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Microphysiological systems modeling acute respiratory distress syndrome

that capture mechanical force-induced injury-inflammation-repair

Article  in  APL Bioengineering · November 2019

DOI: 10.1063/1.5111549

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Microphysiological systems modeling
acute respiratory distress syndrome that
capture mechanical force-induced injury-
inflammation-repair
Cite as: APL Bioeng. 3, 041503 (2019); https://doi.org/10.1063/1.5111549
Submitted: 27 May 2019 . Accepted: 08 November 2019 . Published Online: 22 November 2019

Hannah Viola , Jonathan Chang, Jocelyn R. Grunwell, Louise Hecker, Rabindra Tirouvanziam, James B.
Grotberg, and Shuichi Takayama

COLLECTIONS

Paper published as part of the special topic on Microphysiological Systems

Note: This paper is part of the special topic on Microphysiological Systems.

This paper was selected as an Editor’s Pick

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APL Bioeng. 3, 041503 (2019); https://doi.org/10.1063/1.5111549 3, 041503

© Author(s).
 APL Bioengineering REVIEW scitation.org/journal/apb

Microphysiological systems modeling acute

respiratory distress syndrome that capture
mechanical force-induced injury-inflammation-
repair
Cite as: APL Bioeng. 3, 041503 (2019); doi: 10.1063/1.5111549
Submitted: 27 May 2019 . Accepted: 8 November 2019 .
Published Online: 22 November 2019

Hannah Viola,1,2 Jonathan Chang,3 Jocelyn R. Grunwell,4 Louise Hecker,5 Rabindra Tirouvanziam,6
James B. Grotberg, and Shuichi Takayama2,3,a)
7

AFFILIATIONS
1
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
2
The Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
3
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine,
Atlanta, Georgia 30332, USA
4
Department of Pediatrics, Division of Critical Care Medicine, Children’s Healthcare of Atlanta at Egleston,
Emory University School of Medicine, Atlanta, Georgia 30322, USA
5
Division of Pulmonary, Allergy and Critical Care and Sleep Medicine, University of Arizona, Tucson, Arizona 85724, USA
and Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona 85723, USA
6
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA and Center for CF
and Airways Disease Research, Children’s Healthcare of Atlanta, Atlanta, Georgia 30322, USA
7
Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA

Note: This paper is part of the special topic on Microphysiological Systems.

a)
Author to whom correspondence should be addressed: takayama@gatech.edu

ABSTRACT
Complex in vitro models of the tissue microenvironment, termed microphysiological systems, have enormous potential to transform the process of
discovering drugs and disease mechanisms. Such a paradigm shift is urgently needed in acute respiratory distress syndrome (ARDS), an acute lung
condition with no successful therapies and a 40% mortality rate. Here, we consider how microphysiological systems could improve understanding
of biological mechanisms driving ARDS and ultimately improve the success of therapies in clinical trials. We first discuss how microphysiological
systems could explain the biological mechanisms underlying the segregation of ARDS patients into two clinically distinct phenotypes. Then, we
contend that ARDS-mimetic microphysiological systems should recapitulate three critical aspects of the distal airway microenvironment, namely,
mechanical force, inflammation, and fibrosis, and we review models that incorporate each of these aspects. Finally, we recognize the substantial
challenges associated with combining inflammation, fibrosis, and/or mechanical force in microphysiological systems. Nevertheless, complex
in vitro models are a novel paradigm for studying ARDS, and they could ultimately improve patient care.
C 2019 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://
V
creativecommons.org/licenses/by/4.0/). https://doi.org/10.1063/1.5111549

I. PATHOPHYSIOLOGY AND ENDOTYPES OF ARDS pulmonary inflammation and edema resulting in secondary hypox-
A. Background emia and pulmonary fibroproliferation. ARDS can be triggered by var-
ious insults, whether direct (e.g., aspiration, pneumonia, and
Acute Respiratory Distress Syndrome (ARDS) is a life-threatening mechanical ventilation) or indirect (e.g., sepsis, trauma, and blood
acute lung condition characterized by the sudden onset of severe transfusion).2,8,84 Following such insults, most ARDS patients must be

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placed on positive pressure mechanical ventilation that can cause become activated and deposit fibronectin to re-establish a basement
ventilator-associated lung injury, which exacerbates the initial tissue membrane, and type II alveolar epithelial cells differentiate to type I
injury.101 Despite over 50 years of intense study and attempts at phar- epithelium and restore gas exchange and barrier function to sites of
macological treatment, the mortality rate in ARDS patients hovers at denudation. Immune cells are continuously recruited to mediate tissue
35%–45% and the condition afflicts an estimated 190 000 patients per repair. Hyaline membranes are a characteristic histological finding
year84 in the United States. It is also responsible for up to 10% of during this phase.19 The fibroproliferative phase is characterized by
intensive care admissions globally.11,35,46 Only modest improvements myofibroblast invasion, fibroblast proliferation, and collagen produc-
in survival have been made due to mechanical ventilation strategies tion. Surviving patients often experience a permanent decline in lung
that minimize ventilator associated lung injury.118 So far, no pharma- function.22 For detailed pathophysiology that is outside the scope of
cological therapies have reduced ARDS mortality, including those this review, readers are referred to recent comprehensive reviews by
aimed at attenuating inflammation, preventing or suppressing fibrosis, Matthay et al.84 and Sapru et al.108
addressing infection, or surfactant replacement to reduce fluid
mechanical stress.46,64,67
C. Injury-inflammation-repair in ARDS
B. ARDS pathophysiology Tissue repair, especially restoration of barrier function, is coordi-
Pathophysiology of ARDS occurs in 3 chronological phases. In nated through inflammatory and fibrotic processes that are influenced
the exudative phase, severe inflammation causes diffuse alveolar injury by the mechanical and biochemical microenvironment [Fig. 1 (Refs. 2,
and increased epithelial and microvascular permeability. 7, 15, 27–29, 53, 69, 88, 89, 101, 121, and 123)]. The initial injury is
Proteinaceous vascular fluid leaks into the alveolar lumen, and large caused primarily by neutrophil-dependent and platelet-dependent
amounts of alveolar epithelial cells die. Surfactant production is com- damage to the endothelial and epithelial barriers of the small airways
promised as type II pneumocytes are lost so that the fluid flooding the and alveoli. Studies in large animals showed that alveolar edema
lumen has an abnormally high surface tension.28 Leukocytes, especially occurs only when there is damage to both the endothelium and epithe-
neutrophils, are aggressively recruited and release proinflammatory lium.138 In healthy repair, inflammation and fibrosis restore barrier
cytokines, proteases, and neutrophil extracellular traps. Apoptotic epi- and gas exchange function to the epithelium and endothelium and
thelial cells and neutrophils accumulate in the alveolar lumen and subsequently resolve.4,7,12,27 While the endothelium’s morphology
begin to form hyaline membranes composed of immunoglobulin, appears unaffected aside from its compromised barrier function,
complement, dead cell debris, and fibrin. Fibroblasts infiltrate into this the epithelium experiences significant denudation and apoptosis in
environment to repair the tissue damage sustained by the initial injury. addition to loss of barrier function, which prevents removal of alveolar
In the proliferative phase, type II alveolar epithelial cells and fibroblasts edema fluid and deprives the lung of adequate quantities of
proliferate and cover sites of denudation in the alveoli. Fibroblasts surfactant.84

