Porosity parameters in biomaterial science: Definition, impact, and challenges in tissue engineering

Abstract

Porosity parameters are one of the structural properties of the extracellular microenvironment that have been shown to have a great impact on the cellular phenotype and various biological activities such as diffusion of fluid, initial protein adsorption, permeability, cell penetration and migration, ECM deposition, angiogenesis, and rate and pattern of new tissue formation. The heterogeneity of the study protocols and research methodologies do not allow reliable meta-analysis for definite findings. As such, despite the huge available literature, no generally accepted consensus is defined for the porosity requirements of specific tissue engineering applications. However, based on the biomimetic approach, the biological substitutes should replicate the 3D local microenvironment of the recipient site with matching porosity parameters to best support local cells during tissue regeneration. Ideally, the porosity of biomaterials should mimic the porosity of the substituting natural tissue and match the clinical requirements. Careful analysis of the impact of architectures (i.e., porosity) on biophysical, biochemical, and biological behaviors will support designing smart biomaterials with customized architectural and functional properties that are patient and defect site-specific.

Graphical abstract

Keywords

porosity / pore size / pore geometry / topography / tissue engineering

References

[1] Trivedi N, Hollister-Lock J, Lopez-Avalos M D, . Increase in β-cell mass in transplanted porcine neonatal pancreatic cell clusters is due to proliferation of β-cells and differentiation of duct cells. Endocrinology, 2001, 142(5): 2115–2122

[2] Mørch Y A, Donati I, Strand B L, . Effect of Ca²⁺, Ba²⁺, and Sr²⁺ on alginate microbeads. Biomacromolecules, 2006, 7(5): 1471–1480

[3] Ebrahimi M. Extracellular matrix: The ideal natural fibrous nanocomposite products. In: Inamuddin A M, Asiri A, Mohammad, eds. Applications of Nanocomposite Materials in Orthopedics. Elsevier, 2019, 263–286

[4] Steinberg M S. ECM: Its nature, origin and function in cell aggregation. Experimental Cell Research, 1963, 30(2): 257–279

[5] Mansouri N, SamiraBagheri. The influence of topography on tissue engineering perspective. Materials Science and Engineering C, 2016, 61: 906–921

[6] De Arcangelis A, Georges-Labouesse E. Integrin and ECM functions: Roles in vertebrate development. Trends in Genetics, 2000, 16(9): 389–395

[7] Chen G, Ushida T, Tateishi T. Scaffold design for tissue engineering. Macromolecular Bioscience, 2002, 2(2): 67–77

[8] Loh Q L, Choong C. Three-dimensional scaffolds for tissue engineering applications: Role of porosity and pore size. Tissue Engineering Part B: Reviews, 2013, 19(6): 485–502

[9] Ebrahimi M, Botelho M G, Dorozhkin S V. Biphasic calcium phosphates bioceramics (HA/TCP): Concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research. Materials Science and Engineering C, 2017, 71: 1293–1312

[10] Naderi H, Matin M M, Bahrami A R. Critical issues in tissue engineering: Biomaterials, cell sources, angiogenesis, and drug delivery systems. Journal of Biomaterials Applications, 2011, 26(4): 383–417

[11] Chen F M, Wu L A, Zhang M, . Homing of endogenous stem/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives. Biomaterials, 2011, 32(12): 3189–3209

[12] Teo B K K, Wong S T, Lim C K, . Nanotopography modulates mechanotransduction of stem cells and induces differentiation through focal adhesion kinase. ACS Nano, 2013, 7(6): 4785–4798

[13] Pérez R A, Won J E, Knowles J C, . Naturally and synthetic smart composite biomaterials for tissue regeneration. Advanced Drug Delivery Reviews, 2013, 65(4): 471–496

[14] Hutmacher D W. Scaffolds in tissue engineering bone and cartilage. Biomaterials, 2000, 21(24): 2529–2543

[15] Murphy C M, Duffy G P, Schindeler A, . Effect of collagen–glycosaminoglycan scaffold pore size on matrix mineralization and cellular behavior in different cell types. Journal of Biomedical Materials Research Part A, 2016, 104(1): 291–304

