Towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds to foster bone regeneration.

Substantial tissue loss, such as in large bone defects, represents a clinical challenge for which regenerative therapies and tissue engineering strategies aim at offering treatment alternatives to conventional replacement approaches by metallic implants. 3D printing technologies provide endless opportunities to shape scaffold structures that could support endogenous regeneration. However, it remains unclear which of the numerous parameters at hand eventually enhance tissue regeneration. In the last decades, a significant effort has been made in the development of computer tools to optimize scaffold designs. Here, we aim at giving a more comprehensive overview summarizing current computer optimization framework technologies. We confront these with the most recent advances in scaffold mechano-biological optimization, discuss their limitations and provide suggestions for future development. We conclude that the field needs to move forward to not only optimize scaffolds to avoid implant failures but to improve their mechano-biological behaviour: providing an initial stimulus for fast tissue organisation and healing and accounting for remodelling, scaffold degradation and consecutive filling with host tissue. So far, modelling approaches fall short in including the various scales of tissue dynamics. With this review, we wish to stimulate a move towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds.

[1]  D Kaspar,et al.  Effects of Mechanical Factors on the Fracture Healing Process , 1998, Clinical orthopaedics and related research.

[2]  In Vivo Bone Formation Within Engineered Hydroxyapatite Scaffolds in a Sheep Model , 2016, Calcified Tissue International.

[3]  M. Stevens,et al.  Individual response variations in scaffold-guided bone regeneration are determined by independent strain- and injury-induced mechanisms , 2019, Biomaterials.

[4]  S. Hollister,et al.  Optimal design and fabrication of scaffolds to mimic tissue properties and satisfy biological constraints. , 2002, Biomaterials.

[5]  Amit Bandyopadhyay,et al.  Recent advances in bone tissue engineering scaffolds. , 2012, Trends in biotechnology.

[6]  G. Duda,et al.  Computational analyses of different intervertebral cages for lumbar spinal fusion. , 2015, Journal of biomechanics.

[7]  R. Palmer,et al.  The effect of smoking on bone healing , 2013, Bone & joint research.

[8]  R. Marcucio,et al.  Effects of Aging on Fracture Healing , 2017, Current Osteoporosis Reports.

[9]  Q. Qin,et al.  Topological shape optimization of multifunctional tissue engineering scaffolds with level set method , 2016, Structural and Multidisciplinary Optimization.

[10]  Thomas A Einhorn,et al.  Fracture healing as a post‐natal developmental process: Molecular, spatial, and temporal aspects of its regulation , 2003, Journal of cellular biochemistry.

[11]  H. Ohgushi,et al.  Tissue engineering approach to the treatment of bone tumors: three cases of cultured bone grafts derived from patients' mesenchymal stem cells. , 2006, Artificial organs.

[12]  E R Draper,et al.  The vascular response to fracture micromovement. , 1994, Clinical orthopaedics and related research.

[13]  Georg N Duda,et al.  Insight into the molecular pathophysiology of delayed bone healing in a sheep model. , 2010, Tissue engineering. Part A.

[14]  G. Duda,et al.  Clinical and Research Approaches to Treat Non-union Fracture , 2018, Current Osteoporosis Reports.

[15]  Wei Xu,et al.  Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review. , 2016, Biomaterials.

[16]  P. Prendergast,et al.  A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. , 2002, Journal of biomechanics.

[17]  Panos Y. Papalambros,et al.  Panos Papalambros a Survey of Structural Optimization in Mechanical Product Development , 2022 .

[18]  J. Grotowski,et al.  Prototypes for Bone Implant Scaffolds Designed via Topology Optimization and Manufactured by Solid Freeform Fabrication , 2010 .

[19]  Byran J. Smucker,et al.  Validation of scaffold design optimization in bone tissue engineering: finite element modeling versus designed experiments , 2017, Biofabrication.

[20]  Dietmar W Hutmacher,et al.  Dynamics of in vitro polymer degradation of polycaprolactone-based scaffolds: accelerated versus simulated physiological conditions , 2008, Biomedical materials.

[21]  M. Fiorentino,et al.  Rhombicuboctahedron unit cell based scaffolds for bone regeneration: geometry optimization with a mechanobiology - driven algorithm. , 2018, Materials science & engineering. C, Materials for biological applications.

[22]  Chia-Ying Lin,et al.  Interbody Fusion Cage Design Using Integrated Global Layout and Local Microstructure Topology Optimization , 2004, Spine.