FIG. 1. Injury-inflammation-repair in lung

disease. Inflammation and fibrosis (resolv-
ing or nonresolving) cooperate to remodel
lung tissue after injury.7,27 Both processes
are heavily influenced by stressors in the
tissue microenvironment. In ARDS,
mechanical forces arising from surfactant
dysfunction28 and mechanical ventila-
tion101 interfere with the tissue repair pro-
cess by reinjuring the tissue,2,29,53,69
thereby inducing inflammation123 and pro-
moting fibrosis.15,121,131 The interactions
between tissue stress, inflammation, and
remodeling can direct the tissue toward
successful tissue repair or toward aberrant
remodeling that consists of progressive
fibrosis and systemically dysregulated
immunity.7,15,88,89,131

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Epithelial repair in ARDS is often dysregulated. Blood neutro- II. MODELING ARDS ENDOTYPES
phils are recruited massively to the lumen, where they extend their life- A. Traditional models
span in the lung tissue and perpetuate inflammation.48 Meanwhile,
To understand the biological mechanisms that drive ARDS endo-
activated fibroblasts deposit excess collagen that impairs gas
types, preclinical models of ARDS pathophysiology are essential. The
exchange.86 Most patients require mechanical ventilation and experi-
ideal preclinical model of ARDS pathophysiology should recapitulate
ence surfactant dysfunction, exacerbating epithelial injury during the
only the critical aspects of the complex disease microenvironment,
repair process and imparting sublethal stresses on the epithelium.
focusing on a specific etiology and patient endotype. Current models
Compounding the impact of ventilation is the fact that the epithelium,
are limited in their ability to represent human pathophysiology for the
immune cells, and fibroblasts sense and respond to mechanical
study of disease and drug mechanisms.
forces14,31,60,85,109,121,137,144 in the lung microenvironment. Therefore,
2D monoculture of the airway epithelium in vitro cannot capture
models of inflammation and fibrosis during mechanical ventilation are
intricacies of inflammatory networks and cross talk between processes
critical to understanding how epithelial repair impacts ARDS endo-
of injury, inflammation, and remodeling. This culture method typi-
type development and consequently the patient’s chance of survival.
cally also neglects tissue-level stresses such as mechanical force and
does not account for fluid stresses that are dominant in ARDS due to
D. ARDS endotypes surfactant depletion. Finally, cell lines are limited in their relevance to
ARDS is a clinically heterogeneous condition. Approximately pathophysiology. However, primary human cells are becoming more
10% of ARDS patients recover rapidly and in the acute phase accessible. For example, the Marisco Lung Institute’s CF Center Tissue
(<3 days),110 and these patients may not require intervention aside Procurement and Cell Culture Core has pioneered isolation and cul-
from ventilation. Meanwhile, a larger subset of patients experien- ture techniques for primary human lung cells.43
ces progressive fibrosis80,81,89 and/or systemically dysregulated Animal models, notably mouse models, capture complex interac-
inflammation,17,90,104 both of which are associated with a higher tions between injury, inflammation, and tissue repair in ARDS, mak-
risk of mortality.17,21,65,81,87,118 These nonresolving patients might ing them more suitable than current in vitro studies for drug testing.
benefit from pharmacologic intervention, especially if their risk of For pathophysiology studies, however, species-specific differences in
developing to this stage could be identified prior to the onset of lung physiology could interfere with attempts to correlate biomarkers
symptoms. Additionally, ARDS clinical trials74,106,128 have with pathophysiological mechanisms. There is conflicting evidence
reported inconsistent therapeutic responses. This failure could be regarding whether murine gene expression profiles in response to lung
explained by the syndrome’s heterogeneity. Therefore, there is injury correlate well with those in humans. Sweeney et al. argue for
great interest in predicting (a) which patients will not recover rap- significant similarity between murine and human inflammation after
idly to determine when intensive treatment and/or trial enrollment lung injury,122 although limitations to this study include the small
is most beneficial38 and (b) which nonresolving patients might human sample size (n ¼ 3) and the number of genes evaluated
respond to which therapeutics to enrich clinical trial cohorts with (n ¼ 432). Further, this study compared human samples from patients
potential responders. with non-ARDS lung injury. Seok et al., in contrast, assert that when
To address these urgent questions, clinicians have developed comparing almost 5000 human and murine genes altered by the same
prognostic markers that correlate ARDS outcomes with epidemiology, inflammatory stressors (i.e., burn, trauma, and hypoxemia), mouse
genomics, clinical features, physiology, and biomarkers.26,116 The lad- models of inflammation show a close to random (R2 between 0 and
der classifier is advantageous because it stratifies patients based on 0.1) association to human gene counterparts.112 Inflammation in
indicators of the underlyling biology of their disease. This powerful ARDS involves thousands of responsive genes,104 and a comprehen-
connection to biology might enable clinicians to predict therapeutic sive determination has not been reached about the relevance of murine
responses using these biomarker-based classificiations when the path- gene expression to human ARDS. Therefore, there is interest in study-
ophysiology driving each biomarker profile is better understood. For ing human cells to complement animal studies.
example, Calfee et al.17 used latent class analysis to show that ARDS Inherent limitations hinder the study of primary human samples.
patients cluster into two clinical endotypes based on biomarkers: It is impossible to control the cell types (e.g., immune cells, epithelium,
hyper- and hypoinflammatory. The former experienced higher rates of and fibroblasts) and mediators (e.g., cytokines, chemokines, and extra-
shock and metabolic acidosis, had significantly worse outcomes, and cellular matrix components) present in a patient’s lung microenviron-
had higher mortality in response to mechanical ventilation with low ment, limiting the ability to interrogate individual components’
positive end expiratory pressure. These findings were later verified contribution to pathophysiology. This limitation can result in studies
using cluster analysis,13 and a second retrospective trial analysis that are descriptive rather than mechanistic. Biopsy samples are
showed endotype-associated responses to simvastatin.18 acquired primarily from deceased patients because biopsies are a high-
In these retrospective studies, Calfee’s classifiers have demon- risk procedure for living patients. Because of this, human lung samples
strated the potential to transform patient care by treating patients are biased toward severe disease and provide little opportunity to study
based on the biology driving their disease. However, biomarker-based the evolution of the disease microenvironment from the early to late
endotyping cannot fulfill its promise of predicting endotype-specific stage. Bronchoalveolar lavage fluid (BALF) provides a snapshot of the
responses to drugs until the biological mechanisms behind each endo- distal lung’s cytokine, immune cell, and mucus content, but cellular-
type are understood. Only then will endotyping be a convincing deter- level mechanisms cannot be positively inferred without corroborating
minant of patient enrollment in clinical trials. Sinha and Calfee116 in vitro data.
provide a more extensive review of ARDS endotyping and the need for Whole blood is readily available but provides limited information
biological mechanisms. about the lung microenvironment. Particularly, peripheral neutrophils

