Tissue engineering often involves seeding cells into porous scaffolds and subjecting the scaffold to mechanical stimulation. Current experimental techniques have provided a plethora of data regarding cell responses within scaffolds, but the quantitative understanding of the load transfer process within a cell-seeded scaffold is still relatively unknown. The objective of this work was to develop a finite element representation of the transient and heterogeneous nature of a cell-seeded collagen-GAG-scaffold. By undertaking experimental investigation, characteristics such as scaffold architecture and shrinkage, cellular attachment patterns, and cellular dimensions were used to create a finite element model of a cell-seeded porous scaffold. The results demonstrate that a very wide range of microscopic strains act at the cellular level when a sample value of macroscopic (apparent) strain is applied to the collagen-GAG-scaffold. An external uniaxial strain of 10% generated a cellular strain as high as 49%, although the majority experienced less than 5% strain. The finding that the strain on some cells could be higher than the macroscopic strain was unexpected and proves contrary to previous in vitro investigations. These findings indicate a complex system of biophysical stimuli created within the scaffolds and the difficulty of inducing the desired cellular responses from artificial environments. Future in vitro studies could also corroborate the results from this computational prediction to further explore mechanoregulatory mechanisms in tissue engineering.

1.
Geris
,
L.
,
Vandamme
,
K.
,
Naert
,
I.
,
Vander Sloten
,
J.
,
Duyck
,
J.
, and
Van Oosterwycket
,
H.
, 2007, “
Application of Mechanoregulatory Models to Simulate Peri-Implant Tissue Formation in an In Vivo Bone Chamber
,”
J. Biomech.
0021-9290,
10
, pp.
1016
.
2.
Wu
,
Q.-Q.
, and
Chen
,
Q.
, 2000, “
Mechanoregulation of Chondrocyte Proliferation, Maturation, and Hypertrophy: Ion-Channel Dependent Transduction of Matrix Deformation Signals
,”
Exp. Cell Res.
0014-4827,
256
, pp.
383
391
.
3.
McMahon
,
L. A.
,
Reid
,
A. J.
,
Campbell
,
V. A.
, and
Prendergast
,
P. J.
, 2008, “
Regulatory Effects of Mechanical Strain on the Chondrogenic Differentiation of MSCs in a Collagen-GAG Scaffold: Experimental and Computational Analysis
,”
Ann. Biomed. Eng.
0090-6964,
36
(
2
), pp.
185
194
.
4.
Ignatius
,
A.
,
Blessing
,
H.
,
Liedert
,
A.
,
Schmidt
,
C.
,
Neidlinger-Wilke
,
C.
,
Kaspar
,
D.
,
Friemert
,
B.
, and
Claes
,
L.
, 2005, “
Tissue Engineering of Bone: Effects of Mechanical Strain on Osteoblastic Cells in Type, I. Collagen Matrices
,”
Biomaterials
0142-9612,
26
, pp.
311
318
.
5.
Breuls
,
R. G. M.
,
Sengers
,
B. G.
,
Oomens
,
C. W. J.
, and
Bouten
,
C. V. C.
, and
Baaijens
,
F. P. T.
, 2005, “
Predicting Local Cell Deformations in Engineered Tissue Constructs: A Multilevel Finite Element Approach
,”
ASME J. Biomech. Eng.
0148-0731,
124
, pp.
198
207
.
6.
Di Palma
,
F.
,
Douet
,
M.
,
Boachon
,
C.
,
Guignandon
,
A.
,
Peyroche
,
S.
,
Forest
,
B.
,
Alexandre
,
C.
,
Chamson
,
A.
, and
Rattner
,
A.
, 2003, “
Physiological Strains Induce Differentiation in Human Osteoblasts Cultured on Orthopaedic Biomaterial
,”
Biomaterials
0142-9612,
24
, pp.
3139
3151
.
7.
Raif
,
E. M.
, and
Seedhom
,
B. B.
, 2005, “
Effect of Cyclic Tensile Strain on Proliferation of Synovial Cells Seeded Onto Synthetic Ligament Scaffolds—An In Vitro Simulation
,”
Bone (N.Y.)
8756-3282,
36
, pp.
433
443
.
8.
Sengers
,
B. G.
, and
Taylor
,
M.
