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Principal Investigator: Yong Huang
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2023
Award: $214,733
Funding agency: National Heart Lung and Blood Institute
Project Summary
The overarching goal of this research is to fabricate an in vitro three-dimensional (3D) human respiratory
model with an air-liquid interface (ALI), which can serve as a platform for COVID-19 related biomedical
investigations. A recent COVID-19 outbreak, which is due to the infection of a severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), results in more than 100 million confirmed cases and about 2.3 million
deaths with numbers increasing everyday globally. For COVID-19 related research, there remains an urgent
need for a 3D fully heterogeneous, cellular respiratory model, which can enhance our understanding of how
SARS-CoV-2 induces lung injury and facilitate the development of new treatments as complementary to animal
models and clinical patients. We therefore propose to develop such a human respiratory model, which 1)
expresses angiotensin-converting enzyme 2 (ACE2) protein and transmembrane protease serine type 2
(TMPRSS2) that allow viral entry to study the SARS-CoV-2 infection process, and 2) has the diffusional
permeability between the airway and primary fluid channel to enable the mass transport across ALI, permitting
the screening of clinically proven drugs for COVID-19 use. We hypothesize that an in vitro human respiratory
model can be realized by embedded printing and further developing a perfusable construct in a yield-stress
matrix bath containing primary human stromal, endothelial, and fibroblast cells.
Accordingly, two specific aims are proposed as follows:
Aim 1: Embedded printing and perfusion of a 3D in vitro human respiratory model in a stromal cell-based
cross-linkable yield-stress matrix bath.
Aim 2: Characterization of the human respiratory model via detection of ACE2 receptor and TMPRSS2
protease in the airway epithelium and determination of the diffusional permeability of ALI.
For the first time, a gelatin microgels and gelatin solution-based cross-linkable yield-stress cellular
composite matrix bath will be innovated for embedded printing of perfusable tissue constructs in it, enabling
human respiratory model fabrication. This model development study will result in an in vitro 3D human
respiratory model with ALI and cellular stroma by utilizing the novel cross-linkable yield-stress cellular matrix
bath for embedded printing, and no other models with this physiological complexity exist. Such a human
respiratory model will provide a versatile in vitro platform for studying the COVID-19 pandemic-related infection
process and screening related drugs.
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life><Characteristics><Clinical><CoV-2><CoV2><Cytoskeletal System><Cytoskeleton><Death><Detection><Development><Dextrans><Diffusion><Disease><Disorder><Drug Modelings><Drugs><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Epithelial Cells><Esteroproteases><Exposure to><Fatty Tissue><Fibroblasts><Fluorescein><Gel><Gelatin><Goals><Human><Immune response><Immunofluorescence><Immunofluorescence Immunologic><Immunological response><In Vitro><Infection><Ink><Investigation><Investigators><Isothiocyanates><Liquid substance><Lower respiratory tract structure><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Lung damage><Mediating><Medication><Membrane><Microcirculation><Modeling><Modern Man><Patients><Peptidases><Peptide Hydrolases><Perfusion><Permeability><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiologic><Physiological><Polymerase Chain Reaction><Printing><Process><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Pulmonary Body System><Pulmonary Organ System><Receptor Protein><Research><Research Personnel><Researchers><Respiratory Epithelium><Respiratory System><Respiratory Tracts><Respiratory tract structure><Reverse Transcription><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 outbreak><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Solid><Solid Neoplasm><Solid Tumor><Staining method><Stains><Stress><Stromal Cells><Structure of respiratory epithelium><Study models><Supporting Cell><Surface><System><Therapeutic><Thick><Thickness><Time><Tissue constructs><Tissues><Transcript><Upper respiratory tract><Vaccines><Viral><Virus><Wuhan coronavirus><adipose><airway epithelium><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><bio-printing><bioprinting><capillary><cell biology><cell stress><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infection><coronavirus disease 2019 outbreak><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus 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