A Multimodal and Multifunctional CMOS Cellular Interfacing Array for Digital Physiology and Pathology Featuring an Ultra Dense Pixel Array and Reconfigurable Sampling Rate.

The article presents a fully integrated multimodal and multifunctional CMOS biosensing/actuating array chip and system for multi-dimensional cellular/tissue characterization. The CMOS chip supports up to 1,568 simultaneous parallel readout channels across 21,952 individually addressable multimodal pixels with 13 µm × 13 µm 2-D pixel pitch along with 1,568 Pt reference electrodes. These features allow the CMOS array chip to perform multimodal physiological measurements on living cell/tissue samples with both high throughput and single-cell resolution. Each pixel supports three sensing and one actuating modalities, each reconfigurable for different functionalities, in the form of full array (FA) or fast scan (FS) voltage recording schemes, bright/dim optical detection, 2-/4-point impedance sensing (ZS), and biphasic current stimulation (BCS) with adjustable stimulation area for single-cell or tissue-level stimulation. Each multi-modal pixel contains an 8.84 µm × 11 µm Pt electrode, 4.16 µm × 7.2 µm photodiode (PD), and in-pixel circuits for PD measurements and pixel selection. The chip is fabricated in a standard 130nm BiCMOS process as a proof of concept. The on-chip electrodes are constructed by unique design and in-house post-CMOS fabrication processes, including a critical Al shorting of all pixels during fabrication and Al etching after fabrication that ensures a high-yield planar electrode array on CMOS with high biocompatibility and long-term measurement reliability. For demonstration, extensive biological testing is performed with human and mouse progenitor cells, in which multidimensional biophysiological data are acquired for comprehensive cellular characterization.

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.

Attacking COVID-19 Progression Using Multi-Drug Therapy for Synergetic Target Engagement.

COVID-19 is a devastating respiratory and inflammatory illness caused by a new coronavirus that is rapidly spreading throughout the human population. Over the past 12 months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has already infected over 160 million (>20% located in United States) and killed more than 3.3 million people around the world (>20% deaths in USA). As we face one of the most challenging times in our recent history, there is an urgent need to identify drug candidates that can attack SARS-CoV-2 on multiple fronts. We have therefore initiated a computational dynamics drug pipeline using molecular modeling, structure simulation, docking and machine learning models to predict the inhibitory activity of several million compounds against two essential SARS-CoV-2 viral proteins and their host protein interactors-S/Ace2, Tmprss2, Cathepsins L and K, and Mpro-to prevent binding, membrane fusion and replication of the virus, respectively. All together, we generated an ensemble of structural conformations that increase high-quality docking outcomes to screen over >6 million compounds including all FDA-approved drugs, drugs under clinical trial (>3000) and an additional >30 million selected chemotypes from fragment libraries. Our results yielded an initial set of 350 high-value compounds from both new and FDA-approved compounds that can now be tested experimentally in appropriate biological model systems. We anticipate that our results will initiate screening campaigns and accelerate the discovery of COVID-19 treatments.

Reversed-engineered human alveolar lung-on-a-chip model.

Here, we present a physiologically relevant model of the human pulmonary alveoli. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung.