Research Papers: Design Automation

Design of Hierarchical Three-Dimensional Printed Scaffolds Considering Mechanical and Biological Factors for Bone Tissue Engineering

[+] Author and Article Information
Paul F. Egan

Department of Health Sciences and Technology,
ETH Zurich,
Honggerbergring 64,
Zurich 8093, Switzerland
e-mail: pegan@ethz.ch

Stephen J. Ferguson

Department of Health Sciences and Technology,
Institute for Biomechanics,
ETH Zurich,
Honggerbergring 64,
Zurich 8093, Switzerland
e-mail: sferguson@ethz.ch

Kristina Shea

Department of Mechanical and Process
ETH Zurich,
Zurich 8092, Switzerland
e-mail: kshea@ethz.ch

1Corresponding author.

Contributed by the Design Automation Committee of ASME for publication in the JOURNAL OF MECHANICAL DESIGN. Manuscript received December 3, 2016; final manuscript received March 18, 2017; published online April 24, 2017. Assoc. Editor: Katja Holtta-Otto.

J. Mech. Des 139(6), 061401 (Apr 24, 2017) (9 pages) Paper No: MD-16-1807; doi: 10.1115/1.4036396 History: Received December 03, 2016; Revised March 18, 2017

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.

Copyright © 2017 by ASME
Your Session has timed out. Please sign back in to continue.


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.
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. [CrossRef]
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. [CrossRef]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef]
Hollister, S. J. , and Murphy, W. L. , 2011, “ Scaffold Translation: Barriers Between Concept and Clinic,” Tissue Eng., Part B, 17(6), pp. 459–474. [CrossRef]
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. [CrossRef]
Derby, B. , 2012, “ Printing and Prototyping of Tissues and Scaffolds,” Science, 338(6109), pp. 921–926. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef]
Bose, S. , Roy, M. , and Bandyopadhyay, A. , 2012, “ Recent Advances in Bone Tissue Engineering Scaffolds,” Trends Biotechnol., 30(10), pp. 546–554. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
Olson, G. B. , 1997, “ Computational Design of Hierarchically Structured Materials,” Science, 277(5330), pp. 1237–1242. [CrossRef]
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. [CrossRef]
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. [CrossRef]
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. [CrossRef] [PubMed]
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.
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. [CrossRef] [PubMed]
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. [CrossRef]
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. [CrossRef] [PubMed]
O'brien, F. J. , 2011, “ Biomaterials & Scaffolds for Tissue Engineering,” Mater. Today, 14(3), pp. 88–95. [CrossRef]
McKeen, L. W. , 2014, Plastics Used in Medical Devices, William Andrew Publishing, Oxford, UK, Chap. 3.
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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.
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. [CrossRef]
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. [CrossRef]
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.
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. [CrossRef]
Cohen, Y. H. , Reich, Y. , and Greenberg, S. , 2014, “ Biomimetics: Structure–Function Patterns Approach,” ASME J. Mech. Des., 136(11), p. 111108. [CrossRef]
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. [CrossRef]
Ashby, M. , 2006, “ The Properties of Foams and Lattices,” Philos. Trans. R. Soc., A, 364(1838), pp. 15–30. [CrossRef]
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.
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.
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. [CrossRef]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef] [PubMed]
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. [CrossRef]
Boehm, B. W. , 1988, “ A Spiral Model of Software Development and Enhancement,” Computer, 21(5), pp. 61–72. [CrossRef]
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. [CrossRef]
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. [CrossRef]
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. [CrossRef]
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. [CrossRef] [PubMed]


Grahic Jump Location
Fig. 1

Design approach for testing scaffold samples rescaled for interbody fusion cage products

Grahic Jump Location
Fig. 2

Multilevel scaffold design

Grahic Jump Location
Fig. 3

Scaffold topology types

Grahic Jump Location
Fig. 4

Planar schematic of hierarchical truss with indicated element diameter ø, unit cell length Lc, number of unit cells Nc, and lengths L1, L2, L3, and L4

Grahic Jump Location
Fig. 5

Continuous beam designs with parameters normalized to Nc=12, Lc=2.0 mm, and ø=800 μm for (a) porosity, (b) surface–volume ratio, and (c) relative elastic modulus

Grahic Jump Location
Fig. 6

Designs for each topology type generated by independently sweeping design parameters (a) number of cells Nc, (b) unit cell length Lc, and (c) element diameter ø for (A1, B1, C1) porosity, (A2, B2, C2) surface–volume ratio, and (A3, B3, C3) relative elastic modulus

Grahic Jump Location
Fig. 8

(a) Data from Fig. 7(a) replotted for element diameter ø. A hierarchical truss with number of cells Nc=9, cell length Lc=1.5 mm, and element diameter ø=500 μm is selected and (b) patterned with dimensions relevant for an interbody cage; note that adjacent second-order unit cells share first-order unit cells when patterned to form a tailored structure.

Grahic Jump Location
Fig. 7

Designs for each topology type generated by sweeping element diameter ø from 200 μm to 1400 μm with pore size p=1 mm and scaffold length Ls≤1.5 cm for (a) surface–volume ratio and (b) relative elastic modulus



Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging and repositioning the boxes below.

Related Journal Articles
Related eBook Content
Topic Collections

Sorry! You do not have access to this content. For assistance or to subscribe, please contact us:

  • TELEPHONE: 1-800-843-2763 (Toll-free in the USA)
  • EMAIL: asmedigitalcollection@asme.org
Sign In