Computational approaches have great potential for aiding clinical product development by finding promising candidate designs prior to expensive testing and clinical trials. Here, an approach for designing multilevel bone tissue scaffolds that provide structural support during tissue regeneration is developed by considering mechanical and biological perspectives. Three key scaffold design properties are considered: (1) porosity, which influences potential tissue growth volume and nutrient transport, (2) surface area, which influences biodegradable scaffold dissolution rate and initial cell attachment, and (3) elastic modulus, which influences scaffold deformation under load and, therefore, tissue stimulation. Four scaffold topology types are generated by patterning beam or truss-based unit cells continuously or hierarchically and tuning the element diameter, unit cell length, and number of unit cells. Parametric comparisons suggest that structures with truss-based scaffolds have higher surface areas but lower elastic moduli for a given porosity in comparison to beam-based scaffolds. Hierarchical scaffolds possess a large central pore that increases porosity but lowers elastic moduli and surface area. Scaffold samples of all topology types are 3D printed with dimensions suitable for scientific testing. A hierarchical scaffold is fabricated with dimensions and properties relevant for a spinal interbody fusion cage with a maximized surface-volume ratio, which illustrates a potentially high performing design configured for mechanical and biological factors. These findings demonstrate the merit in using multidisciplinary and computational approaches as a foundation of tissue scaffold development for regenerative medicine.

References

References
1.
Egan
,
P.
,
Sinko
,
R.
,
LeDuc
,
P.
, and
Keten
,
S.
,
2015
, “
The Role of Mechanics in Biological and Synthetic Bio-Inspired Systems
,”
Nat. Commun.
,
6
, p. 7418.
2.
Egan
,
P.
,
Cagan
,
J.
,
Schunn
,
C.
,
Chiu
,
F.
,
Moore
,
J.
, and
LeDuc
,
P.
,
2016
, “
The D3 Methodology: Bridging Science and Design for Bio-Based Product Development
,”
ASME J. Mech. Des.
,
138
(
8
), p.
081101
.
3.
Egan
,
P.
,
Schunn
,
C.
,
Cagan
,
J.
, and
LeDuc
,
P.
,
2015
, “
Improving Human Understanding and Design of Complex Multi-Level Systems With Animation and Parametric Relationship Supports
,”
Des. Sci.
,
1
(e3), pp.
1
31
.
4.
Fisher
,
M. B.
, and
Mauck
,
R. L.
,
2013
, “
Tissue Engineering and Regenerative Medicine: Recent Innovations and the Transition to Translation
,”
Tissue Eng., Part B
,
19
(
1
), pp.
1
13
.
5.
Liu
,
Y.
,
Lim
,
J.
, and
Teoh
,
S.-H.
,
2013
, “
Review: Development of Clinically Relevant Scaffolds for Vascularised Bone Tissue Engineering
,”
Biotechnol. Adv.
,
31
(
5
), pp.
688
705
.
6.
Buonansegna
,
E.
,
Salomo
,
S.
,
Maier
,
A. M.
, and
Li-Ying
,
J.
,
2014
, “
Pharmaceutical New Product Development: Why do Clinical Trials Fail?
,”
R&D Manage.
,
44
(
2
), pp.
189
202
.
7.
Hollister
,
S. J.
, and
Murphy
,
W. L.
,
2011
, “
Scaffold Translation: Barriers Between Concept and Clinic
,”
Tissue Eng., Part B
,
17
(
6
), pp.
459
474
.
8.
Habib
,
F. N.
,
Nikzad
,
M.
,
Masood
,
S. H.
, and
Saifullah
,
A. B. M.
,
2016
, “
Design and Development of Scaffolds for Tissue Engineering Using Three-Dimensional Printing for Bio-Based Applications
,”
3D Print. Addit. Manuf.
,
3
(2), pp.
119
127
.
9.
Derby
,
B.
,
2012
, “
Printing and Prototyping of Tissues and Scaffolds
,”
Science
,
338
(
6109
), pp.
