P-gp substrate doxorubicin and P-gp/BCRP substrate DiOC2, which are not replicated here. The benefit of hypoxia-conditioned hiBEC differentiation is also highlighted. (h, bottom) P-gp inhibition using valspodar and elacridar. The decreases in calcein-AM fluorescence from initial levels are calculated to compare the efflux rates. The effect of elacridar is seen in triculture (EAP) but not in monoculture (E only) [28].