[23]  Helder C. Rodrigues,et al.  A hierarchical model for concurrent material and topology optimisation of three-dimensional structures , 2008 .

[24]  S. Hollister,et al.  Topology optimization of three dimensional tissue engineering scaffold architectures for prescribed bulk modulus and diffusivity , 2010, Structural and multidisciplinary optimization : journal of the International Society for Structural and Multidisciplinary Optimization.

[25]  Liesbet Geris,et al.  Maximizing neotissue growth kinetics in a perfusion bioreactor: An in silico strategy using model reduction and Bayesian optimization , 2018, Biotechnology and bioengineering.

[26]  H. Mehboob,et al.  Effect of structural stiffness of composite bone plate–scaffold assembly on tibial fracture with large fracture gap , 2015 .

[27]  Aaron Schindeler,et al.  Bone remodeling during fracture repair: The cellular picture. , 2008, Seminars in cell & developmental biology.

[28]  G. Rozvany.  Aims, scope, methods, history and unified terminology of computer-aided topology optimization in structural mechanics , 2001 .

[29]  T. Adachi,et al.  Framework for optimal design of porous scaffold microstructure by computational simulation of bone regeneration. , 2006, Biomaterials.

[30]  Y. Yang,et al.  Treatment of critical-sized bone defects: clinical and tissue engineering perspectives , 2018, European Journal of Orthopaedic Surgery & Traumatology.

[31]  José Manuel García-Aznar,et al.  In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2 , 2015, PloS one.

[32]  L. Claes,et al.  Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. , 1998, Journal of biomechanics.

[33]  N. Kikuchi,et al.  A novel method for biomaterial scaffold internal architecture design to match bone elastic properties with desired porosity. , 2004, Journal of biomechanics.

[34]  Wacław Kuś,et al.  Optimization of bone scaffold structures using experimental and numerical data , 2016 .

[35]  J M García-Aznar,et al.  On scaffold designing for bone regeneration: A computational multiscale approach. , 2009, Acta biomaterialia.

[36]  J. Argenson,et al.  Can we achieve bone healing using the diamond concept without bone grafting for recalcitrant tibial nonunions? , 2015, Injury.

[37]  Yi Min Xie,et al.  Topology optimization of functionally graded cellular materials , 2013, Journal of Materials Science.

[38]  Luciano Lamberti,et al.  A Mechanobiology-based Algorithm to Optimize the Microstructure Geometry of Bone Tissue Scaffolds , 2016, International journal of biological sciences.

[39]  Georg N Duda,et al.  Porous scaffold architecture guides tissue formation , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  S. Hollister,et al.  Optimization of scaffold design for bone tissue engineering: A computational and experimental study. , 2014, Medical engineering & physics.

[41]  Scott J. Hollister,et al.  Computational design of tissue engineering scaffolds , 2007 .

[42]  Richard A. Robb,et al.  Schwarz meets Schwann: Design and fabrication of biomorphic and durataxic tissue engineering scaffolds , 2006, Medical Image Anal..

[43]  D. Hutmacher,et al.  BMP delivery complements the guiding effect of scaffold architecture without altering bone microstructure in critical-sized long bone defects: A multiscale analysis. , 2015, Acta biomaterialia.

[44]  Klaus Mecke,et al.  Minimal surface scaffold designs for tissue engineering. , 2011, Biomaterials.

[45]  R Cancedda,et al.  Repair of large bone defects with the use of autologous bone marrow stromal cells. , 2001, The New England journal of medicine.

[46]  S. Hollister.  Scaffold Design and Manufacturing: From Concept to Clinic , 2009, Advanced materials.

[47]  Di Wang,et al.  Topology optimization of microstructure and selective laser melting fabrication for metallic biomaterial scaffolds , 2012 .

[48]  S M Giannitelli,et al.  Current trends in the design of scaffolds for computer-aided tissue engineering. , 2014, Acta biomaterialia.

[49]  J. Aldazabal,et al.  Computer Simulation of Scaffold Degradation , 2010 .

[50]  M. Dembo,et al.  Cell movement is guided by the rigidity of the substrate. , 2000, Biophysical journal.

[51]  Matthijs Langelaar,et al.  Topology optimization of 3D self-supporting structures for additive manufacturing , 2016 .

[52]  Alok Sutradhar,et al.  Topological optimization for designing patient-specific large craniofacial segmental bone replacements , 2010, Proceedings of the National Academy of Sciences.