921
926
.
10.
Melchels
,
F. P.
,
Bertoldi
,
K.
,
Gabbrielli
,
R.
,
Velders
,
A. H.
,
Feijen
,
J.
, and
Grijpma
,
D. W.
,
2010
, “
Mathematically Defined Tissue Engineering Scaffold Architectures Prepared by Stereolithography
,”
Biomaterials
,
31
(
27
), pp.
6909
6916
.
11.
Stanković
,
T.
,
Mueller
,
J.
,
Egan
,
P.
, and
Shea
,
K.
,
2015
, “
A Generalized Optimality Criteria Method for Optimization of Additively Manufactured Multimaterial Lattice Structures
,”
ASME J. Mech. Des.
,
137
(11), p.
111705
.
12.
Byrne
,
D. P.
,
Lacroix
,
D.
,
Planell
,
J. A.
,
Kelly
,
D. J.
, and
Prendergast
,
P. J.
,
2007
, “
Simulation of Tissue Differentiation in a Scaffold as a Function of Porosity, Young's Modulus and Dissolution Rate: Application of Mechanobiological Models in Tissue Engineering
,”
Biomaterials
,
28
(
36
), pp.
5544
5554
.
13.
Boccaccio
,
A.
,
Uva
,
A. E.
,
Fiorentino
,
M.
,
Lamberti
,
L.
, and
Monno
,
G.
,
2016
, “
A Mechanobiology-Based Algorithm to Optimize the Microstructure Geometry of Bone Tissue Scaffolds
,”
Int. J. Biol. Sci.
,
12
(
1
), p.
1
.
14.
Geris
,
L.
,
Guyot
,
Y.
,
Schrooten
,
J.
, and
Papantoniou
,
I.
,
2016
, “
In Silico Regenerative Medicine: How Computational Tools Allow Regulatory and Financial Challenges to be Addressed in a Volatile Market
,”
Interface Focus
,
6
(
2
), p.
20150105
.
15.
Giannitelli
,
S.
,
Accoto
,
D.
,
Trombetta
,
M.
, and
Rainer
,
A.
,
2014
, “
Current Trends in the Design of Scaffolds for Computer-Aided Tissue Engineering
,”
Acta Biomater.
,
10
(
2
), pp.
580
594
.
16.
Sanz-Herrera
,
J.
,
García-Aznar
,
J.
, and
Doblaré
,
M.
,
2009
, “
On Scaffold Designing for Bone Regeneration: A Computational Multiscale Approach
,”
Acta Biomater.
,
5
(
1
), pp.
219
229
.
17.
Naing
,
M.
,
Chua
,
C.
,
Leong
,
K.
, and
Wang
,
Y.
,
2005
, “
Fabrication of Customised Scaffolds Using Computer-Aided Design and Rapid Prototyping Techniques
,”
Rapid Prototyping J.
,
11
(
4
), pp.
249
259
.
18.
Bose
,
S.
,
Roy
,
M.
, and
Bandyopadhyay
,
A.
,
2012
, “
Recent Advances in Bone Tissue Engineering Scaffolds
,”
Trends Biotechnol.
,
30
(
10
), pp.
546
554
.
19.
Guldberg
,
R.
,
Caldwell
,
N.
,
Guo
,
X.
,
Goulet
,
R.
,
Hollister
,
S.
, and
Goldstein
,
S.
,
1997
, “
Mechanical Stimulation of Tissue Repair in the Hydraulic Bone Chamber
,”
J. Bone Mineral Res.
,
12
(
8
), pp.
1295
1302
.
20.
Baas
,
E.
,
Kuiper
,
J. H.
,
Yang
,
Y.
,
Wood
,
M. A.
, and
El Haj
,
A. J.
,
2010
, “
In Vitro Bone Growth Responds to Local Mechanical Strain in Three-Dimensional Polymer Scaffolds
,”
J. Biomech.
,
43
(
4
), pp.