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are often studied in ARDS, but their relevance to the lung microenvi- ARDS model.96 However, these models do not capture endotype-
ronment is unclear because lung neutrophils appear to acquire novel specific ARDS.
phenotypes upon recruitment to the airways. In vitro, transepithelial MPSs are uniquely suited to become the first preclinical ARDS
migration of primary peripheral neutrophils into pediatric ARDS endotype models. MPSs can undergo iterative prototyping until a
patient airway fluid activates neutrophils toward a proinflammatory desired pathophysiological feature is adequately captured. This strat-
phenotype with paradoxically decreased bacterial killing potency.51 egy is illustrated in Fig. 2. MPS designers compare their prototype to
Additionally, primary neutrophils isolated from adult ARDS BALF the human phenotype using metrics such as biomarkers, immune cell
display impaired bacterial killing and superoxide production com- phenotypes, and responses to stimuli (e.g., strain, hypoxia, and infec-
pared to blood and local arterial neutrophils.83 Overall, human sam- tion). The prototype is then adjusted to better reflect in vivo metrics
ples are a vital component of ARDS pathophysiology research but through the precise control of microenvironmental factors such as cell
corresponding in vitro data from more sophisticated models are types, inflammatory and fibrotic mediators, and type/degree of
needed to study mechanisms. For a more in-depth review of preclini- mechanical force. MPSs capture disease processes to the extent neces-
cal ARDS models, see the excellent analysis by Laffey and Kavanagh.72 sary to produce endotype-specific biomarkers but remain simple
enough to obtain a high signal-to-noise ratio, which is a desirable
B. Modeling ARDS in microphysiological systems feature of in vitro models.
(MPSs) This review focuses on the bioengineering challenges of construct-
Microphysiological systems (MPSs) are in vitro cell culture sys- ing an ARDS microphysiological system that could address clinical
tems incorporating 3-D culture, coculture, physical forces, or other problems, especially the need to understand endotype pathophysiology.
tissue-level phenomena that aim to create a tissue-mimetic microenvi- Critical aspects of the alveolar microenvironment during ARDS should
ronment. They capture complex tissue-level physiology and disease be identified and included in experimental models of ARDS. This
phenomena in vitro using primary human cells and fluids from review highlights mechanical forces, inflammation, and fibrosis because
patients,68 lending them the potential to bridge the gap between ani- they are central to ARDS pathophysiology and tissue repair, difficult to
mal models and human pathophysiology. MPSs supplement human capture in vitro with traditional methods, and readily adaptable to
and animal models and provide a third paradigm for the study of com- existing MPS technology.
plex disease processes and drug mechanisms. MPS modeling different III. CAPTURING MECHANICAL FORCES IN MPS
ARDS endotypes could explain the different responses to simvastatin
and protective ventilation that were observed between hyperinflamma- A. Physiological forces in the distal airways
tory and hypoinflammatory cohorts in clinical trials. Because a majority of ARDS patients are mechanically ventilated,
Of course, the challenge of recreating a pathophysiology that is it is important to understand how the forces inflicted by positive pres-
poorly understood, for the purpose of advancing its understanding, sure ventilation and mechanical stress from excess fluid in the bron-
cannot be overstated. ARDS endotypes are not correlated strongly choalveolar region impact the tissue repair process. After ARDS onset,
with disease etiology or epidemiology, and as a result, there are cur- surfactant function is compromised due to the death of type II alveolar
rently no preclinical models of endotype-specific ARDS. There are sev- epithelial cells and flooding of distal airways with proteinaceous fluid.8
eral excellent etiology-specific models: Hecker and colleagues recently This increases the surface tension of the liquid covering the surface of
developed a “two-hit” murine model of ARDS combined with aging the alveolar and small airway epithelia, leading to abnormally high lev-
that resembles human ARDS more closely than traditional mouse els of fluid stresses. These are exacerbated by alveolar collapse and
models and may prove more clinically relevant for therapeutic efficacy reopening (atelectasis), overdistension of the alveoli (volutrauma),
evaluation.99 Nemzek et al. have studied a two-hit aspiration-induced and/or high peak inspiratory or driving pressures (barotrauma) during

