Thanks to their softness, biocompatibility, porosity, and ready availability, hydrogels are commonly used in microfluidic assays and organ-on-chip devices as a matrix for cells. They not only provide a supporting scaffold for the differentiating cells and the developing organoids, but also serve as the medium for transmitting oxygen, nutrients, various chemical factors, and mechanical stimuli to the cells. From a bioengineering viewpoint, the transmission of forces from fluid perfusion to the cells through the hydrogel is critical to the proper function and development of the cell colony. In this paper, we develop a poroelastic model to represent the fluid flow through a hydrogel containing a biological cell modeled as a hyperelastic inclusion. In geometries representing shear and normal flows that occur frequently in microfluidic experiments, we use finite-element simulations to examine how the perfusion engenders interstitial flow in the gel and displaces and deforms the embedded cell. The results show that pressure is the most important stress component in moving and deforming the cell, and the model predicts the velocity in the gel and stress transmitted to the cell that is comparable to in vitro and in vivo data. This work provides a computational tool to design the geometry and flow conditions to achieve optimal flow and stress fields inside the hydrogels and around the cell.

1.
T.-C.
Ho
,
C.-C.
Chang
,
H.-P.
Chan
,
T.-W.
Chung
,
C.-W.
Shu
,
K.-P.
Chuang
,
T.-H.
Duh
,
M.-H.
Yang
, and
Y.-C.
Tyan
, “
Hydrogels: Properties and applications in biomedicine
,”
Molecules
27
(
9
),
2902
(
2022
).
2.
M. W.
Tibbitt
and
K. S.
Anseth
, “
Hydrogels as extracellular matrix mimics for 3D cell culture
,”
Biotechnol. Bioeng.
103
(
4
),
655
663
(
2009
).
3.
J. S.
Jeon
,
S.
Bersini
,
M.
Gilardi
,
G.
Dubini
,
J. L.
Charest
,
M.
Moretti
, and
R. D.
Kamm
, “
Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation
,”
Proc. Natl. Acad. Sci. U.S.A.
112
(
1
),
214
219
(
2015
).
4.
V.
van Duinen
,
S. J.
Trietsch
,
J.
Joore
,
P.
Vulto
, and
T.
Hankemeier
, “
Microfluidic 3D cell culture: From tools to tissue models
,”
Curr. Opin. Biotechnol.
35
,
118
126
(
2015
).
5.
H.
Liu
,
Y.
Wang
,
K.
Cui
,
Y.
Guo
,
X.
Zhang
, and
J.
Qin
, “
Advances in hydrogels in organoids and organs-on-a-chip
,”
Adv. Mater.
31
(
50
),
1902042
(
2019
).
6.
N.
Dadgar
,
A. M.
Gonzalez-Suarez
,
P.
Fattahi
,
X.
Hou
,
J. S.
Weroha
,
A.
Gaspar-Maia
,
G.
Stybayeva
, and
A.
Revzin
, “
A microfluidic platform for cultivating ovarian cancer spheroids and testing their responses to chemotherapies
,”
Microsyst. Nanoeng.
6
(
1
),
93
(
2020
).
7.
O.
Habanjar
,
M.
Diab-Assaf
,
F.
Caldefie-Chezet
, and
L.
Delort
, “
3D cell culture systems: Tumor application, advantages, and disadvantages
,”
Int. J. Mol. Sci.
22
(
22
),
12200
(
2021
).
8.
A.
Clancy
,
D.
Chen
,
J.
Bruns
,
J.
Nadella
,
S.
Stealey
,
Y.
Zhang
,
A.
Timperman
, and
S. P.
Zustiak
, “
Hydrogel-based microfluidic device with multiplexed 3D in vitro cell culture
,”
Sci. Rep.
12
(
1
),
17781
(
2022
).
9.
G.
Choe
,
J.
Park
,
H.
Park
, and
J. Y.
Lee
, “
Hydrogel biomaterials for stem cell microencapsulation
,”
Polymers
10
(
9
),
997
(
2018
).
10.
S.
Trombino
,
C.
Servidio
,
F.
Curcio
, and
R.