[16] Dalby M J, Gadegaard N, Oreffo R O C. Harnessing nanotopography and integrin-matrix interactions to influence stem cell fate. Nature Materials, 2014, 13(6): 558–569

[17] Marklein R A, Burdick J A. Controlling stem cell fate with material design. Advanced Materials, 2010, 22(2): 175–189

[18] Keung A J, Kumar S, Schaffer D V. Presentation counts: Microenvironmental regulation of stem cells by biophysical and material cues. Annual Review of Cell and Developmental Biology, 2010, 26(1): 533–556

[19] Hing K A, Annaz B, Saeed S, . Microporosity enhances bioactivity of synthetic bone graft substitutes. Journal of Materials Science: Materials in Medicine, 2005, 16(5): 467–475

[20] Perez R A, Mestres G. Role of pore size and morphology in musculo-skeletal tissue regeneration. Materials Science and Engineering C, 2016, 61: 922–939

[21] Rosa A L, Beloti M M, van Noort R. Osteoblastic differentiation of cultured rat bone marrow cells on hydroxyapatite with different surface topography. Dental Materials, 2003, 19(8): 768–772

[22] Habibovic P, Yuan H, van der Valk C M, . 3D microenvironment as essential element for osteoinduction by biomaterials. Biomaterials, 2005, 26(17): 3565–3575

[23] Rouahi M, Gallet O, Champion E, . Influence of hydroxyapatite microstructure on human bone cell response. Journal of Biomedical Materials Research Part A, 2006, 78A(2): 222–235

[24] Vagaská B, Bacáková L, Filová E, . Osteogenic cells on bio-inspired materials for bone tissue engineering. Physiological Research, 2010, 59(3): 309–322

[25] Acarregui A, Murua A, Pedraz J L, . A perspective on bioactive cell microencapsulation. BioDrugs, 2012, 26(5): 283–301

[26] Ginebra M P, Espanol M, Montufar E B, . New processing approaches in calcium phosphate cements and their applications in regenerative medicine. Acta Biomaterialia, 2010, 6(8): 2863–2873

[27] Yeong W Y, Chua C K, Leong K F, . Rapid prototyping in tissue engineering: challenges and potential. Trends in Biotechnology, 2004, 22(12): 643–652

[28] Ebrahimi M, Botelho M, Lu W, . Integrated approach in designing biphasic nanocomposite collagen/nBCP scaffolds with controlled porosity and permeability for bone tissue engineering. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2020, 108(4): 1738–1753

[29] Goulet R W, Goldstein S A, Ciarelli M J, . The relationship between the structural and orthogonal compressive properties of trabecular bone. Journal of Biomechanics, 1994, 27(4): 375–389

[30] Tsang V L, Bhatia S N. Three-dimensional tissue fabrication. Advanced Drug Delivery Reviews, 2004, 56(11): 1635–1647

[31] Sherwood J K, Riley S L, Palazzolo R, . A three-dimensional osteochondral composite scaffold for articular cartilage repair. Biomaterials, 2002, 23(24): 4739–4751

[32] Leong K F, Chua C K, Sudarmadji N, . Engineering functionally graded tissue engineering scaffolds. Journal of the Mechanical Behavior of Biomedical Materials, 2008, 1(2): 140–152

[33] Yang S, Leong K F, Du Z, . The design of scaffolds for use in tissue engineering. Part II. Rapid prototyping techniques. Tissue Engineering, 2002, 8(1): 1–11

[34] Pompe W, Worch H, Epple M, . Functionally graded materials for biomedical applications. Materials Science and Engineering A, 2003, 362(1–2): 40–60

[35] Miao X, Sun D. Graded/gradient porous biomaterials. Materials, 2009, 3(1): 26–47

[36] Woodfield T B F, Van Blitterswijk C A, De Wijn J, . Polymer scaffolds fabricated with pore-size gradients as a model for studying the zonal organization within tissue-engineered cartilage constructs. Tissue Engineering, 2005, 11(9–10): 1297–1311

[37] Karpiak J V, Ner Y, Almutairi A. Density gradient multilayer polymerization for creating complex tissue. Advanced Materials, 2012, 24(11): 1466–1470

[38] Zhu Y, Wu H, Sun S, . Designed composites for mimicking compressive mechanical properties of articular cartilage matrix. Journal of the Mechanical Behavior of Biomedical Materials, 2014, 36: 32–46