FIG. 2. Iterative model design with validation against patient phenotype will lead to an endotype-specific model of ARDS that can be used for predictive enrichment of ARDS
clinical trials. Endotype-specific metrics such as cytokine ratios, immune cell functions (e.g., bacterial killing, metabolism, and NETosis), and degree of surfactant production
can be compared between patients and in vitro models. Iterative adjustments to model parameters, such as genetics (e.g., MUC5A upregulated epithelium), physical forces,
degree of initial injury, degree of fibrosis, and the type and ratio of inflammatory mediators, could enable the development of a model that produces biomarkers or functional
characteristics (e.g., response to therapeutics, response to mechanical strain, and immune cell phenotype changes such as enhanced NETosis), mimicking those of a specific
endotype. The model should also be validated by testing functional outputs such as barrier function of the epithelium and tissue healing (scratch wound assay). The final model
provides the opportunity for pathophysiological mechanisms of disease to be clarified and for drug candidates to be tested in vitro. Both pathophysiology and drug testing will
help predict whether a certain endotype is likely to respond to novel treatments.

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mechanical ventilation.45,97,98 Figure 3(A) illustrates forces experi- that allow for strain or compressive stress to be applied to well-
enced by the small airways and alveoli during ARDS. Of note, surfac- differentiated cell lines or primary airway cells in air-liquid interface
tant trials to alleviate fluid stress have not succeeded. Studies suggest (ALI) culture (Table I).
they may have failed as a result of inadequate delivery to the alveoli Complex fluid stresses also contribute significantly to lung
due to low instilled dose volume, as indicated by computational injury.2,49,101,107 Investigators have modeled the fluid stresses
modeling.39,50 imparted by liquid plug propagation and rupture, small airway col-
lapse and reopening, and alveolar collapse and reopening. The
Gaver group was the first to report an in vitro system for modeling
B. Existing mechanical force MPS the stress field associated with alveolar recruitment using a moving
Lung mechanical forces can be categorized broadly as compres- air bubble [Fig. 3(D) (Refs. 10 and 142)]. They showed that slower
sive stress, shear stress, and stretch [Fig. 3(B)].140 Shear stress is the bubble speeds increase cell death, despite a milder shear gradient,
force per area that acts parallel to a plane, often considered a “slipping” because the pressure gradient is significantly increased.70 In the
force. Strain (stretch) is the change in the length of a plane divided by same moving air bubble model, Higuita-Castro et al. showed that
the initial length. Compressive stress is the force per area applied per- increasing the substrate stiffness caused greater cell death after 1
pendicular to a plane; it includes pressure and normal force. The and 5 bubbles57 [Fig. 4(c)].
effects of mechanical forces on pulmonary epithelia have been studied Additionally, Takayama and colleagues modeled liquid plug
in vitro for several decades.76,137 Most models incorporate membranes propagation and rupture in vitro61,126 [Fig. 4(a) (Refs. 42, 54, and 61)].

FIG. 3. Physiologic mechanical forces in the bronchoalveolar region and their computational models. (A) The acinus consists of alveoli sacs that branch off of common terminal
bronchiole (d) or (h); sacs (e), (f), and (g) are depicted in this figure. Sac (e) is cut off from air flow by the stagnant plug at (d); sac (f) is overinflated, and sac (g) is flooded
with proteinaceous fluid. (B) Shear, strain, and compression are the main components of force present in the lungs, either independently or in concert. In the above depiction,
strain results from overinflation of sac (f) due to obstruction of sac (d) and collapse of sac (g). Compression of adjacent sac results from the overinflation of (f). Shear stress is
a component of the stress field produced during airway reopening at (h).10,142 Interfacial flow damages the small airways when liquid plugs propagate and rupture during inspi-
ration61,126 (a)–(c) Transient liquid plugs form when the small airways collapse slightly and liquid on either side of the airways meets, forming the plug depicted in (a). Upon
inspiration, the plug is pushed by pressure-driven flow, becoming thinner and thinner (b) until it loses integrity and pops (c), creating the crackle sounds that are observed upon
auscultation of the lungs. (C) Hassan et al.54 modeled liquid plug propagation and rupture and found that the leading edge of the plug creates a narrow capillary wave (circled).
The wave’s extreme pressure gradient imparts severe stress on the airway wall. (D) The first in vitro model of airway reopening was introduced by Bilek et al.10 Using this
model, Yalcin et al. found that smaller airway diameters experience greater stress.142 Reproduced with permission from Hassan et al., Int. J. Numer. Methods Fluids 67, 1373
(2011). Copyright 2011, John Wiley and Sons.54 Reproduced with permission from Bilek et al. J. Appl. Physiol. 94, 770 (2003). Copyright 2003, American Physiological
Society.10

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APL Bioengineering
TABLE I. Representative sample of in vitro platforms that replicate mechanical forces in the lungs.