,
Please
,
C. P.
, and
Oreffo
,
R. O. C.
, 2007, “
Computational Modelling of Cell Spreading and Tissue Regeneration in Porous Scaffolds
,”
Biomaterials
0142-9612,
28
, pp.
1926
1940
.
9.
Yannas
,
I. V.
, 1992, “
Tissue Regeneration by Use of Collagen-Glycosaminoglycan Copolymers
,”
Clinical Materials
,
9
(
3–4
), pp.
179
187
.
10.
Freyman
,
T. M.
,
Yannas
,
I. V.
,
Pek
,
Y.-S.
,
Yokoo
,
R.
, and
Gibson
,
L. J.
, 2001, “
Micromechanics of Fibroblast Contraction of a Collagen-GAG Matrix
,”
Exp. Cell Res.
0014-4827,
269
, pp.
140
153
.
11.
Freyman
,
T.
,
Yannas
,
I.
, and
Gibson
,
L.
, 2001, “
Cellular Materials as Porous Scaffolds for Tissue Engineering
,”
Prog. Mater. Sci.
0079-6425,
46
, pp.
273
282
.
12.
Freyman
,
T.
,
Yannas
,
I.
,
Yokoo
,
R.
, and
Gibson
,
L.
, 2001, “
Fibroblast Contraction of a Collagen-GAG Matrix
,”
Biomaterials
0142-9612,
22
, pp.
2883
2891
.
13.
Kinner
,
B.
, and
Spector
,
M.
, 2002, “
Expression of Smooth Muscle Actin in Osteoblasts in Human Bone
,”
J. Orthop. Res.
0736-0266,
20
, pp.
622
632
.
14.
Lee
,
C. R.
,
Grodzinsky
,
A. J.
, and
Spector
,
M.
, 2001, “
The Effects of Cross-Linking of Collagen-Glycosaminoglycan Scaffolds on Compressive Stiffness, Chondrocyte-Mediated Contraction, Proliferation and Biosynthesis
,”
Biomaterials
0142-9612,
22
(
23
), pp.
3145
3154
.
15.
Menard
,
C.
,
Mitchell
,
S.
, and
Spector
,
M.
, 2000, “
Contractile Behavior of Smooth Muscle Actin-Containing Osteoblasts in Collagen-GAG Matrices In Vitro: Implant-Related Cell Contraction
,”
Biomaterials
0142-9612,
21
, pp.
1867
1877
.
16.
Schulz Torres
,
D.
,
Freyman
,
T.
,
Yannas
,
I.
, and
Spector
,
M.
, 2000, “
Tendon Cell Contraction of Collagen-GAG Matrices In Vitro: Effect of Crosslinking
,”
Biomaterials
0142-9612,
21
, pp.
1607
1619
.
17.
Zaleskas
,
J.
,
Kinner
,
B.
,
Freyman
,
T.
,
Yannas
,
I.
,
Gibson
,
L.
, and
Spector
,
M.
, 2004, “
Contractile Forces Generated by Articular Chondrocytes in Collagen-Glycosaminoglycan Matrices
,.”
Biomaterials
0142-9612,
25
, pp.
1299
1308
.
18.
Jaecques
,
S. V. N.
,
Van Oosterwyck
,
H.
,
Muraru
,
L.
,
Van Cleynenbreugel
,
T.
,
De Smet
,
E.
,
Wevers
,
M.
,
Naert
,
I.
, and
Vander Sloten
,
J.
, 2004, “
Individualised, Micro CT-Based Finite Element Modelling as a Tool for Biomechanical Analysis Related to Tissue Engineering of Bone
,”
Biomaterials
0142-9612,
25
(
9
), pp.
1683
1696
.
19.
Lacroix
,
D.
,
Chateau
,
A.
,
Ginebra
,
M.-P.
, and
Planell
,
J. A.
, 2006, “
Micro-Finite Element Models of Bone Tissue-Engineering Scaffolds
,”
Biomaterials
0142-9612,
27
, pp.
5326
5334
.
20.
Muraru
,
L.
,
Jaecques
,
S. V. N.
,
Demol
,
J.
,
Naert
,
I.
, and
Vander Sloten
,
J.
, 2006, “
Validation of Image-Enhanced In Vivo MicroCT Based FE Models by Strain Gauge Measurements
,”
J. Biomech.
0021-9290,
39
, p.