[39] Oh S H, Park I K, Kim J M, . In vitro and in vivo characteristics of PCL scaffolds with pore size gradient fabricated by a centrifugation method. Biomaterials, 2007, 28(9): 1664–1671

[40] Bružauskaitė I, Bironaitė D, Bagdonas E, . Scaffolds and cells for tissue regeneration: Different scaffold pore sizes-different cell effects. Cytotechnology, 2016, 68(3): 355–369

[41] Causa F, Netti P A, Ambrosio L. A multi-functional scaffold for tissue regeneration: The need to engineer a tissue analogue. Biomaterials, 2007, 28(34): 5093–5099

[42] Sung H J, Meredith C, Johnson C, . The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis. Biomaterials, 2004, 25(26): 5735–5742

[43] Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials, 2005, 26(27): 5474–5491

[44] Hollister S J. Porous scaffold design for tissue engineering. Nature Materials, 2005, 4(7): 518–524

[45] Macchetta A, Turner I G, Bowen C R. Fabrication of HA/TCP scaffolds with a graded and porous structure using a camphene-based freeze-casting method. Acta Biomaterialia, 2009, 5(4): 1319–1327

[46] Almeida H A, Bártolo P J. Topological optimisation of scaffolds for tissue engineering. Procedia Engineering, 2013, 59: 298–306

[47] Rainer A, Giannitelli S M, Accoto D, . Load-adaptive scaffold architecturing: a bioinspired approach to the design of porous additively manufactured scaffolds with optimized mechanical properties. Annals of Biomedical Engineering, 2012, 40(4): 966–975

[48] Mitsak A G, Kemppainen J M, Harris M T, . Effect of polycaprolactone scaffold permeability on bone regeneration in vivo. Tissue Engineering Part A, 2011, 17(13–14): 1831–1839

[49] O’Brien F J, Harley B A, Waller M A, . The effect of pore size on permeability and cell attachment in collagen scaffolds for tissue engineering. Technology and Health Care, 2007, 15(1): 3–17

[50] Emans P J, Jansen E J P, van Iersel D, . Tissue-engineered constructs: The effect of scaffold architecture in osteochondral repair. Journal of Tissue Engineering and Regenerative Medicine, 2013, 7(9): 751–756

[51] Lu J X, Flautre B, Anselme K, . Role of interconnections in porous bioceramics on bone recolonization in vitro and in vivo. Journal of Materials Science. Materials in Medicine, 1999, 10(2): 111–120

[52] Otsuki B, Takemoto M, Fujibayashi S, . Pore throat size and connectivity determine bone and tissue ingrowth into porous implants: Three-dimensional micro-CT based structural analyses of porous bioactive titanium implants. Biomaterials, 2006, 27(35): 5892–5900

[53] Starly B, Yildirim E, Sun W. A tracer metric numerical model for predicting tortuosity factors in three-dimensional porous tissue scaffolds. Computer Methods and Programs in Biomedicine, 2007, 87(1): 21–27

[54] Hrabe J, Hrabetová S, Segeth K. A model of effective diffusion and tortuosity in the extracellular space of the brain. Biophysical Journal, 2004, 87(3): 1606–1617

[55] Zalc J M, Reyes S C, Iglesia E. The effects of diffusion mechanism and void structure on transport rates and tortuosity factors in complex porous structures. Chemical Engineering Science, 2004, 59(14): 2947–2960

[56] Botchwey E A, Dupree M A, Pollack S R, . Tissue engineered bone: Measurement of nutrient transport in three-dimensional matrices. Journal of Biomedical Materials Research Part A, 2003, 67A(1): 357–367

[57] Silva M M C G, Cyster L A, Barry J J A, . The effect of anisotropic architecture on cell and tissue infiltration into tissue engineering scaffolds. Biomaterials, 2006, 27(35): 5909–5917

[58] Dorj B, Won J E, Purevdorj O, . A novel therapeutic design of microporous-structured biopolymer scaffolds for drug loading and delivery. Acta Biomaterialia, 2014, 10(3): 1238–1250