Mechanical Force application Key metrics in response to

References Stimuli Disease Cell type(s) Model type method force

Ressler et al.105 Compression Asthma Rat tracheal epithelial Transwell Air pressurization RNA coding for Egr-1, endo-
above culture thelin-1, TGF-b
Swartz et al.121 Compression Asthma Normal human bronchial Transwell epithelium Air pressurization Quantitative production of
epithelial and normal culture over fibroblasts above culture collagen, fibronectin
human lung fibroblast
(CCL-186)
Tschumperlin et al.132 Compression Asthma Normal human bronchial Transwell Air pressurization MAP kinase and herparin-
epithelial above culture binding epidermal growth
factor (HB-EGF)
Bilek et al.10 Stress field, pres- VILI Fetal rat pulmonary epithe- Parallel plate flow Air bubble propagation Cell death (live/dead stain)
sure gradient lial (CCL-149) chamber
Chu et al.24 Compression Asthma Normal human bronchial Transwell Air pressurization Quantitative expression of
epithelial above culture epidermal growth factor
receptor ligands HB-EGF,
epiregulin, amphiregulin,
TGF-b
Tarran et al.125 Shear stress Cystic fibrosis Primary human epithelial Transwell Phasic motion of Adenosine triphosphate (ATP)
culture release, periciliary layer
thickness
Choe et al.23 Compression Asthma Human fetal lung Tissue-engineered Dynamic lateral com- Deposition of types III and
fibroblast (CCL-186) human airway wall pressive strain IV collagen, MMPs-2 and-9
Huh et al.61 Shear stress, Pulmonary Primary human small Microfluidic chip Liquid plug propaga- Cell death (live/dead stain)
pressure gradient edema airway epithelial tion and rupture
Yalcin et al.142 Shear stress, ARDS Fetal rat pulmonary Height adjustable Air bubble propagation Cell death (live/dead stain)
pressure gradient epithelial (CCL-149) parallel plate flow
chamber
Sidhaye et al.114 Shear stress General Normal human bronchial Cell culture insert Laminar fluid flow Paracellular permeability

REVIEW
epithelial
Fronius et al.41 Shear stress Cystic fibrosis Xenopus oocyte Xenopus oocyte Fluid stream Epithelial sodium channel
activation
Huh et al.63 Strain General Human pulmonary micro- Microfluidic chip Stretching porous ICAM-1 (endothelium), ROS
vascular endothelial and membrane generation (epithelium),

scitation.org/journal/apb
alveolar epithelial, periph- nanoparticle translocation
eral neutrophil (H441,
A549, E10)
Douville et al.32 Shear stress, ARDS Human alveolar basal epi- Microfluidic chip with Membrane stretch and Cell death (live/dead stain)
strain thelial (A549) and primary flexible membrane air-liquid interface
murine alveolar epithelial oscillation
Jacob and Gaver69 Stress field, pres- ARDS Human pulmonary epithe- Parallel plate flow Air bubble propagation Paracellular permeability;
sure gradient lial (H441) chamber Distribution of tight junction
3, 041503-6

proteins ZO-1 and claudin 4

 APL Bioengineering REVIEW scitation.org/journal/apb

They found that liquid plug propagation caused cell death even with-
Key metrics in response to

Proteoglycans, aSMA, colla-

gens I and III, MMPs 2 & 8,
Proliferation, IL-8 secretion

Cell viability, NF-jB, stress

out plug rupture. To explain this observation, Fujioka et al. showed
that the front meniscus of a moving liquid plug imparts large stresses
on the airway wall due to a narrow capillary wave that appears ahead
of the plug’s leading edge [Fig. 3(C), capillary wave circled].42,54
force

Recently, Muradoglu et al. also showed that surfactant reduces the

mechanical stress imparted by the liquid plug.95 In an alveolar closure/
reopening model, Douville et al. showed that repeat strain combined
fibers with fluid stress caused cell death and detachment, suggesting a mech-
IL-8

anism for how atelectasis affects lung function32 [Fig. 4(b)]. The work
of the preceding investigators has brought attention to the major role
of fluid stresses in promoting lung injury. Additionally, we provide a
Force application

representative history of all types of pulmonary epithelial force models

in Table I.10,23,24,32,41,61,63,69,79,105,114,117,119,121,125,132,142
Microdiaphragm
method

Cyclic strain

propagation
Liquid plug

C. Limitations of mechanical force MPS

stretching

Few pulmonary force models consider the physical properties of

the extracellular matrix, such as stiffness and substrate ligands. It is
well established that substrate ligands affect epithelial and endothelial
properties and that focal adhesions mediate mechanosensing.1,73 Of
relevance to mechanical force models, aligned collagen fibers in the
Model type

Microfluidic chip

Microfluidic chip

substrate amplify cell-cell mechanotransduction across distances

Flexible silastic

greater than several cell diameters.78 In the moving air-finger model

membranes

[Fig. 4(c) (Refs. 10, 57, 58, 69, 70, and 142)], Higuita-Castro et al.
showed that increased substrate compliance leads to greater cell
detachment and less necrosis.57 More investigation is needed to deter-
mine the effects of substrate properties on physiology in mechanical
force models.
human pulmonary alveolar

Obstructive Primary human small air-

pressure gradient lung diseases way epithelial (CC-2547)

Mechanical force models rarely contain multiple stress types,

(16HBE14o), primary

despite indications that stressors work synergistically to promote

Cell type(s)