Cassano
, “
Strategies for hyaluronic acid-based hydrogel design in drug delivery
,”
Pharmaceutics
11
(
8
),
407
(
2019
).
11.
C. A.
Dreiss
, “
Hydrogel design strategies for drug delivery
,”
Curr. Opin. Colloid Interface Sci.
48
,
1
17
(
2020
).
12.
S.-M.
Kang
,
J.-H.
Lee
,
Y. S.
Huh
, and
S.
Takayama
, “
Alginate microencapsulation for three-dimensional in vitro cell culture
,”
ACS Biomater. Sci. Eng.
7
(
7
),
2864
2879
(
2020
).
13.
P.
Fattahi
,
A.
Rahimian
,
M. Q.
Slama
,
K.
Gwon
,
A. M.
Gonzalez-Suarez
,
J.
Wolf
,
H.
Baskaran
,
C. D.
Duffy
,
G.
Stybayeva
,
Q. P.
Peterson
et al., “
Core–shell hydrogel microcapsules enable formation of human pluripotent stem cell spheroids and their cultivation in a stirred bioreactor
,”
Sci. Rep.
11
(
1
),
7177
(
2021
).
14.
A.
Löwa
,
J. J.
Feng
, and
S.
Hedtrich
, “
Human disease models in drug development
,”
Nat. Rev. Bioeng.
1
,
545
559
(
2023
).
15.
C.-H.
Heldin
,
K.
Rubin
,
K.
Pietras
, and
A.
Östman
, “
High interstitial fluid pressure—An obstacle in cancer therapy
,”
Nat. Rev. Cancer
4
(
10
),
806
813
(
2004
).
16.
M. A.
Swartz
and
M. E.
Fleury
, “
Interstitial flow and its effects in soft tissues
,”
Annu. Rev. Biomed. Eng.
9
,
229
256
(
2007
).
17.
Y.
Shou
,
X. Y.
Teo
,
K. Z.
Wu
,
B.
Bai
,
A. R. K.
Kumar
,
J.
Low
,
Z.
Le
, and
A.
Tay
, “
Dynamic stimulations with bioengineered extracellular matrix-mimicking hydrogels for mechano cell reprogramming and therapy
,”
Adv. Sci.
10
(
21
),
2300670
(
2023
).
18.
C. T.
Mierke
, “
Extracellular matrix cues regulate mechanosensing and mechanotransduction of cancer cells
,”
Cells
13
,
96
(
2024
).
19.
S.-F.
Chang
,
C. A.
Chang
,
D.-Y.
Lee
,
P.-L.
Lee
,
Y.-M.
Yeh
,
C.-R.
Yeh
,
C.-K.
Cheng
,
S.
Chien
, and
J.-J.
Chiu
, “
Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad
,”
Proc. Natl. Acad. Sci. U.S.A.
105
(
10
),
3927
3932
(
2008
).
20.
O.
Chaudhuri
, “
Viscoelastic hydrogels for 3D cell culture
,”
Biomater. Sci.
5
(
8
),
1480
1490
(
2017
).
21.
S. G.
Mina
,
P.
Huang
,
B. T.
Murray
, and
G. J.
Mahler
, “
The role of shear stress and altered tissue properties on endothelial to mesenchymal transformation and tumor-endothelial cell interaction
,”
Biomicrofluidics
11
(
4
),
044104
(
2017
).
22.
C. M.
Novak
,
E. N.
Horst
,
C. C.
Taylor
,
C. Z.
Liu
, and
G.
Mehta
, “
Fluid shear stress stimulates breast cancer cells to display invasive and chemoresistant phenotypes while upregulating PLAU in a 3D bioreactor
,”
Biotechnol. Bioeng.
116
(
11
),
3084
3097
(
2019
).
23.
E.
Akbari
,
G. B.
Spychalski
,
K. K.
Rangharajan
,
S.
Prakash
, and
J. W.
Song
, “
Competing fluid forces control endothelial sprouting in a 3-D microfluidic vessel bifurcation model
,”
Micromachines
10
(
7
),
451
(
2019
).
24.
L. C.
Delon
,
Z.
Guo
,
A.
Oszmiana
,
C.-C.