733
739
.
21.
Rumpler
,
M.
,
Woesz
,
A.
,
Dunlop
,
J. W.
,
van Dongen
,
J. T.
, and
Fratzl
,
P.
,
2008
, “
The Effect of Geometry on Three-Dimensional Tissue Growth
,”
J. R. Soc. Interface
,
5
(
27
), pp.
1173
1180
.
22.
Polikeit
,
A.
,
Ferguson
,
S. J.
,
Nolte
,
L. P.
, and
Orr
,
T. E.
,
2003
, “
Factors Influencing Stresses in the Lumbar Spine After the Insertion of Intervertebral Cages: Finite Element Analysis
,”
Eur. Spine J.
,
12
(
4
), pp.
413
420
.
23.
Abbah
,
S. A.
,
Lam
,
C. X.
,
Hutmacher
,
D. W.
,
Goh
,
J. C.
, and
Wong
,
H.-K.
,
2009
, “
Biological Performance of a Polycaprolactone-Based Scaffold Used as Fusion Cage Device in a Large Animal Model of Spinal Reconstructive Surgery
,”
Biomaterials
,
30
(
28
), pp.
5086
5093
.
24.
Bashkuev
,
M.
,
Checa
,
S.
,
Postigo
,
S.
,
Duda
,
G.
, and
Schmidt
,
H.
,
2015
, “
Computational Analyses of Different Intervertebral Cages for Lumbar Spinal Fusion
,”
J. Biomech.
,
48
(
12
), pp.
3274
3282
.
25.
Yamada
,
K.
,
Ito
,
M.
,
Akazawa
,
T.
,
Murata
,
M.
,
Yamamoto
,
T.
, and
Iwasaki
,
N.
,
2015
, “
A Preclinical Large Animal Study on a Novel Intervertebral Fusion Cage Covered With High Porosity Titanium Sheets With a Triple Pore Structure Used for Spinal Fusion
,”
Eur. Spine J.
,
24
(
11
), pp.
2530
2537
.
26.
Zhong
,
Z.-C.
,
Wei
,
S.-H.
,
Wang
,
J.-P.
,
Feng
,
C.-K.
,
Chen
,
C.-S.
, and
Yu
,
C.-H.
,
2006
, “
Finite Element Analysis of the Lumbar Spine With a New Cage Using a Topology Optimization Method
,”
Med. Eng. Phys.
,
28
(
1
), pp.
90
98
.
27.
Otto
,
K. N.
,
Hölttä-Otto
,
K.
,
Simpson
,
T. W.
,
Krause
,
D.
,
Ripperda
,
S.
, and
Moon
,
S. K.
,
2016
, “
Global Views on Modular Design Research: Linking Alternative Methods to Support Modular Product Family Concept Development
,”
ASME J. Mech. Des.
,
138
(
7
), p.
071101
.
28.
Hollister
,
S. J.
,
Flanagan
,
C. L.
,
Zopf
,
D. A.
,
Morrison
,
R. J.
,
Nasser
,
H.
,
Patel
,
J. J.
,
Ebramzadeh
,
E.
,
Sangiorgio
,
S. N.
,
Wheeler
,
M. B.
, and
Green
,
G. E.
,
2015
, “
Design Control for Clinical Translation of 3D Printed Modular Scaffolds
,”
Ann. Biomed. Eng.
,
43
(
3
), pp.
774
786
.
29.
Olivares
,
A. L.
,
Marsal
,
È.
,
Planell
,
J. A.
, and
Lacroix
,
D.
,
2009
, “
Finite Element Study of Scaffold Architecture Design and Culture Conditions for Tissue Engineering
,”
Biomaterials
,
30
(
30
), pp.
6142
6149
.
30.
Iura
,
A.
,
McNerny
,
E. G.
,
Zhang
,
Y.
,
Kamiya
,
N.
,
Tantillo
,
M.
,
Lynch
,
M.
,
Kohn
,
D. H.
, and
Mishina
,
Y.