Bronchial epithelial

epithelial, HUVEC

injury. For example, simultaneous surfactant loss and overstretching

Primary bronchial

of the alveoli cooperatively promote secondary lung injury during

mechanical ventilation.97,98 Even models that do capture complex
fibroblasts

force combinations or stress fields often fall short of describing the

force’s downstream effects on the tissue. Huh et al. and Douville et al.,
shown in Figs. 4(a) and 4(b), capture complex forces but characterize
only cell death and detachment. Ghadiali and colleagues, in contrast,
have characterized mechanotransduction in the moving air-finger
model [Fig. 4(c)].57,58,69 Still, both models lack immune and fibroblast
General

Asthma
Disease

coculture.
Because tissue repair is an essential component of recovery from
ARDS, it is critical to capture the interaction between tissue repair and
mechanical forces. This dynamic relationship remains poorly under-
stood despite two decades of in vitro studies on the effects of mechani-
Mechanical

cal forces on isolated epithelial, fibroblast, and immune

Stimuli

Shear stress,

cells.85,127,137,144 In the following, we discuss the challenges and oppor-

tunities for modeling this aspect of ARDS in MPS.
Strain

Strain

IV. CAPTURING INFLAMMATION AND FIBROSIS IN MPS

A. Inflammation and fibrosis in ARDS
Manuyakorn et al.79

Inflammation in ARDS is characterized by early and persistent

TABLE I. (Continued.)

neutrophilia, mast cell recruitment and activation,135 and recruitment

Stucki et al.119

of monocytes and macrophages in the distal airways and alveoli.84

Song et al.117

Neutrophil activity is believed to damage tissue in ARDS.48,146

References

Neutrophils secrete proteases, such as neutrophil elastase and matrix

metalloproteases (MMPs), which degrade the extracellular matrix, and
neutrophils promote hypoxia through rapid oxygen consumption and

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FIG. 4. MPS models of mechanical force

in lung disease. (a) (i) A microfluidic
device replicates the generation of crackle
sounds frequently heard in the distal air-
ways of patients with pulmonary edema.
(ii) The device generates liquid plugs that
propagate and rupture in channels over
alveolar type I pneumocytes. (iii) Plugs
result in epithelial cell death (red) during
propagation (left) and especially at the
rupture site (right). Scale bar, 150 lM. (iv)
Fluid dynamic simulations show that the
leading edge of the plug applies severe
shear stress to the epithelium.42,54
Reproduced with permission from Huh
et al. Proc. Natl. Acad. Sci. U. S. A.
104(48), 18886–18891 (2007). Copyright
2007 National Academy of Sciences.61 (b)
(i) Douville et al. report a device that
applies simultaneous fluid shear stress
and mechanical strain to alveolar epithe-
lium; vacuum stretches the membrane
and simultaneously lowers the fluid level.
(ii) Fluid stress and strain result in death
(red cells) and detachment of alveolar epi-
thelium in the device. Scale bar, 1 mm.
Reproduced with permission from Lab on
a Chip 11, 609–619 (2011). Copyright
2011 Royal Society of Chemistry.32 (c) (i)
Higuita-Castro et al. mimic small airway or
alveolar reopening by propagating an air
bubble over the epithelium.57 The device
design, first conceived by Bilek et al.,10
has been extensively used to characterize
the damage of liquid stress during atelec-
tasis and airway reopening.57,58,69,70,142
(ii) and (iii) Higuita-Castro et al. show that
the fluid meniscus causes increasing cell
death and detachment with increasing
substrate stiffness. Reproduced with per-
mission from Higuita-Castro et al., J. Appl.
Physiol. 117, 1231 (2014). Copyright 2014
American Physiological Society.57

the excessive production of reactive oxygen species (ROSs).25,48,146 Concurrently, fibroproliferation and tissue repair proceed in
Neutrophils are also affected by mechanical stressors in vitro and response to both the primary tissue injury and the damage caused by
in vivo. Force induces the production of chemotactic factors, including recruited neutrophils. In the terminal bronchioles and alveoli, type II
TNF-a,60,102,103,129 IL-8,102,131,136 and IL-6.103,123,129,141 IL-6 has long pneumocytes proliferate and fibroblasts become activated. Proliferating
been considered a biomarker of ventilator-induced lung injury, and fibroblasts deposit provisional extracellular matrix (ECM) consisting of
TNF-a and IL-8 are master regulators of inflammation. fibronectin, and later collagen, to repair ECM damage and restore

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epithelial integrity.84,89 Dysregulated fibroproliferative repair can

develop into nonresolving fibrosis that has a poor prognosis in
ARDS and is refractory to treatment.80,81,87 Aside from the intro-
duction of protective ventilation strategies that limit ventilator-
associated lung injury, attempts to prevent the occurrence of non-
resolving fibrosis and dysregulated immunity, or to slow progres-
sion, have not yielded success.
Crosstalk between the epithelium and immune system in
response to mechanical force plays a significant role in mediating tis-
sue repair. This process is poorly characterized due to its complexity
and heterogeneity, but general mechanisms of mechanical force-
induced epithelial-immune cross talk that have been reported individ-
ually are presented in Fig. 5 (Refs. 5, 12, 16, 20, 27, 30, 31, 33, 34, 40,
44, 48, 52, 56, 59, 60, 66, 75, 77, 82, 85, 92–94, 100, 107, 113, 115, 117,
120, 121, 123, 124, 130, 133, 137, 139, and 143–146).