Chien
,
R.
Gibson
,
C.
Prestidge
, and
B.
Thierry
, “
A systematic investigation of the effect of the fluid shear stress on Caco-2 cells towards the optimization of epithelial organ-on-chip models
,”
Biomaterials
225
,
119521
(
2019
).
25.
J. M.
Hope
,
J. A.
Dombroski
,
R. S.
Pereles
,
M.
Lopez-Cavestany
,
J. D.
Greenlee
,
S. C.
Schwager
,
C. A.
Reinhart-King
, and
M. R.
King
, “
Fluid shear stress enhances T cell activation through Piezo1
,”
BMC Biol.
20
(
1
),
61
(
2022
).
26.
D.
Brindley
,
K.
Moorthy
,
J. H.
Lee
,
C.
Mason
,
H. W.
Kim
, and
I.
Wall
, “
Bioprocess forces and their impact on cell behavior: Implications for bone regeneration therapy
,”
J. Tissue Eng.
2011
,
620247
(
2011
).
27.
F.
Friedland
,
S.
Babu
,
R.
Springer
,
J.
Konrad
,
Y.
Herfs
,
S.
Gerlach
,
J.
Gehlen
,
H.-J.
Krause
,
L.
De Laporte
,
R.
Merkel
, and
E.
Noetzel
, “
ECM-transmitted shear stress induces apoptotic cell extrusion in early breast gland development
,”
Front. Cell Dev. Biol.
10
,
947430
(
2022
).
28.
R.
De Piano
,
D.
Caccavo
,
A. A.
Barba
, and
G.
Lamberti
, “
Polyelectrolyte hydrogels in biological systems: Modeling of swelling and deswelling behavior
,”
Chem. Eng. Sci.
279
,
118959
(
2023
).
29.
W.
Hong
,
X.
Zhao
,
J.
Zhou
, and
Z.
Suo
, “
A theory of coupled diffusion and large deformation in polymeric gels
,”
J. Mech. Phys. Solids
56
(
5
),
1779
1793
(
2008
).
30.
A.
Lucantonio
,
P.
Nardinocchi
, and
L.
Teresi
, “
Transient analysis of swelling-induced large deformations in polymer gels
,”
J. Mech. Phys. Solids
61
(
1
),
205
218
(
2013
).
31.
Y.
Hu
and
Z.
Suo
, “
Viscoelasticity and poroelasticity in elastomeric gels
,”
Acta Mech. Sol. Sin.
25
(
5
),
441
458
(
2012
).
32.
D.
Caccavo
,
G.
Lamberti
, and
A. A.
Barba
, “
Mechanics and drug release from poroviscoelastic hydrogels: Experiments and modeling
,”
Eur. J. Pharm. Biopharm.
152
,
299
306
(
2020
).
33.
T.
Bertrand
,
J.
Peixinho
,
S.
Mukhopadhyay
, and
C. W.
MacMinn
, “
Dynamics of swelling and drying in a spherical gel
,”
Phys. Rev. Appl.
6
,
064010
(
2016
).
34.
G. L.
Celora
,
M. G.
Hennessy
,
A.
Münch
,
B.
Wagner
, and
S. L.
Waters
, “
A kinetic model of a polyelectrolyte gel undergoing phase separation
,”
J. Mech. Phys. Solids
160
,
104771
(
2022
).
35.
L.
Li
,
J.
Zhang
,
Z.
Xu
,
Y.-N.
Young
,
J. J.
Feng
, and
P.
Yue
, “
An arbitrary Lagrangian–Eulerian method for simulating interfacial dynamics between a hydrogel and a fluid
,”
J. Comput. Phys.
451
,
110851
(
2022
).
36.
Z.
Xu
,
P.
Yue
, and
J. J.
Feng
, “
A theory of hydrogel mechanics that couples swelling and external flow
,”
Soft Matter
20
,
5389
5406
(
2024
).
37.
W. J.
Polacheck
,
R.
Li
,
S. G. M.
Uzel
, and
R. D.
Kamm
, “
Microfluidic platforms for mechanobiology
,”
Lab Chip
13
,
2252
2267
(
2013
).