,
2015
, “
Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse When BMP Signaling is Specifically Ablated in Osteoblasts
,”
PloS One
,
10
(
10
), p.
e0141345
.
31.
Woodard
,
J. R.
,
Hilldore
,
A. J.
,
Lan
,
S. K.
,
Park
,
C.
,
Morgan
,
A. W.
,
Eurell
,
J. A. C.
,
Clark
,
S. G.
,
Wheeler
,
M. B.
,
Jamison
,
R. D.
, and
Johnson
,
A. J. W.
,
2007
, “
The Mechanical Properties and Osteoconductivity of Hydroxyapatite Bone Scaffolds With Multi-Scale Porosity
,”
Biomaterials
,
28
(
1
), pp.
45
54
.
32.
Laschke
,
M.
,
Strohe
,
A.
,
Scheuer
,
C.
,
Eglin
,
D.
,
Verrier
,
S.
,
Alini
,
M.
,
Pohlemann
,
T.
, and
Menger
,
M.
,
2009
, “
In Vivo Biocompatibility and Vascularization of Biodegradable Porous Polyurethane Scaffolds for Tissue Engineering
,”
Acta Biomater.
,
5
(
6
), pp.
1991
2001
.
33.
Olson
,
G. B.
,
1997
, “
Computational Design of Hierarchically Structured Materials
,”
Science
,
277
(
5330
), pp.
1237
1242
.
34.
Loh
,
Q. L.
, and
Choong
,
C.
,
2013
, “
Three-Dimensional Scaffolds for Tissue Engineering Applications: Role of Porosity and Pore Size
,”
Tissue Eng., Part B
,
19
(
6
), pp.
485
502
.
35.
Sicchieri
,
L. G.
,
Crippa
,
G. E.
,
de Oliveira
,
P. T.
,
Beloti
,
M. M.
, and
Rosa
,
A. L.
,
2012
, “
Pore Size Regulates Cell and Tissue Interactions With PLGA–CaP Scaffolds Used for Bone Engineering
,”
J. Tissue Eng. Regener. Med.
,
6
(
2
), pp.
155
162
.
36.
Wieding
,
J.
,
Wolf
,
A.
, and
Bader
,
R.
,
2014
, “
Numerical Optimization of Open-Porous Bone Scaffold Structures to Match the Elastic Properties of Human Cortical Bone
,”
J. Mech. Behav. Biomed. Mater.
,
37
, pp.
56
68
.
37.
Minardi
,
S.
,
Corradetti
,
B.
,
Taraballi
,
F.
,
Sandri
,
M.
,
Van Eps
,
J.
,
Cabrera
,
F.
,
Weiner
,
B. K.
,
Tampieri
,
A.
, and
Tasciotti
,
E.
,
2015
, “
Evaluation of the Osteoinductive Potential of a Bio-Inspired Scaffold Mimicking the Osteogenic Niche for Bone Augmentation
,”
Biomaterials
,
62
, pp. 128–137.
38.
Fielding
,
G. A.
,
Bandyopadhyay
,
A.
, and
Bose
,
S.
,
2012
, “
Effects of Silica and Zinc Oxide Doping on Mechanical and Biological Properties of 3D Printed Tricalcium Phosphate Tissue Engineering Scaffolds
,”
Dent. Mater.
,
28
(
2
), pp.
113
122
.
39.
Meza
,
L. R.
,
Zelhofer
,
A. J.
,
Clarke
,
N.
,
Mateos
,
A. J.
,
Kochmann
,
D. M.
, and
Greer
,
J. R.
,
2015
, “
Resilient 3D Hierarchical Architected Metamaterials
,”
Proc. Natl. Acad. Sci.
,
112
(
37
), pp.
11502
11507
.
40.
Zheng
,
X.
,
Lee
,
H.
,
Weisgraber
,
T. H.
,
Shusteff
,
M.
,
DeOtte
,
J.