[53]  M. Neo,et al.  Repair of segmental long bone defect in rabbit femur using bioactive titanium cylindrical mesh cage. , 2003, Biomaterials.

[54]  K. Svanberg.  The method of moving asymptotes—a new method for structural optimization , 1987 .

[55]  Óscar L. Rodríguez-Montaño,et al.  Comparison of the mechanobiological performance of bone tissue scaffolds based on different unit cell geometries. , 2018, Journal of the mechanical behavior of biomedical materials.

[56]  A. Göpferich,et al.  Mechanisms of polymer degradation and erosion. , 1996, Biomaterials.

[57]  G. Duda,et al.  Experience in the Adaptive Immunity Impacts Bone Homeostasis, Remodeling, and Healing , 2019, Front. Immunol..

[58]  Scott J Hollister,et al.  Scaffold translation: barriers between concept and clinic. , 2011, Tissue engineering. Part B, Reviews.

[59]  Jan Sokolowski,et al.  Introduction to shape optimization , 1992 .

[60]  James C. Weaver,et al.  Mechanobiologically optimized 3D titanium-mesh scaffolds enhance bone regeneration in critical segmental defects in sheep , 2018, Science Translational Medicine.

[61]  Shiwei Zhou,et al.  Microstructure design of biodegradable scaffold and its effect on tissue regeneration. , 2011, Biomaterials.

[62]  Antonio Boccaccio,et al.  Geometry Design Optimization of Functionally Graded Scaffolds for Bone Tissue Engineering: A Mechanobiological Approach , 2016, PloS one.

[63]  Eleftherios Tsiridis,et al.  Current concepts of molecular aspects of bone healing. , 2005, Injury.

[64]  C. Pappalettere,et al.  Finite Element Method (FEM), Mechanobiology and Biomimetic Scaffolds in Bone Tissue Engineering , 2011, International journal of biological sciences.

[65]  Shiwei Zhou,et al.  Computational design for scaffold tissue engineering , 2017 .

[66]  Alireza Fathi,et al.  Optimal design of a 3D-printed scaffold using intelligent evolutionary algorithms , 2016, Appl. Soft Comput..

[67]  Q. Rong,et al.  Finite-element design and optimization of a three-dimensional tetrahedral porous titanium scaffold for the reconstruction of mandibular defects. , 2017, Medical engineering & physics.

[68]  K. Schaser,et al.  Shaping scaffold structures in rapid manufacturing implants: a modeling approach toward mechano-biologically optimized configurations for large bone defect. , 2012, Journal of biomedical materials research. Part B, Applied biomaterials.

[69]  D W Hutmacher,et al.  Evolutionary design of bone scaffolds with reference to material selection , 2012, International journal for numerical methods in biomedical engineering.

[70]  Henrique de Amorim Almeida,et al.  Virtual topological optimisation of scaffolds for rapid prototyping. , 2010, Medical engineering & physics.

[71]  H. Chuah,et al.  Topology optimisation of spinal interbody cage for reducing stress shielding effect , 2010, Computer methods in biomechanics and biomedical engineering.

[72]  Qing Li,et al.  On stiffness of scaffolds for bone tissue engineering-a numerical study. , 2010, Journal of biomechanics.

[73]  José Manuel García-Aznar,et al.  Micro–macro numerical modelling of bone regeneration in tissue engineering , 2008 .

[74]  Liesbet Geris,et al.  Size Does Matter: An Integrative In Vivo-In Silico Approach for the Treatment of Critical Size Bone Defects , 2014, PLoS Comput. Biol..

[75]  Jan Wieding,et al.  Numerical optimization of open-porous bone scaffold structures to match the elastic properties of human cortical bone. , 2014, Journal of the mechanical behavior of biomedical materials.

[76]  Di Wang,et al.  Evaluation of topology-optimized lattice structures manufactured via selective laser melting , 2018 .

[77]  K. Shinomiya,et al.  Efficacy and safety of porous hydroxyapatite/type 1 collagen composite implantation for bone regeneration: A randomized controlled study. , 2016, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[78]  James K. Guest,et al.  Optimizing multifunctional materials: Design of microstructures for maximized stiffness and fluid permeability , 2006 .

[79]  Maarten Moesen,et al.  Characterization and optimization of cell seeding in scaffolds by factorial design: quality by design approach for skeletal tissue engineering. , 2011, Tissue engineering. Part C, Methods.

[80]  Helder C. Rodrigues,et al.  Multiscale modeling of bone tissue with surface and permeability control , 2011 .