38.
J. J.
Feng
and
Y.-N.
Young
, “
Boundary conditions at a gel-fluid interface
,”
Phys. Rev. Fluids
5
(
12
),
124304
(
2020
).
39.
Z.
Xu
,
J.
Zhang
,
Y.-N.
Young
,
P.
Yue
, and
J. J.
Feng
, “
A comparison of four boundary conditions for the fluid-hydrogel interface
,”
Phys. Rev. Fluids
7
,
093301
(
2022
).
40.
Z.
Xu
,
P.
Yue
, and
J. J.
Feng
, “
Estimating the interfacial permeability for flow into a poroelastic medium
,”
Soft Matter
20
,
7357
7361
(
2024
).
41.
W. J.
Polacheck
,
J. L.
Charest
, and
R. D.
Kamm
, “
Interstitial flow influences direction of tumor cell migration through competing mechanisms
,”
Proc. Natl. Acad. Sci. U.S.A.
108
(
27
),
11115
11120
(
2011
).
42.
B.
Bachmann
,
S.
Spitz
,
M.
Rothbauer
,
C.
Jordan
,
M.
Purtscher
,
H.
Zirath
,
P.
Schuller
,
C.
Eilenberger
,
S. F.
Ali
,
S.
Mühleder
,
E.
Priglinger
,
M.
Harasek
,
H.
Redl
,
W.
Holnthoner
, and
P.
Ertl
, “
Engineering of three-dimensional pre-vascular networks within fibrin hydrogel constructs by microfluidic control over reciprocal cell signaling
,”
Biomicrofluidics
12
(
4
),
042216
(
2018
).
43.
Q.
Luo
,
D.
Kuang
,
B.
Zhang
, and
G.
Song
, “
Cell stiffness determined by atomic force microscopy and its correlation with cell motility
,”
Biochim. Biophys. Acta, Gen. Subj.
1860
(
9
),
1953
1960
(
2016
).
44.
D.
Lee
,
H.
Zhang
, and
S.
Ryu
, “Elastic modulus measurement of hydrogels,” in Cellulose-based Superabsorbent Hydrogels, edited by M. I. H. Mondal (Springer International Publishing, Cham, 2018), pp. 1–21.
45.
D.
Arndt
,
W.
Bangerth
,
M.
Bergbauer
,
M.
Feder
,
M.
Fehling
,
J.
Heinz
,
T.
Heister
,
L.
Heltai
,
M.
Kronbichler
,
M.
Maier
,
P.
Munch
,
J.-P.
Pelteret
,
B.
Turcksin
,
D.
Wells
, and
S.
Zampini
, “
The deal.II library, version 9.5
,”
J. Numer. Math.
31
(
3
),
231
246
(
2023
).
46.
E.
Gabriel
,
G. E.
Fagg
,
G.
Bosilca
,
T.
Angskun
,
J. J.
Dongarra
,
J. M.
Squyres
,
V.
Sahay
,
P.
Kambadur
,
B.
Barrett
,
A.
Lumsdaine
,
R. H.
Castain
,
D. J.
Daniel
,
R. L.
Graham
, and
T. S.
Woodall
, “Open MPI: Goals, concept, and design of a next generation MPI implementation,” in Recent Advances in Parallel Virtual Machine and Message Passing Interface: 11th European PVM/MPI Users’ Group Meeting Budapest, 19-22 September 2004. Proceedings 11 (Springer, 2004), pp. 97–104.
47.
T. A.
Davis
, “UMFPACK Version 5.2.0 User Guide,” Tech. Rep. (University of Florida, Gainesville, FL, 2007).
48.
M. A.
Heroux
and
J. M.
Willenbring
, “
A new overview of the Trilinos project
,”
Sci. Program.
20
(
2
),
83
88
(
2012
).
49.
A.
Prokopenko
,
J.
Hu
,
T.
Wiesner
,
C.
Siefert
, and
R.
Tuminaro
, “MueLu User’s Guide 1.0 (Trilinos version 11.12),” Tech. Rep. SAND2014-18874, Sandia National Laboratories, Albuquerque, NM 87185 and Livermore, CA 94550 (October 2014).