[59] Nikkhah M, Edalat F, Manoucheri S, . Engineering microscale topographies to control the cell–substrate interface. Biomaterials, 2012, 33(21): 5230–5246

[60] Lien S M, Ko L Y, Huang T J. Effect of pore size on ECM secretion and cell growth in gelatin scaffold for articular cartilage tissue engineering. Acta Biomaterialia, 2009, 5(2): 670–679

[61] Murphy C M, O’Brien F J. Understanding the effect of mean pore size on cell activity in collagen-glycosaminoglycan scaffolds. Cell Adhesion & Migration, 2010, 4(3): 377–381

[62] Zhao Y, Tan K, Zhou Y, . A combinatorial variation in surface chemistry and pore size of three-dimensional porous poly(ε-caprolactone) scaffolds modulates the behaviors of mesenchymal stem cells. Materials Science and Engineering C, 2016, 59: 193–202

[63] Nehrer S, Breinan H A, Ramappa A, . Matrix collagen type and pore size influence behaviour of seeded canine chondrocytes. Biomaterials, 1997, 18(11): 769–776

[64] Klawitter J J, Bagwell J G, Weinstein A M, . An evaluation of bone growth into porous high density polyethylene. Journal of Biomedical Materials Research, 1976, 10(2): 311–323

[65] Huri P Y, Ozilgen B A, Hutton D L, . Scaffold pore size modulates in vitro osteogenesis of human adipose-derived stem/stromal cells. Biomedical Materials, 2014, 9(4): 045003

[66] Sicchieri L G, Crippa G E, de Oliveira P T, . Pore size regulates cell and tissue interactions with PLGA-CaP scaffolds used for bone engineering. Journal of Tissue Engineering and Regenerative Medicine, 2012, 6(2): 155–162

[67] Kujala S, Ryhänen J, Danilov A, . Effect of porosity on the osteointegration and bone ingrowth of a weight-bearing nickel-titanium bone graft substitute. Biomaterials, 2003, 24(25): 4691–4697

[68] Kim T H, Oh S H, Kwon E B, . In vitro evaluation of osteogenesis and myogenesis from adipose-derived stem cells in a pore size gradient scaffold. Macromolecular Research, 2013, 21(8): 878–885

[69] Murphy C M, Haugh M G, O’Brien F J. The effect of mean pore size on cell attachment, proliferation and migration in collagen–glycosaminoglycan scaffolds for bone tissue engineering. Biomaterials, 2010, 31(3): 461–466

[70] Lim T C, Chian K S, Leong K F. Cryogenic prototyping of chitosan scaffolds with controlled micro and macro architecture and their effect on in vivo neo-vascularization and cellular infiltration. Journal of Biomedical Materials Research Part A, 2010, 94A(4): 1303‒1311

[71] Lee J W, Ahn G, Kim J Y, . Evaluating cell proliferation based on internal pore size and 3D scaffold architecture fabricated using solid freeform fabrication technology. Journal of Materials Science: Materials in Medicine, 2010, 21(12): 3195–3205

[72] Mygind T, Stiehler M, Baatrup A, . Mesenchymal stem cell ingrowth and differentiation on coralline hydroxyapatite scaffolds. Biomaterials, 2007, 28(6): 1036–1047

[73] Tsuruga E, Takita H, Itoh H, . Pore size of porous hydroxyapatite as the cell-substratum controls BMP-induced osteogenesis. Journal of Biochemistry, 1997, 121(2): 317–324

[74] Roosa S M M, Kemppainen J M, Moffitt E N, . The pore size of polycaprolactone scaffolds has limited influence on bone regeneration in an in vivo model. Journal of Biomedical Materials Research Part A, 2010, 92A(1): 359–368

[75] Hulbert S F, Young F A, Mathews R S, . Potential of ceramic materials as permanently implantable skeletal prostheses. Journal of Biomedical Materials Research, 1970, 4(3): 433–456

[76] Akin F A, Zreiqat H, Jordan S, . Preparation and analysis of macroporous TiO₂ films on Ti surfaces for bone-tissue implants. Journal of Biomedical Materials Research, 2001, 57(4): 588–596

[77] Akay G, Birch M A, Bokhari M A. Microcellular polyHIPE polymer supports osteoblast growth and bone formation in vitro. Biomaterials, 2004, 25(18): 3991–4000

