Device modeling of two-steps oxygen anneal-based submicron InGaZnO back-end-of-line field-effect transistor enabling short-channel effects suppression.

Amorphous oxide semiconductor (AOS) field-effect transistors (FETs) have been integrated with complementary metal-oxide-semiconductor (CMOS) circuitry in the back end of line (BEOL) CMOS process; they are promising devices creating new and various functionalities. Therefore, it is urgent to understand the physics determining their scalability and establish a physics-based model for a robust device design of AOS BEOL FETs. However, the advantage emphasized to date has been mainly an ultralow leakage current of these devices. A device modeling that comprehensively optimizes the threshold voltage (VT), the short-channel effect (SCE), the subthreshold swing (SS), and the field-effect mobility (µFE) of short-channel AOS FETs has been rarely reported. In this study, the device modeling of two-steps oxygen anneal-based submicron indium-gallium-zinc-oxide (IGZO) BEOL FET enabling short-channel effects suppression is proposed and experimentally demonstrated. Both the process parameters determining the SCE and the device physics related to the SCE are elucidated through our modeling and a technology computer-aided design (TCAD) simulation. In addition, the procedure of extracting the model parameters is concretely supplied. Noticeably, the proposed device model and simulation framework reproduce all of the measured current-voltage (I-V), VT roll-off, and drain-induced barrier lowering (DIBL) characteristics according to the changes in the oxygen (O) partial pressure during the deposition of IGZO film, device structure, and channel length. Moreover, the results of an analysis based on the proposed model and the extracted parameters indicate that the SCE of submicron AOS FETs is effectively suppressed when the locally high oxygen-concentration region is used. Applying the two-step oxygen annealing to the double-gate (DG) FET can form this region, the beneficial effect of which is also proven through experimental results; the immunity to SCE is improved as the O-content controlled according to the partial O pressure during oxygen annealing increases. Furthermore, it is found that the essential factors in the device optimization are the subgap density of states (DOS), the oxygen content-dependent diffusion length of either the oxygen vacancy (VO) or O, and the separation between the top-gate edge and the source-drain contact hole. Our modeling and simulation results make it feasible to comprehensively optimize the device characteristic parameters, such as VT, SCE, SS, and µFE, of the submicron AOS BEOL FETs by independently controlling the lateral profile of the concentrations of VO and O in two-step oxygen anneal process.

Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101.

TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive. Therefore, an intravenous study of TLC-ART 101 in nonhuman primates was conducted to elucidate the degree of association of drugs in vivo, estimate subcutaneous bioavailability, and refine a mechanism-based pharmacokinetic (MBPK2) model. The MBPK2 model considers TLC-ART 101 systemic drug clearances, nanoparticle-associated/dissociated species, more detailed mechanisms of lymphatic first-pass retention of associated-drugs after subcutaneous administrations, and the prediction of drug concentration time-courses in lymph node mononuclear cells. For all 3 drugs, we found a high association with the nanoparticles in plasma (>87% lopinavir-ritonavir, 97% tenofovir), and an incomplete subcutaneous bioavailability (<29% lopinavir-ritonavir, 85% tenofovir). As hypothesized by the MBPK2 model, the incomplete SC bioavailability observed is due to sequestration into a lymphatic node depot after subcutaneous absorption (unlike most intramuscular nanodrug products having near-to-injection depots), which contributes to long-acting profiles detected in plasma and target cells. This combined experimental and modeling approach may be applicable for the clinical development of other long-acting drug-combination injectables.

Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection.

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.

Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain.

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.

Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate.

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.