S428
.
21.
Tuan Ho
,
S.
, and
Hutmacher
,
D. W.
, 2006, “
A Comparison of Micro CT With Other Techniques Used in the Characterization of Scaffolds
,”
Biomaterials
0142-9612,
27
(
8
), pp.
1362
1376
.
22.
Mullins
,
L. P.
,
McGarry
,
J. P.
,
Bruzzi
,
M. S.
, and
McHugh
,
P. E.
, 2007, “
Micromechanical Modelling of Cortical Bone
,”
Comput. Methods Biomech. Biomed. Eng.
1025-5842,
10
(
3
), pp.
159
169
.
23.
Cowin
,
S. C.
, 2004, “
Anisotropic Poroelasticity: Fabric Tensor Formulation
,”
Mech. Mater.
0167-6636,
36
, pp.
665
677
.
24.
Hart
,
R. T.
, 1990, “
A Theoretical Study of the Influence of Bone Maturation Rate on Surface Remodeling Predictions: Idealized Models
,”
J. Biomech.
0021-9290,
23
(
3
), pp.
241
257
.
25.
Sander
,
E. A.
,
Downs
,
J. C.
,
Hart
,
R. T.
,
Burgoyne
,
C. F.
, and
Nauman
,
E. A.
, 2006, “
In-Plane Mechanics of the Optic Nerve Head With Cellular Solids Models
,”
J. Biomech.
0021-9290,
39
, p.
S385
.
26.
Hutmacher
,
D. W.
,
Sittinger
,
M.
, and
Risbud
,
M. V.
, 2004, “
Scaffold-Based Tissue Engineering: Rationale for Computer-Aided Design and Solid Free-Form Fabrication Systems
,”
Trends Biotechnol.
0167-7799,
22
(
7
), pp.
354
362
.
27.
Jones
,
A. C.
,
Arns
,
C. H.
,
Sheppard
,
A. P.
,
Hutmacher
,
D. W.
,
Milthorpe
,
B. K.
, and
Knackstedt
,
M. A.
, 2007, “
Assessment of Bone Ingrowth Into Porous Biomaterials Using Micro-CT
,”
Biomaterials
0142-9612,
28
(
15
), pp.
2491
2504
.
28.
Sun
,
W.
,
Starly
,
B.
,
Nam
,
J.
, and
Darling
,
A.
, 2005, “
Bio-CAD Modeling and Its Applications in Computer-Aided Tissue Engineering
,”
Comput.-Aided Des.
0010-4485,
37
(
11
), pp.
1097
1114
.
29.
Van Lenthe
,
G. H.
,
Hagenmüller
,
H.
,
Bohner
,
M.
,
Hollister
,
S. J.
,
Meinel
,
L.
, and
Müller
,
R.
, 2007, “
Nondestructive Micro-Computed Tomography for Biological Imaging and Quantification of Scaffold-Bone Interaction In Vivo
,”
Biomaterials
0142-9612,
28
(
15
), pp.
2479
2490
.
30.
Yannas
,
I. V.
, and
Hill
,
B. J.
, 2004, “
Selection of Biomaterials for Peripheral Nerve Regeneration Using Data From the Nerve Chamber Model
,”
Biomaterials
0142-9612,
25
(
9
), pp.
1593
1600
.
31.
Farrell
,
E.
,
Prendergast
,
P. J.
,
O’Brien
,
F. J.
, and
Campbell
,
V. A.
, 2006, “
Temporal Expression of Osteogenic Markers in Mesenchymal Stem Cells When Cultured in Monolayer and on Collagen Glycosaminoglycan Scaffolds
,”
J. Biomech.
0021-9290,
39
(
1
), p.
S215
.
32.
O’Brien
,
F. J.
,
Harley
,
B. A.
,
Yannas
,
I. V.
, and
Gibson
,
L. G.
, 2006, “
The Effect of Pore Size on Cell Adhesion in Collagen-GAG Scaffolds
,”
Biomaterials
0142-9612,
26
, pp.
433
441
.
33.
Thomson
,
S. W
, 1887, “
On the Division of Space With Minimum Partitional Area
,”
Acta Math.
0001-5962,
11
, pp.
121
134
.
34.
Harley
,
B. A.
,
Leung
,
J. H.
,
Silva
,
E.