[78] von Doernberg M C, von Rechenberg B, Bohner M, . In vivo behavior of calcium phosphate scaffolds with four different pore sizes. Biomaterials, 2006, 27(30): 5186–5198

[79] Itälä A I, Ylänen H O, Ekholm C, . Pore diameter of more than 100 microm is not requisite for bone ingrowth in rabbits. Journal of Biomedical Materials Research, 2001, 58(6): 679–683

[80] Sánchez-Salcedo S, Arcos D, Vallet-Regí M. Upgrading calcium phosphate scaffolds for tissue engineering applications. Key Engineering Materials, 2008, 377: 19–42

[81] Simske S J, Ayers R A, Bateman T A. Porous materials for bone engineering. Materials Science Forum, 1997, 250: 151–182

[82] Kim H J, Kim U J, Vunjak-Novakovic G, . Influence of macroporous protein scaffolds on bone tissue engineering from bone marrow stem cells. Biomaterials, 2005, 26(21): 4442–4452

[83] Mandal B B, Kundu S C. Cell proliferation and migration in silk fibroin 3D scaffolds. Biomaterials, 2009, 30(15): 2956–2965

[84] Oh S H, Kim T H, Im G I, . Investigation of pore size effect on chondrogenic differentiation of adipose stem cells using a pore size gradient scaffold. Biomacromolecules, 2010, 11(8): 1948–1955

[85] Duan P, Pan Z, Cao L, . The effects of pore size in bilayered poly(lactide-co-glycolide) scaffolds on restoring osteochondral defects in rabbits. Journal of Biomedical Materials Research Part A, 2014, 102(1): 180–192

[86] Penk A, Förster Y, Scheidt H A, . The pore size of PLGA bone implants determines the de novo formation of bone tissue in tibial head defects in rats. Magnetic Resonance in Medicine, 2013, 70(4): 925–935

[87] Klenke F M, Liu Y, Yuan H, . Impact of pore size on the vascularization and osseointegration of ceramic bone substitutes in vivo. Journal of Biomedical Materials Research Part A, 2008, 85A(3): 777–786

[88] Hausner T, Schmidhammer R, Zandieh S, . Nerve regeneration using tubular scaffolds from biodegradable polyurethane. Acta Neurochirurgica Supplementum, 2007, 100: 69–72

[89] Bozkurt A, Deumens R, Beckmann C, . In vitro cell alignment obtained with a Schwann cell enriched microstructured nerve guide with longitudinal guidance channels. Biomaterials, 2009, 30(2): 169–179

[90] Yuan N, Tian W, Sun L, . Neural stem cell transplantation in a double-layer collagen membrane with unequal pore sizes for spinal cord injury repair. Neural Regeneration Research, 2014, 9(10): 1014–1019

[91] Lee M, Wu B M, Dunn J C Y. Effect of scaffold architecture and pore size on smooth muscle cell growth. Journal of Biomedical Materials Research Part A, 2008, 87A(4): 1010–1016

[92] Harley B A C, Kim H D, Zaman M H, . Microarchitecture of three-dimensional scaffolds influences cell migration behavior via junction interactions. Biophysical Journal, 2008, 95(8): 4013–4024

[93] Yannas I V. Tissue regeneration by use of collagen–glycosaminoglycan copolymers. Clinical Materials, 1992, 9(3–4): 179–187

[94] Knight T, Basu J, Rivera E A, . Fabrication of a multi-layer three-dimensional scaffold with controlled porous micro-architecture for application in small intestine tissue engineering. Cell Adhesion & Migration, 2013, 7(3): 267–274

[95] Reilly G C, Engler A J. Intrinsic extracellular matrix properties regulate stem cell differentiation. Journal of Biomechanics, 2010, 43(1): 55–62

[96] Harley B A, Leung J H, Silva E C C M, . Mechanical characterization of collagen-glycosaminoglycan scaffolds. Acta Biomaterialia, 2007, 3(4): 463–474

[97] Kim M Y, Li D J, Pham L K, . Microfabrication of high-resolution porous membranes for cell culture. Journal of Membrane Science, 2014, 452: 460–469