B. Challenges of modeling inflammation and fibrosis

in MPS
The choice of cell types, source, and degree of activation or polar-
ization can greatly affect cell phenotype and responses to stimuli.
Tissue repair in vivo involves the migration, activation, and cross-
contact of multiple cell types including fibroblasts, neutrophils, mono-
cytes, and lymphocytes. The ideal model would capture a high degree
of in vivo cell functionality including fibroblast proliferation, immune
transmigration and in situ activation, degranulation, neutrophil extra-
cellular trap (NET) formation, and elevated phagocytosis. However,
many of these behaviors are difficult to control and modulate in com-
plex model systems with multiple cell types. For example, TGF-b acti-
vates fibroblasts but may have concurrent effects on the epithelium
and immune cells. MPSs should capture the minimal activation neces-
sary to recapitulate the disease mechanism of interest.
Barkal et al., for example, focused on neutrophil activation in
their small airway-on-a-chip model of fungal infection. Neutrophils FIG. 5. Reported mechanical stress-induced cell behaviors and inflammatory medi-
migrated toward volatile fungal chemoattractants through the endo- ators that enable cross talk between pulmonary epithelium and immune cells.
Mechanical stresses due to surfactant dysfunction, edema, and mechanical ventila-
thelium and epithelium [Fig. 6(a)].6 In a model of invasive aspergillo- tion cause the epithelium to produce inflammatory and fibrotic mediators107,130 and
sis, the device recapitulated the well-characterized inflammatory may induce the integrated stress response, a key mediator of mechanical stress-
cytokine response and increased recruitment of neutrophils observed induced epithelial injury.31 Mechanical force-induced cell behaviors and mediators
in murine and zebrafish models. In another example, Choe et al. of cross talk between the epithelium and immune cells are listed in Fig. 5. Such
focused on activation of fibroblasts.23 They applied strain to a cocul- cross talk drives remodeling pathways; for example, hyperactivated neutrophils
deplete oxygen in their microenvironment through the excessive production of reac-
ture of human bronchial epithelial cells atop a fibroblast-seeded colla-
tive oxygen species (ROSs). This hypoxia stresses the epithelium and leads to apo-
gen gel. They found that strain induced myofibroblast differentiation ptosis or inflammatory signaling that promotes fibroblast activation and epithelial
and type III and IV collagen deposition. Both myofibroblasts and type proliferation. Neutrophils also contribute directly to remodeling during epithelial
III collagen were concentrated close to the basal side of the epithelium, transmigration;12 massive neutrophil influx compromises tight junction integrity and
suggesting that the epithelium is a source of profibrotic mediators that stimulates repair of the lamina propria.146 Mechanically activated neutrophils and
promote matrix remodeling. Their in vitro model included the mini- alveolar macrophages also secrete proteases that degrade the extracellular matrix
(ECM), such as neutrophil elastase, and promote continued ECM destruction and
mum cell types and activating stimuli to capture remodeling events.
activation of fibroblasts to repair the ECM damage.27,44,124 Because neutrophils are
Furthermore, the model showed that the pathway is not mediated by significant drivers of this destructive remodeling cycle, they are a target of therapeu-
immune cells because they were not present. The rational choice of the tic research.120
required cell types and activating stimuli enables MPSs to remain sim-
ple enough for analysis but sophisticated enough to capture inflamma-
tion and remodeling in vitro. multifactorial. As such, they should be further explored in ARDS
Immune cell and fibroblast cocultures greatly improve the physi- MPSs that can incorporate physiological forces in coculture systems.
ological relevance of ARDS MPSs but present significant design chal- Additionally, the presence of multiple cell types obfuscates the source
lenges. First, very few MPSs have studied the impact of mechanical of inflammatory and fibrotic mediators (e.g., cytokines, proteases,
strain on fibrosis. Swartz et al.121 and Choe et al.23 showed that strain- miRNA, reactive oxygen species, and TGF-b). To overcome this hur-
induced fibrosis can be mediated by the epithelium, but such mechani- dle, MPS data are sometimes analyzed with systems biology techniques
cal force pathways that induce fibrosis are likely complex and similar to those used to parse out in vivo signaling pathways.9,134

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FIG. 6. Models of pulmonary inflammation

in vitro. (a) (i) A microfluidic small airway-
on-a-chip replicates the endothelium,
interstitial fibroblasts, and epithelium. (ii)
Fungal infection is simulated by inoculat-
ing the epithelium with wild type
Aspergillus fumigatus, a model fungal
pathogen. (iii) Neutrophils are added to
the endothelial channels after the hyphae
have extended into the interstitial space.
Scale bar, 200 lM. (iv) Neutrophils che-
motax from the endothelium through the
interstitium toward fungal hyphae,
attracted by volatile compounds produced
by the fungus. Scale bars, 100 lM.
Reproduced with permission from Barkal
et al. Nat. Commun. 8, 1770 (2017).
Copyright 2017 Authors, licensed under a
CC BY 4.0 (https://creativecommons.org/
licenses/by/4.0/).6 (b) (i) and (ii) A micro-
fluidic alveolus-on-a-chip incorporates
strain and neutrophil transmigration in a
bilayer epithelium-endothelium coculture
model. (iii) E. coli on the epithelium
attracts neutrophils to transmigrate from
the basal channel through endothelium
and epithelium. (iv) Two E. coli bacteria
(green) on the epithelium are chased and
phagocytosed by a neutrophil (red) on the
epithelium of the device. Reproduced with
permission from Huh et al., Science 328,
1662 (2010). Copyright 2010 AAAS.63

