Toward in silico modeling‐based replacement of in vivo and in vitro experiments

Development of In Silico Human Model for Airborne Transmission Analysis
in Indoor Environment
健康影響を可視化するin silico⼈体モデルの開発と環境設計への展開

in vivoin vitro

in silico
Numerical modeling and simulation

Kazuhide Ito
Kyushu University, Japan
ito@kyudai.jp / www.phe‐kyudai.jp

Development of in silico experiments that can complement in vivo and in vitro experiments for human volunteers or animal models

In silico human model development platform for Indoor Environmental Design

Numerical Models required for Airborne Transmission Analysis(1) Modeling of generation and exhalation
mechanism of virus‐laden droplet (VLD)(2) Transport dynamics of VLD that reach theepithelial tissue in respiratory tract via indoor air

Euler‐Lagrange Analysis of virus laden droplet＋ Particle Deposition Analysis (Hot‐Spot inAirway)＋ Mucus Transport

3D Cloth‐model(4) Implementation of Indoor Environmental Design(3) Development of Bio‐regulation model that describe
Host Cell Dynamics associated with Infection
TargetCells
InfectedCells

Kato and Murakami (1990)

D. Sorensen (2003)

Ito et al. (2013 ‐)Fiala Thermo‐regulation ModeldT (t )   T (t )V (t )dtdI (t )  T (t )V (t )   I (t )dtdV (t ) pI (t )  cV (t )dt(Virus)

In Silico human forInhalation Exposure and Airborne Airway Infection

Droplet and Droplet Nuclei Dispersion[1] Chemical Compounds[2] Virus/Bacteria

PBPK/TK (Physiologically Based
Pharmaco/Toxico Kinetics) forHCD (Host Cell Dynamics) for

Inhalation Exposure(Target Cells)(Mucosa + Epithelium)

VCCt  max1C t  K f Ct  KbCt  Dt  2CttK m1  Ct

(Sub‐mucosa)Cb  K f Cb  KbCb   Qb Vb  Cb  Db 2Cb
tEpithelial Tissue

Lumen(Many Thanks, Prof Tsubokura, RIKEN)

Airborne Airway Infection(Infected Cells)(Virus)dT (t )   T (t )V (t )dtdI (t )
  T (t )V (t )   I (t )dtdV (t )
 pI (t )  cV (t )
dt


du p
dt

Blood flow
Cartilage  p     g  F  F
1  ' u  u  up BS

pCiliaAirflow

Virus VβE

Target Cell T

ContaminantMucosaβT

Infected Cell I

Submucosal Tissue

Where and how much indoor air do we actually breathe?

Droplet and Droplet Nuclei Dispersion

Contribution ratio of inhaled and exhaled air
Inhaled Air

Start of Inhalation

5.6%
Inhaled

1m Physical distance

1m Physical distance

Steady inhalation of Targeted subject

Transient inhalation of Targeted subject

t =0.0st =1.0st =2.0st =3.0st =4.0st =3.0st =4.0s

Exhaled Air
Start of Exhalation

0.15%
InhaledDiffusion ofExhaled air

2m Physical distance

2m Physical distance

Steady inhalation of TS

Transient inhalation of TS

t =0.0st =1.0st =2.0s(Indoor Air, 2022)

Regional deposition of airborne SARS‐CoV‐2‐laden droplets in the upper airway and its
effects determined using host cell dynamics

Virus (RNA Copies) replication
on epithelial tissue surface

Host Cell Dynamics Model
Coupling of target‐cell limited model and convection‐diffusion model

Mucociliary/mucustransport
Mucus Flow:𝑆𝜌 ∇·𝑢Source term was added to the continuity equation for the mucus domaindT (t )   T (t )V (t )dtdI (t )  T (t )V (t )   I (t )dt

 2Vp'Virus load/concentration  V U iVI  cV
[RNA copies/ml]  t  x  Dm x 2  Viimucus

V U j V
 2Vp' Dm 2 I j  cV
tx j
x j Vmucus

Susceptible target cells[cells]Infected cells[cells]Bioregulation – Host Cell Dynamics(Host cells, Pathogen, Adaptive Immune System)

Resultant viral replication

Visualization of SARS‐CoV‐2 Diffusion in the Nasal Cavity–Nasopharynx model
Viral replication [RNA copies/mL][1m physical distance, 20 days]
5.6%
InhaledVirus concentration
1.0e+71.0e+6 T   TV t I t   TV   I

(1)

(2)

(3)
β : infection rate [1/(RNA copies/ml)/day]Application/evolvement of in silico modeling of animals
Pressure loss calculation in upper airway of French Bulldog and Virtual Surgery

Viral replication [RNA copies/mL][2m physical distance, 20 days]
0.15%
InhaledEgashira ‐ Kotetsu

1.0e+5

3.9[Pa]8.8[Pa]Kinoshita – Guran

109[Pa]1.0e+4

Virtual surgery
of external nostril stenosis inbrachycephalic dogs

1.0e+3

1.9[Pa]1.0e+2

Side view

Side view
1.0e+1

109[Pa]Inoue – Kotetsu (Pre) Real surgery“rhinoplasty”

Fujiwara ‐ Gombe< 10 [Pa]1.0e+0[RNA copies/ml]

Top view

Top view

16[Pa]
Nomura ‐ Veve

102[Pa]Inoue – Kotetsu (Post rhinoplasty surgery)(Comput. Biol. Medi., 2021)

What can we do for “in vivo” animal models?

In Silico Human Model based Indoor Environmental Design•

Multi‐stage optimization of local environmental quality by in silico human model
as a sensor for HVAC control

HCHO concentrationin respiratory tract(Source: Life Investigation Agency)

HVAC control result over time:(a) ventilation flow rate

Skin surface temp.

HVAC control (b) heat
input for air conditioning