,
Duoss
,
E. B.
,
Kuntz
,
J. D.
,
Biener
,
M. M.
,
Ge
,
Q.
, and
Jackson
,
J. A.
,
2014
, “
Ultralight, Ultrastiff Mechanical Metamaterials
,”
Science
,
344
(
6190
), pp.
1373
1377
.
41.
O'brien
,
F. J.
,
2011
, “
Biomaterials & Scaffolds for Tissue Engineering
,”
Mater. Today
,
14
(
3
), pp.
88
95
.
42.
McKeen
,
L. W.
,
2014
,
Plastics Used in Medical Devices
,
William Andrew Publishing
,
Oxford, UK
, Chap. 3.
43.
Wu
,
L.
, and
Ding
,
J.
,
2004
, “
In Vitro Degradation of Three-Dimensional Porous Poly (D, L-Lactide-co-Glycolide) Scaffolds for Tissue Engineering
,”
Biomaterials
,
25
(
27
), pp.
5821
5830
.
44.
Chen
,
Y.
,
Zhou
,
S.
, and
Li
,
Q.
,
2011
, “
Microstructure Design of Biodegradable Scaffold and Its Effect on Tissue Regeneration
,”
Biomaterials
,
32
(
22
), pp.
5003
5014
.
45.
Mehdizadeh
,
H.
,
Bayrak
,
E. S.
,
Lu
,
C.
,
Somo
,
S. I.
,
Akar
,
B.
,
Brey
,
E. M.
, and
Cinar
,
A.
,
2015
, “
Agent-Based Modeling of Porous Scaffold Degradation and Vascularization: Optimal Scaffold Design Based on Architecture and Degradation Dynamics
,”
Acta Biomater.
, 27, pp. 167–178.
46.
Cheah
,
C.
,
Chua
,
C.
,
Leong
,
K.
, and
Chua
,
S.
,
2003
, “
Development of a Tissue Engineering Scaffold Structure Library for Rapid Prototyping—Part 1: Investigation and Classification
,”
Int. J. Adv. Manuf. Technol.
,
21
(
4
), pp.
291
301
.
47.
Cheah
,
C.
,
Chua
,
C.
,
Leong
,
K.
, and
Chua
,
S.
,
2003
, “
Development of a Tissue Engineering Scaffold Structure Library for Rapid Prototyping—Part 2: Parametric Library and Assembly Program
,”
Int. J. Adv. Manuf. Technol.
,
21
(
4
), pp.
302
312
.
48.
Fu
,
K.
,
Moreno
,
D.
,
Yang
,
M.
, and
Wood
,
K.
,
2014
, “
Bio-Inspired Design: An Overview Investigating Open Questions From the Broader Field of Design-by-Analogy
,”
ASME J. Mech. Des.
,
136
(11), p. 111102.
49.
Cheong
,
H.
, and
Shu
,
L.
,
2014
, “
Retrieving Causally Related Functions From Natural-Language Text for Biomimetic Design
,”
ASME J. Mech. Des.
,
136
(
8
), p.
081008
.
50.
Cohen
,
Y. H.
,
Reich
,
Y.
, and
Greenberg
,
S.
,
2014
, “
Biomimetics: Structure–Function Patterns Approach
,”
ASME J. Mech. Des.
,
136
(
11
), p.
111108
.
51.
Nagel
,
J. K.
,
Nagel
,
R. L.
,
Stone
,
R. B.
, and
McAdams
,
D. A.
,
2010
, “
Function-Based, Biologically Inspired Concept Generation
,”
Artif. Intell. Eng. Des. Anal. Manuf.
,
24
(
04
), pp.
521
535
.
52.
Ashby
,
M.
,
2006
, “
The Properties of Foams and Lattices
,”
Philos. Trans. R. Soc., A
,
364
(
1838
), pp.
15
30
.
53.
Vetsch
,
J. R.
,
Müller
,
R.
, and
Hofmann
,
S.