[98] Chang H I, Wang Y. Cell responses to surface and architecture of tissue engineering scaffolds. In: Eberli D, ed. Regenerative Medicine and Tissue Engineering: Cells and Biomaterials.Croatia: InTech, 2011, 569–588

[99] Peyton S R, Kalcioglu Z I, Cohen J C, . Marrow-derived stem cell motility in 3D synthetic scaffold is governed by geometry along with adhesivity and stiffness. Biotechnology and Bioengineering, 2011, 108(5): 1181–1193

[100] Zhang M, Methot D, Poppa V, . Cardiomyocyte grafting for cardiac repair: Graft cell death and anti-death strategies. Journal of Molecular and Cellular Cardiology, 2001, 33(5): 907–921

[101] Lee J S, Cha H D, Shim J H, . Effect of pore architecture and stacking direction on mechanical properties of solid freeform fabrication-based scaffold for bone tissue engineering. Journal of Biomedical Materials Research Part A, 2012, 100A(7): 1846–1853

[102] Phadke A, Hwang Y S, Kim S H, . Effect of scaffold microarchitecture on osteogenic differentiation of human mesenchymal stem cells. European Cells & Materials, 2013, 25: 114–129

[103] Liu X, Rahaman M N, Fu Q. Bone regeneration in strong porous bioactive glass (13–93) scaffolds with an oriented microstructure implanted in rat calvarial defects. Acta Biomaterialia, 2013, 9(1): 4889–4898

[104] Fu Q, Rahaman M N, Bal B S, . In vitro cellular response to hydroxyapatite scaffolds with oriented pore architectures. Materials Science and Engineering C, 2009, 29(7): 2147–2153

[105] Brouwer K M, Daamen W F, van Lochem N, . Construction and in vivo evaluation of a dual layered collagenous scaffold with a radial pore structure for repair of the diaphragm. Acta Biomaterialia, 2013, 9(6): 6844–6851

[106] Sanzana E S, Navarro M, Ginebra M P, . Role of porosity and pore architecture in the in vivo bone regeneration capacity of biodegradable glass scaffolds. Journal of Biomedical Materials Research Part A, 2014, 102(6): 1767–1773

[107] Yilgor P, Sousa R A, Reis R L, . 3D plotted PCL scaffolds for stem cell based bone tissue engineering. Macromolecular Symposia, 2008, 269(1): 92–99

[108] Jeong C G, Hollister S J. Mechanical and biochemical assessments of three-dimensional poly(1,8-octanediol-co-citrate) scaffold pore shape and permeability effects on in vitro chondrogenesis using primary chondrocytes. Tissue Engineering Part A, 2010, 16(12): 3759–3768

[109] Bidan C M, Kommareddy K P, Rumpler M, . Geometry as a factor for tissue growth: Towards shape optimization of tissue engineering scaffolds. Advanced Healthcare Materials, 2013, 2(1): 186–194

[110] Engelmayr G C Jr, Papworth G D, Watkins S C, . Guidance of engineered tissue collagen orientation by large-scale scaffold microstructures. Journal of Biomechanics, 2006, 39(10): 1819–1831

[111] Nelson C M, Jean R P, Tan J L, . Emergent patterns of growth controlled by multicellular form and mechanics. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(33): 11594–11599

[112] Rumpler M, Woesz A, Dunlop J W C, . The effect of geometry on three-dimensional tissue growth. Journal of the Royal Society: Interface, 2008, 5(27): 1173–1180

[113] Scarano A, Degidi M, Perrotti V, . Experimental evaluation in rabbits of the effects of thread concavities in bone formation with different titanium implant surfaces. Clinical Implant Dentistry and Related Research, 2014, 16(4): 572–581

[114] Ripamonti U, Roden L C, Renton L F. Osteoinductive hydroxyapatite-coated titanium implants. Biomaterials, 2012, 33(15): 3813–3823

[115] Zadpoor A A. Bone tissue regeneration: The role of scaffold geometry. Biomaterials Science, 2015, 3(2): 231–245

[116] Melchels F P W, Tonnarelli B, Olivares A L, . The influence of the scaffold design on the distribution of adhering cells after perfusion cell seeding. Biomaterials, 2011, 32(11): 2878–2884