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Additionally, airway epithelia, especially from primary cells, the greater research community. Designers must consider what aspect
require many days or weeks to polarize. Media optimization may not of pathophysiology they desire to model and carefully consider what
be adequate to maintain the health and desired phenotype of all cell features are necessary to capture the phenomenon while minimizing
types present in coculture in the long term. Sellgren et al. reported a the components of the system.
triple coculture of primary airway epithelium, fibroblasts, and endo- ARDS pathophysiology is complex and involves multiple stages
thelium but noted that an airwaylike phenotype (cobblestone mor- with different characteristics. The designer must consider what aspects
phology, mucus production, and cilia) was difficult to maintain in of disease progression to model. For example, Huh et al. captured pul-
coculture conditions.111 MPS designers should consider if long-term monary edema, fibrin deposition, and impaired gas exchange in
coculture can be avoided, and if not, what media formulations can response to toxic levels of IL-2 in a lung-on-a-chip microdevice
maintain cocultured cells in their desired phenotypes. including only the epithelium and endothelium (Fig. 7). They discov-
Substrate properties and mechanical forces also affect immune ered that immune cells and fibroblasts were not necessary to produce
and fibroblast cell phenotypes. MPSs should have physiologically rele- these tissue-level functions, but strain was necessary, indicating that
vant physical forces and substrate properties so that immune and strain is a significant initiator of early pulmonary drug toxicity
fibroblast phenotype mimic those in vivo. While models have indepen- responses in vivo.
dently considered immune cell and fibroblast mechanobiology in Conversely, designers must consider whether even the most com-
response to single stresses such as substrate stiffness or mechanical plex MPS is comprehensive enough to replicate the phenomenon of
force, few combine multiple stress types in the same microenviron- interest. For example, a single MPS could not capture multiple organ
ment. Although Huh et al. (2010) [Fig. 6(b)] incorporated interstitial failure. Systemic dysregulated immunity that is observed in sepsis is
flow, strain, and transmigration into their alveolus on-a-chip, they did likewise unlikely to be captured in a single MPS. Many MPSs also lack
not study how these forces affected the neutrophils in the model. an immune component, a challenge that has not been addressed suffi-
V. GENERAL CHALLENGES OF MODELING ARDS IN ciently. However, the simplicity of MPSs compared to in vivo models
MPS is often a benefit because it allows the isolation of confounding factors
from the system, such as in Choe et al.23 and Huh et al.62
A. Complexity
A major challenge of designing MPSs is determining the level of
model complexity. An overly complex model will produce noisy data, B. Heterogeneity
but an overly simplistic one is not useful. One option is to utilize func- Because ARDS is a heterogeneous syndrome, it is impossible to
tional readouts that are already familiar to the biology community, construct a unifying model that incorporates every possible phenotype.
such as phenotypic assays (e.g., assays for bacterial phagocytosis and MPSs could, however, be used to generate high throughput microen-
killing by neutrophils), to reduce the dimensionality of the data while vironments mimicking the phenotypes to better understand divergent
keeping the model relatively complex. MPSs are, however, limited in biological pathways driving phenotypic differences. For cell culture,
how complex they can become before losing physiological relevance. primary human cell heterogeneity is also a significant challenge.
A model that is too complicated could create conditions that induce Quality control of primary-cell-sourced cultures is difficult, especially
nonphysiological cell behaviors. Additionally, elaborate models are dif- in microfluidic culture with very small cell populations, due to vari-
ficult to fabricate, which limits their throughput and accessibility to ability across patients and even among cells from a single source.

FIG. 7. In vitro models of the lung microenvironment could be applied to study fibroproliferative disease in ARDS. (i) A lung-on-a-chip that replicates vascular leakage, leading
to pulmonary edema and fibrin clotting.62 (ii) Strain is applied, by pulling vacuum on either side of the chamber, to a membrane (iii) with alveolar epithelium on the apical side
and endothelium on the basal side. Scale bar, 200 lM. (iv) IL-2 induces endothelial and epithelial permeability allowing basal media loaded with prothrombin and fibrin to pass
through the membrane and flood the apical channel, simulating pulmonary edema. Scale bar, 200 lM. (v) and (vi) Fibrin clots form on the apical channel after it becomes
flooded with basal media containing fibrin and prothrombin. Scale bar (v), 50 lM. Scale bar (vi), 5 lM. Reproduced with permission from Huh et al. Sci. Transl. Med. 4,
159ra147 (2012). Copyright 2012 AAAS.62

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Conversely, models constructed with cell lines typically lack adequate ACKNOWLEDGMENTS
cell heterogeneity. For example, models of the small airways that use
We are thankful for financial support from the NIH (No.
H441 club cell lines lack the small populations of goblet cells, basal cells,
HL136141 to S.T. and J.B.G.; No. AG061687 to S.T. and L.H.; No.
and macrophages also present in this microenvironment. Most MPSs
HL126603 to R.T.; No. 5T32EB006343-08 to H.V.). L.H. was
mimicking the alveoli only include alveolar type I pneumocytes and
supported by the Office of the Assistance Secretary of Defense for
neglect type II pneumocytes, macrophages, and fibroblasts. Mertz et al.91
Health Affairs, through the Peer Reviewed Medical Research Program
provide a discussion of the considerations of cell heterogeneity in MPSs.
under Award No. W81XWH-17-1-0443; the Veterans Administration
Health System Grant No. 1 I01 BX003919-01A1; and NIH Grant No.
C. Data collection in microfluidic systems
1R41HL140741. J.R.G. was supported by the Atlanta Pediatric
Traditional assays are difficult to adapt to microfluidic MPSs. Scholars Program (No. NICHD K12 HD072245). J.C. was supported
Epithelial barrier permeability measurement is usually absent from by the NSF Graduate Research Fellowship Program (No. 1650114).
microfluidic devices, especially real time permeability.55 This measure Opinions, interpretations, conclusions, and recommendations are
of epithelial response to stress and recovery from injury would greatly those of the authors and are not necessarily endorsed by the
increase the information provided by microfluidic MPSs. Similarly, Department of Defense, Department of Veterans Affairs, Atlanta
the scratch wound assay is a common metric of epithelial repair and Pediatric Scholars Program, National Science Foundation, or NIH.
recovery from injury that has only been adapted to microfluidics by Figures 1, 2, 3, and 5 were created with BioRender.
Felder et al.36,37 in a custom device. Cytokine levels produced by very
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