,
2013
, “
The Evolution of Simulation Techniques for Dynamic Bone Tissue Engineering in Bioreactors
,”
J. Tissue Eng. Regener. Med.
,
9
(8), pp. 903–917.
54.
Egan
,
P.
,
Ferguson
,
S.
, and
Shea
,
K.
,
2016
, “
Design and 3D Printing of Hierarchical Tissue Engineering Scaffolds Based on Mechanics and Biology Perspectives
,”
ASME
Paper No. DETC2016-59554.
55.
Jonitz-Heincke
,
A.
,
Wieding
,
J.
,
Schulze
,
C.
,
Hansmann
,
D.
, and
Bader
,
R.
,
2013
, “
Comparative Analysis of the Oxygen Supply and Viability of Human Osteoblasts in Three-Dimensional Titanium Scaffolds Produced by Laser-Beam or Electron-Beam Melting
,”
Materials
,
6
(
11
), pp.
5398
5409
.
56.
Truscello
,
S.
,
Kerckhofs
,
G.
,
Van Bael
,
S.
,
Pyka
,
G.
,
Schrooten
,
J.
, and
Van Oosterwyck
,
H.
,
2012
, “
Prediction of Permeability of Regular Scaffolds for Skeletal Tissue Engineering: A Combined Computational and Experimental Study
,”
Acta Biomater.
,
8
(
4
), pp.
1648
1658
.
57.
Khayyeri
,
H.
,
Checa
,
S.
,
Tägil
,
M.
, and
Prendergast
,
P. J.
,
2009
, “
Corroboration of Mechanobiological Simulations of Tissue Differentiation in an In Vivo Bone Chamber Using a Lattice-Modeling Approach
,”
J. Orthop. Res.
,
27
(
12
), pp.
1659
1666
.
58.
Guyot
,
Y.
,
Papantoniou
,
I.
,
Chai
,
Y. C.
,
Van Bael
,
S.
,
Schrooten
,
J.
, and
Geris
,
L.
,
2014
, “
A Computational Model for Cell/ECM Growth on 3D Surfaces Using the Level Set Method: A Bone Tissue Engineering Case Study
,”
Biomech. Model. Mechanobiol.
,
13
(
6
), pp.
1361
1371
.
59.
Thorne
,
B. C.
,
Bailey
,
A. M.
, and
Peirce
,
S. M.
,
2007
, “
Combining Experiments With Multi-Cell Agent-Based Modeling to Study Biological Tissue Patterning
,”
Briefings Bioinf.
,
8
(
4
), pp.
245
257
.
60.
Boehm
,
B. W.
,
1988
, “
A Spiral Model of Software Development and Enhancement
,”
Computer
,
21
(
5
), pp.
61
72
.
61.
Kang
,
H.-W.
, and
Cho
,
D.-W.
,
2012
, “
Development of an Indirect Stereolithography Technology for Scaffold Fabrication With a Wide Range of Biomaterial Selectivity
,”
Tissue Eng., Part C
,
18
(
9
), pp.
719
729
.
62.
Li
,
X.
,
Li
,
D.
,
Lu
,
B.
, and
Wang
,
C.
,
2008
, “
Fabrication of Bioceramic Scaffolds With Pre-Designed Internal Architecture by Gel Casting and Indirect Stereolithography Techniques
,”
J. Porous Mater.
,
15
(
6
), pp.
667
671
.
63.
Mueller
,
J.
,
Shea
,
K.
, and
Daraio
,
C.
,
2015
, “
Mechanical Properties of Parts Fabricated With Inkjet 3D Printing Through Efficient Experimental Design
,”
Mater. Des.
,
86
, pp.
902
912
.
64.
Walser
,
J.
,
Stok
,
K. S.
,
Caversaccio
,
M. D.
, and
Ferguson
,
S. J.
,
2016
, “
Direct Electrospinning of 3D Auricle-Shaped Scaffolds for Tissue Engineering Applications
,”
Biofabrication
,
8
(
2
), p.
025007
.
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