50.
P. R.
Amestoy
,
I. S.
Duff
,
J.-Y.
L’Excellent
, and
J.
Koster
, “MUMPS: A general purpose distributed memory sparse solver,” in International Workshop on Applied Parallel Computing (Springer, 2000), pp. 121–130.
51.
O. V.
Semenova
,
V. A.
Petrov
,
T. N.
Gerasimenko
,
A. V.
Aleksandrova
,
O. A.
Burmistrova
,
A. A.
Khutornenko
,
A. I.
Osipyants
,
A. A.
Poloznikov
, and
D. A.
Sakharov
, “
Effect of circulation parameters on functional status of HepaRG spheroids cultured in microbioreactor
,”
Bull. Exp. Biol. Med.
161
,
425
429
(
2016
).
52.
Y.
Du
,
N.
Li
,
H.
Yang
,
C.
Luo
,
Y.
Gong
,
C.
Tong
,
Y.
Gao
,
S.
, and
M.
Long
, “
Mimicking liver sinusoidal structures and functions using a 3d-configured microfluidic chip
,”
Lab Chip
17
,
782
794
(
2017
).
53.
W.
Li
,
Y.
Wu
,
W.
Hu
,
J.
Zhou
,
X.
Shu
,
X.
Zhang
,
Z.
Zhang
,
H.
Wu
,
Y.
Du
,
D.
,
S.
,
N.
Li
, and
M.
Long
, “
Direct mechanical exposure initiates hepatocyte proliferation
,”
JHEP Rep.
5
,
100905
(
2023
).
54.
S.
Haber
and
R.
Mauri
, “
Boundary conditions for Darcy’s flow through porous media
,”
Int. J. Multiphase Flow
9
,
561
574
(
1983
).
55.
O.
Coussy
,
Poromechanics
(
John Wiley & Sons
,
2004
).
56.
J. Y.
Park
,
J. B.
White
,
N.
Walker
,
C.-H.
Kuo
,
W.
Cha
,
M. E.
Meyerhoff
, and
S.
Takayama
, “
Responses of endothelial cells to extremely slow flows
,”
Biomicrofluidics
5
(
2
),
022211
(
2011
).
57.
X.
Zhang
,
S.
Zhang
, and
T.
Wang
, “
How the mechanical microenvironment of stem cell growth affects their differentiation: A review
,”
Stem Cell Res. Ther.
13
,
415
(
2022
).
58.
J. A.
Espina
,
M. H.
Cordeiro
,
M.
Milivojevic
,
I.
Pajić-Lijaković
, and
E. H.
Barriga
, “
Response of cells and tissues to shear stress
,”
J. Cell Sci.
136
(
18
),
jcs260985
(
2023
).
59.
M. H.
Rahman
,
Q.
Xiao
,
S.
Zhao
,
F.
Qu
,
C.
Chang
,
A.-C.
Wei
, and
Y.-P.
Ho
, “
Demarcating the membrane damage for the extraction of functional mitochondria
,”
Microsyst. Nanoeng.
4
,
39
(
2018
).
60.
C. H. H.
Chan
,
M. J.
Simmonds
,
K. H.
Fraser
,
K.
Igarashi
,
K. K.
Ki
,
T.
Murashige
,
M. T.
Joseph
,
J. F.
Fraser
,
G. D.
Tansley
, and
N.
Watanabe
, “
Discrete responses of erythrocytes, platelets, and von Willebrand factor to shear
,”
J. Biomech.
130
,
110898
(
2022
).
61.
H.
Dafni
,
T.
Israely
,
Z. M.
Bhujwalla
,
L. E.
Benjamin
, and
M.
Neeman
, “
Overexpression of vascular endothelial growth factor 165 drives peritumor interstitial convection and induces lymphatic drain: Magnetic resonance imaging, confocal microscopy, and histological tracking of triple-labeled albumin
,”
Cancer Res.
62
,
6731
6739
(
2002
).
62.
Y.
Zhang
and
P.
Habibovic
, “
Delivering mechanical stimulation to cells: State of the art in materials and devices design
,”
Adv. Mater.
34
(
32
),
2110267
(
2022
).