[117] Wu J, Zhao Q, Sun J, . Preparation of poly(ethylene glycol) aligned porous cryogels using a unidirectional freezing technique. Soft Matter, 2012, 8(13): 3620

[118] Jia S, Liu L, Pan W, . Oriented cartilage extracellular matrix-derived scaffold for cartilage tissue engineering. Journal of Bioscience and Bioengineering, 2012, 113(5): 647–653

[119] Arora A, Kothari A, Katti D S. Pore orientation mediated control of mechanical behavior of scaffolds and its application in cartilage-mimetic scaffold design. Journal of the Mechanical Behavior of Biomedical Materials, 2015, 51: 169–183

[120] Sobral J M, Caridade S G, Sousa R A, . Three-dimensional plotted scaffolds with controlled pore size gradients: Effect of scaffold geometry on mechanical performance and cell seeding efficiency. Acta Biomaterialia, 2011, 7(3): 1009–1018

[121] Salerno A, Guarnieri D, Iannone M, . Effect of micro- and macroporosity of bone tissue three-dimensional poly(ε-caprolactone) scaffold on human mesenchymal stem cells invasion, proliferation, and differentiation in vitro. Tissue Engineering Part A, 2010, 16(8): 2661–2673

[122] Choi S W, Zhang Y, Xia Y. Three-dimensional scaffolds for tissue engineering: The importance of uniformity in pore size and structure. Langmuir, 2010, 26(24): 19001–19006

[123] Declercq H A, Desmet T, Dubruel P, . The role of scaffold architecture and composition on the bone formation by adipose-derived stem cells. Tissue Engineering Part A, 2014, 20(1–2): 434–444

[124] Hing K A. Bioceramic bone graft substitutes: Influence of porosity and chemistry. International Journal of Applied Ceramic Technology, 2005, 2(3): 184–199

[125] Chen P, Tao J, Zhu S, . Radially oriented collagen scaffold with SDF-1 promotes osteochondral repair by facilitating cell homing. Biomaterials, 2015, 39: 114–123

[126] de Mulder E L W, Hannink G, Verdonschot N, . Effect of polyurethane scaffold architecture on ingrowth speed and collagen orientation in a subcutaneous rat pocket model. Biomedical Materials, 2013, 8(2): 025004

[127] Lee J, Shanbhag S, Kotov N A. Inverted colloidal crystals as three-dimensional microenvironments for cellular co-cultures. Journal of Materials Chemistry, 2006, 16(35): 3558

[128] Godbey W T, Hindy B S S, Sherman M E, . A novel use of centrifugal force for cell seeding into porous scaffolds. Biomaterials, 2004, 25(14): 2799–2805

[129] Mauney J R, Blumberg J, Pirun M, . Osteogenic differentiation of human bone marrow stromal cells on partially demineralized bone scaffolds in vitro. Tissue Engineering, 2004, 10(1–2): 81–92

[130] Nieponice A, Soletti L, Guan J, . Development of a tissue-engineered vascular graft combining a biodegradable scaffold, muscle-derived stem cells and a rotational vacuum seeding technique. Biomaterials, 2008, 29(7): 825–833

[131] Liu H, Roy K. Biomimetic three-dimensional cultures significantly increase hematopoietic differentiation efficacy of embryonic stem cells. Tissue Engineering, 2005, 11(1–2): 319–330

[132] Meinel L, Fajardo R, Hofmann S, . Silk implants for the healing of critical size bone defects. Bone, 2005, 37(5): 688–698

[133] Chang B S, Lee C K, Hong K S, . Osteoconduction at porous hydroxyapatite with various pore configurations. Biomaterials, 2000, 21(12): 1291–1298

[134] Gariboldi M I, Best S M. Effect of ceramic scaffold architectural parameters on biological response. Frontiers in Bioengineering and Biotechnology, 2015, 3: 151

[135] Lord M S, Foss M, Besenbacher F. Influence of nanoscale surface topography on protein adsorption and cellular response. Nano Today, 2010, 5(1): 66–78

[136] Annaz B, Hing K A, Kayser M, . Porosity variation in hydroxyapatite and osteoblast morphology: A scanning electron microscopy study. Journal of Microscopy, 2004, 215(Pt 1): 100–110