, and
Gibson
,
L. J.
, 2007, “
Mechanical Characterization of Collagen-Glycosaminoglycan Scaffolds
,”
Acta Biomaterialia
,
3
, pp.
463
474
.
35.
O’Brien
,
F. J.
,
Harley
,
B. A.
,
Yannas
,
I. V.
, and
Gibson
,
L. G.
, 2004, “
Influence of Freezing Rate on Pore Structure in Freeze-Dried Collagen-GAG Scaffolds
,”
Biomaterials
0142-9612,
25
, pp.
1077
1086
.
36.
Gibson
,
L. J.
, 2005, “
Biomechanics of Cellular Solids
,”
J. Biomech.
0021-9290,
38
, pp.
377
399
.
37.
Kiviranta
,
P.
,
Rieppo
,
J.
,
Korhonen
,
R. K.
,
Julkunen
,
P.
,
Toyras
,
J.
, and
Jurvelin
,
J. S.
, 2006, “
Collagen Network Primarily Controls Poisson’s Ratio of Bovine Articular Cartilage in Compression
,”
J. Orthop. Res.
0736-0266,
24
(
4
), pp.
690
699
.
38.
Stylianopoulos
,
T.
, and
Barocas
,
V. H.
, 2007, “
Volume-Averaging Theory for the Study of the Mechanics of Collagen Networks
,”
Comput. Methods Appl. Mech. Eng.
0045-7825,
196
, pp.
2981
2990
.
39.
Li
,
L. P.
,
Herzog
,
W.
,
Korhonen
,
R. K.
, and
Jurvelin
,
J. S.
, 2005, “
The Role of Viscoelasticity of Collagen Fibers in Articular Cartilage: Axial Tension Versus Compression
,”
Med. Eng. Phys.
1350-4533,
27
, pp.
51
57
.
40.
Thoumine
,
O.
,
Ott
,
A.
, and
Cardoso
,
O.
, 1999, “
Microplates: A New Tool for Manipulation and Mechanical Perturbation of Individual Cells
,”
J. Biochem. Biophys. Methods
0165-022X,
39
, pp.
47
62
.
41.
Eastwood
,
M.
,
Porter
,
R.
,
Khan
,
U.
,
McGrouther
,
G.
, and
Brown
,
R.
, 1996, “
Quantitative Analysis of Collagen Gel Contractile Forces Generated by Dermal Fibroblasts and the Relationship to Cell Morphology
,”
J. Cell Physiol.
0021-9541,
166
, pp.
33
42
.
42.
Freyman
,
T.
,
Yannas
,
I.
,
Yokoo
,
R.
, and
Gibson
,
L.
, 2002, “
Fibroblast Contractile Force is Independent of the Stiffness Which Resists the Contraction
,”
Exp. Cell Res.
0014-4827,
272
, pp.
153
162
.
43.
Wrobel
,
L.
,
Fray
,
T.
,
Molloy
,
J.
,
Adams
,
J.
,
Armitage
,
M.
, and
Sparrow
,
J.
, 2002, “
Contractility of Single Human Dermal Myofibroblasts and Fibroblasts
,”
Cell Motil. Cytoskeleton
0886-1544,
52
, pp.
82
90
.
44.
Gibson
,
L. J.
, and
Ashby
,
M. F.
, 1997,
Cellular Solids: Structure and Properties
,
2nd ed.
,
Cambridge University Press
,
Cambridge
.
45.
Zhu
,
H. X.
,
Knott
,
J. F.
, and
Mills
,
N. J.
, 1997, “
Analysis of the Elastic Properties of Open-Cell Foams With Tetrakaidecahedral Cells
,”
J. Mech. Phys. Solids
0022-5096,
45
(
3
), pp.
319
343
.
46.
Roberts
,
A. P.
, and
Garboczi
,
E. J.
, 2002, “
Elastic Properties of Model Random Three-Dimensional Open-Cell Solids
,”
J. Mech. Phys. Solids
0022-5096,
50
, pp.
33
55
.
47.
Wall
,
M.
,
Weinhold
,
P. S.
,
Siu
,
T.
,
Brown
,
T. D.
, and
Banes
,
A. J.
, 2007, “
Comparison of Cellular Strain With Applied Substrate Strain In Vitro
,”
J. Biomech.
0021-9290,
40
, pp.
173
181
.
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