63.
P. A.
Janmey
and
C. A.
McCulloch
, “
Cell mechanics: Integrating cell responses to mechanical stimuli
,”
Annu. Rev. Biomed. Eng.
9
,
1
34
(
2007
).
64.
P.
Lu
,
K.
Takai
,
V. M.
Weaver
, and
Z.
Werb
, “
Extracellular matrix degradation and remodeling in development and disease
,”
Cold Spring Harb. Perspect. Biol.
3
(
12
),
a005058
(
2011
).
65.
M.
Franchi
,
Z.
Piperigkou
,
N. S.
Mastronikolis
, and
N.
Karamanos
, “
Extracellular matrix biomechanical roles and adaptation in health and disease
,”
FEBS J.
291
(
3
),
430
440
(
2024
).
66.
D. N.
Alasaadi
and
R.
Mayor
, “
Mechanically guided cell fate determination in early development
,”
Cell. Mol. Life Sci.
81
,
242
(
2024
).
67.
R.
Agha
,
R.
Ogawa
,
G.
Pietramaggiori
, and
D. P.
Orgill
, “
A review of the role of mechanical forces in cutaneous wound healing
,”
J. Surg. Res.
171
(
2
),
700
708
(
2011
).
68.
N.
Annabi
,
J. W.
Nichol
,
X.
Zhong
,
C.
Ji
,
S.
Koshy
,
A.
Khademhosseini
, and
F.
Dehghani
, “
Controlling the porosity and microarchitecture of hydrogels for tissue engineering
,”
Tissue Eng., Part B
16
(
4
),
371
383
(
2010
).
69.
N. L.
Cuccia
,
S.
Pothineni
,
B.
Wu
,
J.
Méndez Harper
, and
J. C.
Burton
, “
Pore-size dependence and slow relaxation of hydrogel friction on smooth surfaces
,”
Proc. Natl. Acad. Sci. U.S.A.
117
(
21
),
11247
11256
(
2020
).
70.
J.
Yoon
,
S.
Cai
,
Z.
Suo
, and
R. C.
Hayward
, “
Poroelastic swelling kinetics of thin hydrogel layers: Comparison of theory and experiment
,”
Soft Matter
6
(
23
),
6004
(
2010
).
71.
Y.-N.
Young
,
Y.
Mori
, and
M. J.
Miksis
, “
Slightly deformable Darcy drop in linear flows
,”
Phys. Rev. Fluids
4
,
063601
(
2019
).
72.
W. R.
Trickeya
,
F. P. T.
Baaijens
,
T. A.
Laursen
,
L. G.
Alexopoulos
, and
F.
Guilak
, “
Determination of the Poisson’s ratio of the cell: Recovery properties of chondrocytes after release from complete micropipette aspiration
,”
J. Biomech.
39
,
78
87
(
2006
).
73.
Z.
Xu
,
P.
Yue
, and
J. J.
Feng
, “
Hystereses in flow-induced compression of a poroelastic hydrogel
,”
Soft Matter
20
,
6940
6951
(
2024
).
74.
Y.-C.
Chiu
,
M.-H.
Cheng
,
H.
Engel
,
S.-W.
Kao
,
J. C.
Larson
,
S.
Gupta
, and
E. M.
Brey
, “
The role of pore size on vascularization and tissue remodeling in PEG hydrogels
,”
Biomaterials
32
(
26
),
6045
6051
(
2011
).
75.
A.
Salerno
,
R.
Borzacchiello
, and
P. A.
Netti
, “
Pore structure and swelling behavior of porous hydrogels prepared via a thermal reverse-casting technique
,”
J. Appl. Polym. Sci.
122
,
3651
3660
(
2011
).
76.
S.
Sornkamnerd
,
M. K.
Okajima
, and
T.
Kaneko
, “
Tough and porous hydrogels prepared by simple lyophilization of LC gels
,”
ACS Omega
2
(
8
),
5304
5314
(
2017
).
77.
D. F.
James
and
A. M.
Davis
, “
Flow at the interface of a model fibrous porous medium
,”
J. Fluid Mech.
426
,
47
72
(
2001
).
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