Application of lung microphysiological systems to COVID-19 modeling and drug discovery: a review

Abstract

There is a pressing need for effective therapeutics for coronavirus disease 2019 (COVID-19), the respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The process of drug development is a costly and meticulously paced process, where progress is often hindered by the failure of initially promising leads. To aid this challenge, in vitro human microphysiological systems need to be refined and adapted for mechanistic studies and drug screening, thereby saving valuable time and resources during a pandemic crisis. The SARS-CoV-2 virus attacks the lung, an organ where the unique three-dimensional (3D) structure of its functional units is critical for proper respiratory function. The in vitro lung models essentially recapitulate the distinct tissue structure and the dynamic mechanical and biological interactions between different cell types. Current model systems include Transwell, organoid and organ-on-a-chip or microphysiological systems (MPSs). We review models that have direct relevance toward modeling the pathology of COVID-19, including the processes of inflammation, edema, coagulation, as well as lung immune function. We also consider the practical issues that may influence the design and fabrication of MPS. The role of lung MPS is addressed in the context of multi-organ models, and it is discussed how high-throughput screening and artificial intelligence can be integrated with lung MPS to accelerate drug development for COVID-19 and other infectious diseases.

Keywords: Bioengineering; COVID-19; Drug development; Lung; Microfluidics; Microvascular networks; Organ-on-a-chip.

Fig. 1

Lung microphysiological systems for COVID-19. a The lung has structurally unique tissue organization, characterized by a successively finer branching system of airways that terminate in the alveoli where oxygenation of blood from the circulatory system occurs. An accurate and rapidly deployable alveolar-level lung model is needed to develop drugs against the pathological damage caused by COVID-19, the disease resulting from SARS-CoV-2 viral infection. b Preceding the development of true lung MPS, Transwell systems used a membrane fitted insert into multiwell cell culture assay plates. Inserts with membranes that prevent fluid passage create an air–liquid interface where alveolar epithelial cells and vascular endothelial cells can be grown on each side. c Organoids can be formed by seeding an extracellular matrix with stem cells and then using a sequence of growth factors to differentiate them into a set of lung cells that organize spatially complex tissues resembling in vivo tissue architecture. d Lung microphysiological systems or lung-on-a-chip; a PDMS microdevice with a thin PDMS layer coated with ECM acting as an alveolar epithelial–capillary border. Breathing motions are recreated by applying vacuum to side compartments generating mechanical stretch of the alveolar–capillary membrane. Reproduced with permission from Huh et al. [19], Copyright 2010

Fig. 2

Pumpless organoid MPS. a Organoids can be loaded into the MPS, which is then perfused by microfluidic flow. Reproduced with permission from Frey et al. [35], Copyright 2015. b Pumpless flow is driven by gravity, where alternate setup allows continuous flow. c Human tissue organoid (hLiMT) perfused in the MPS shown at 5 × magnification. d Colored dye is used to show stacking of up to 60 experiments. e Cancer cell (HCT116) spheroid shown at 1 × magnification

Fig. 3

Overview of COVID pathology and therapeutics in relation to in vitro modeling. COVID-19 is generally agreed to have three phases: an acute phase characterized by inflammation, coagulopathy, and immune malfunction, an intermediate phase characterized by edema and a recovery phase characterized by the buildup of fibrotic extracellular matrix. Drug discovery for each stage presents unique challenges that can be overcome by adapting the usage of lung MPS

Fig. 4

Challenges to lung MPS and upcoming advances. a Small, typically lipophilic molecules bind to surfaces such as PDMS channel walls and can be characterized by the Langmuir–Freundlich isotherm. Coating a PDMS surface with paralyne or using sol–gel methods can prevent lipophilic binding [156, 157]. a1 Baricitinib, a Janus-associated kinase (JAK/STAT) inhibitor immunosuppressant, is used to treat COVID-associated hemophagocytic lymphohistiocytosis (HLH) [76]. a2 Fingolimod, a repurposed multiple sclerosis drug [89]. Aliphatic domains such as the hydrophobic tail create opportunities for the drug to bind to channel walls. a3 Budesonide, an anti-inflammatory steroid compared tested on lung MPS [90]. b Biologics such as antibodies and recombinant proteins adsorb to PDMS channel walls; methods to prevent adsorption include oxygen plasma treatment, amphilic, self-assembled monolayer and hydrophilic polymer graft coating [157, 161]. c Integrating MPS devices with automated liquid handling and continuous flow will introduce a new potential for streamlining drug discovery workflows and increasing throughput for screening lead compounds. d Machine learning and artificial intelligence algorithms such as neural networks can aid drug discovery through molecular docking and design, image analysis and toxicity predictions. Effective usage includes generating and seeking out sufficiently large datasets to train algorithms to make accurate predictions