Microfluidic bioprinting of tough hydrogel-based vascular conduits for functional blood vessels.

Three-dimensional (3D) bioprinting of vascular tissues that are mechanically and functionally comparable to their native counterparts is an unmet challenge. Here, we developed a tough double-network hydrogel (bio)ink for microfluidic (bio)printing of mono- and dual-layered hollow conduits to recreate vein- and artery-like tissues, respectively. The tough hydrogel consisted of energy-dissipative ionically cross-linked alginate and elastic enzyme-cross-linked gelatin. The 3D bioprinted venous and arterial conduits exhibited key functionalities of respective vessels including relevant mechanical properties, perfusability, barrier performance, expressions of specific markers, and susceptibility to severe acute respiratory syndrome coronavirus 2 pseudo-viral infection. Notably, the arterial conduits revealed physiological vasoconstriction and vasodilatation responses. We further explored the feasibility of these conduits for vascular anastomosis. Together, our study presents biofabrication of mechanically and functionally relevant vascular conduits, showcasing their potentials as vascular models for disease studies in vitro and as grafts for vascular surgeries in vivo, possibly serving broad biomedical applications in the future.

Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.

BACKGROUND: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. METHODS: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. FINDINGS: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. CONCLUSIONS: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials. FUNDING: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560).

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

SARS-CoV-2 monoclonal antibodies with therapeutic potential: Broad neutralizing activity and No evidence of antibody-dependent enhancement.

Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection. In this study, plaque reduction neutralization assays demonstrated that mAb 1741-LALA neutralizes SARS-CoV-2 strains B.1.351, D614 and D614G. MAbs S1D2-hIgG1 and S1D2-LALA mutant (STI-1499-LALA) did not neutralize B.1.351, but did neutralize SARS-CoV-2 strains D614 and D614G. LALA mutations did not result in substantial differences in neutralizing abilities between clones S1D2-hIgG1 vs STI-1499-LALA. S1D2-hIgG1, STI-1499-LALA, and convalescent plasma showed minimal ability to induce ADE in human blood monocyte-derived macrophages. Further, no differences in pharmacokinetic clearance of S1D2-hIgG1 vs STI-1499-LALA were observed in mice expressing human FcRn. These findings confirm that SARS-CoV-2 has already escaped some mAbs, and identify a mAb candidate that may neutralize multiple SARS-CoV-2 variants. They also suggest that risk of ADE in macrophages may be low with SARS-CoV-2 D614, and LALA Fc change impacts neither viral neutralization nor Ab clearance.

Intelligent facemask based on triboelectric nanogenerator for respiratory monitoring.

The fast-spreading of novel coronavirus disease (COVID-19) has been sweeping around the globe and brought heavy casualties and economic losses, which creates dire needs for technological solutions into medical preventive actions. In this work, triboelectric nanogenerator for respiratory sensing (RS-TENG) has been designed and integrated with facemask, which endows the latter with respiratory monitoring function. The output of RS-TENG for respiratory flow can reach up to about 8 V and 0.8 µA respectively although it varies with different respiratory status, which proves the high sensitivity of RS-TENG for respiratory monitoring. An apnea alarm system can be constructed by combining the smart facemask with circuit modules so that timely alarm can be transmitted after people stop breathing. Furthermore, RS-TENG can be used to control household appliances, which brings convenience to the life of the disabled people. Considering its incomparable advantages such as small volume, easy fabrication, simple installation and economical applicability, such design is helpful for developing multifunctional health monitoring gadgets during the COVID-19 pandemic.

A case describing patients with COVID-19 that secondarily transmitted.

BACKGROUND: The recent emergence of coronavirus disease 2019 (COVID-19) is a major global health threat. Monitoring viral transmission and disease characteristics as the disease spreads globally is vital. This study aimed to describe the clinical characteristics and source of infection in patients with secondary transmission of COVID-19 outside the outbreak area. METHODS: The epidemiological, demographic, clinical, laboratory, radiological, and treatment data of five patients with laboratory-confirmed COVID-19 who were treated in the General Hospital of Ningxia Medical University (Ningxia, China) from 1 January 2020 to 1 March 2020 were presented. The final follow-up evaluation was performed on 12 March 2020. RESULTS: The five participants included two couples and a young woman, none of whom had visited Hubei. It was likely that four of the participants had been infected by exposure to asymptomatic visitors from Wuhan. The other participant lived in a densely-populated community with potential COVID-19 cases. A variety of symptoms were presented by four participants, including cough, fevers, sputum, breathlessness, chest pain, fatigue, sore limbs, sore throats, headaches, and rhinorrhea. A severe infection, with dyspnea and decreased oxygen saturation, was experienced by one participant who had a history of chronic bronchitis. A single participant was asymptomatic, but had ground-glass opacities (GGOs) on chest imaging. Another two participants also displayed GGOs. Lymphopenia was noted in three participants. During the follow-up period, all participants were cured and discharged to their homes. CONCLUSIONS: This study included patients who had acquired infections of COVID-19 through local transmission. These findings will provide a better understanding of secondary transmission of COVID-19.