3D Cellular models and organs-on-chips are poised to add tremendous value to translational research. However, these biologically complex systems typically require extensive expertise and lack the throughput necessary for therapeutics discovery. We will discuss these translational obstacles and highlight novel solutions, including scaling up both primary and iPSC-based 3D organoid models (specifically contractile muscle models) to meet the high-throughput requirements of drug discovery in widely-accessible platforms.

Reports suggest a role of the microbiome in tumor progression through multiple mechanisms.  Fusobacterium is frequently found in colorectal tumors and is associated with disease progression. There is a lack of practical approaches that enable culturing of anaerobic microbes with aerobic eukaryotic cells due to the different oxygen requirements.  We found that 3D tumor spheroids facilitate anaerobic microbe growth and applied imaging, transcriptomics, and metabolomic analysis to this co-culture assay.

In this talk, I will discuss 1) “tissue-like” electronics that possesses tissue-like properties for long-term stable single-cell electrophysiology; 2) “cyborg organoids," where stretchable sensor arrays are embedded in 2D sheets of stem/progenitor cells and reconfigured through 2D-to-3D organogenesis, enabling 3D electrophysiology during development; and 3) “in-situ electro-sequencing” that integrates “tissue-like” electronics, in-situ sequencing, and machine learning to chart cell electrophysiology and gene expression at single-cell resolution across time and space.

CRISPR screening is proving to be a robust platform for identifying and validating new biological targets for disease treatment. Despite progress, such screens may not fully recapitulate physiologic cell behavior or allow a comprehensive understanding of population complexity and dynamics. Here I will cover screening in complex systems including organoids, and in vivo models, which should aid in identifying more physiologically relevant targets and potentially decreasing drugs failing in clinical trials.

The increasing incidence of potential pandemic viruses–such as influenza virus and SARS-CoV-2–necessitates new preclinical approaches that can accelerate the development of effective therapeutics. We have developed human Airway Chips and Alveolus Chips that enable faithful mimic of the human lung. These models allow us to study more complex disease pathology, uncover novel drug targets and develop treatments that will better translate into humans for this and future pandemics.

3D biofabrication offers great versatility in the generation of biomimetic volumetric tissues that are structurally and functionally relevant. This talk will discuss our recent efforts in developing high-content human-based models through biofabrication, which when combined with microfluidic chip-based systems, are likely to provide new opportunities for fighting against diseases and pandemics.

Use of bone marrow microphysiological systems (MPS) to generate safety and efficacy data for drug development with improved clinical relevance over more traditional 2D cell culture and animal models. Case study showing data generated from these systems that demonstrate the utility of MPS for safety assessment. 

Microphysiological systems provide platforms with enhanced physiological relevance to test drug effects in human populations. New models of the dermal microenvironment reproduce functional blood and lymphatic microvessels to assess drug distribution to the blood and lymph compartments after subcutaneous injection. The use of microphysiological models of the dermal vasculature can aid the prediction of subcutaneous distribution in vivo and the development of molecules with improved bioavailability.

10x Genomics provides single cell and spatial solutions that enable researchers to resolve highly complex biological systems. Learn how the tools from 10x Genomics helps to uncover molecular insights, dissect cell-type differences, detect novel subtypes and biomarkers, define gene regulatory interactions, and decipher spatiotemporal gene expression patterns in 3D cellular models. Enabling deeper insight into organoids models in cancer, immunology, neuroscience, and developmental biology.

A wide range of 3D organotypic cellular models are being developed for scientific research and drug efficacy and safety testing. The integration of these complex human cellular models into drug R&D pipelines requires rigorous scientific validation, clinical benchmarking, and operationalization as robust screening assay platforms. This presentation will show work at the NCATS 3D Tissue Bioprinting Laboratory to operationalize the use of 3D organotypic models as predictive preclinical assay platforms.

We have recently successfully derived longterm proliferating organoids from cirrhotic NASH patient liver. Hepatically differentiated NASH patient liver organoids faithfully recapitulate human NASH, including increased lipid accumulation and increased sensitivity to apoptotic stimuli (McCarron et al. Hepatology, 2021, PMID: 33901295). We also found that they exhibit increased permissiveness to SARS-CoV-2, leading to strong chemokine induction, consistent with the high death rate of COVID-19 patients with preexisting NASH.