[137] Deligianni D D, Katsala N D, Koutsoukos P G, . Effect of surface roughness of hydroxyapatite on human bone marrow cell adhesion, proliferation, differentiation and detachment strength. Biomaterials, 2001, 22(1): 87–96

[138] Bignon A, Chouteau J, Chevalier J, . Effect of micro- and macroporosity of bone substitutes on their mechanical properties and cellular response. Journal of Materials Science: Materials in Medicine, 2003, 14(12): 1089–1097

[139] Zhao G, Raines A L, Wieland M, . Requirement for both micron- and submicron scale structure for synergistic responses of osteoblasts to substrate surface energy and topography. Biomaterials, 2007, 28(18): 2821–2829

[140] Anselme K, Linez P, Bigerelle M, . The relative influence of the topography and chemistry of TiAl6V4 surfaces on osteoblastic cell behaviour. Biomaterials, 2000, 21(15): 1567–1577

[141] Anselme K, Bigerelle M, Noel B, . Qualitative and quantitative study of human osteoblast adhesion on materials with various surface roughnesses. Journal of Biomedical Materials Research, 2000, 49(2): 155–166

[142] Isaac J, Hornez J C, Jian D, . β-TCP microporosity decreases the viability and osteoblast differentiation of human bone marrow stromal cells. Journal of Biomedical Materials Research Part A, 2008, 86A(2): 386–393

[143] Takahashi Y, Tabata Y. Effect of the fiber diameter and porosity of non-woven PET fabrics on the osteogenic differentiation of mesenchymal stem cells. Journal of Biomaterials Science: Polymer Edition, 2004, 15(1): 41–57

[144] Kasten P, Beyen I, Niemeyer P, . Porosity and pore size of β-tricalcium phosphate scaffold can influence protein production and osteogenic differentiation of human mesenchymal stem cells: An in vitro and in vivo study. Acta Biomaterialia, 2008, 4(6): 1904–1915

[145] Malmström J, Adolfsson E, Arvidsson A, . Bone response inside free-form fabricated macroporous hydroxyapatite scaffolds with and without an open microporosity. Clinical Implant Dentistry and Related Research, 2007, 9(2): 79–88

[146] Deligianni D D, Katsala N D, Koutsoukos P G, . Effect of surface roughness of hydroxyapatite on human bone marrow cell adhesion, proliferation, differentiation and detachment strength. Biomaterials, 2001, 22(1): 87–96

[147] Laurie S W S, Kaban L B, Mulliken J B, . Donor-site morbidity after harvesting rib and iliac bone. Plastic and Reconstructive Surgery, 1984, 73(6): 933–938

[148] Ruijtenberg S, van den Heuvel S. Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression. Cell Cycle, 2016, 15(2): 196–212

[149] Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: Several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene, 2009, 28(33): 2925–2939

[150] Boward B, Wu T, Dalton S. Control of cell fate through cell cycle and pluripotency networks. Stem Cells, 2016, 34(6): 1427–1436

[151] Cao J, Spielmann M, Qiu X, . The single-cell transcriptional landscape of mammalian organogenesis. Nature, 2019, 566(7745): 496–502

[152] Kim D H, Khatau S B, Feng Y, . Actin cap associated focal adhesions and their distinct role in cellular mechanosensing. Scientific Reports, 2012, 2(1): 555

[153] Martins R P, Finan J D, Guilak F, . Mechanical regulation of nuclear structure and function. Annual Review of Biomedical Engineering, 2012, 14(1): 431–455

[154] Dupont S, Morsut L, Aragona M, . Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474(7350): 179–183

[155] Halder G, Dupont S, Piccolo S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nature Reviews: Molecular Cell Biology, 2012, 13(9): 591–600

[156] Janoštiak R, Pataki A C, Brábek J, . Mechanosensors in integrin signaling: The emerging role of p130Cas. European Journal of Cell Biology, 2014, 93(10–12): 445–454

[157] Zhang J, Barbieri D, ten Hoopen H, . Microporous calcium phosphate ceramics driving osteogenesis through surface architecture. Journal of Biomedical Materials Research Part A, 2015, 103(3): 1188–1199

[158] Habibovic P, Sees T M, van den Doel M A, . Osteoinduction by biomaterials: Physicochemical and structural influences. Journal of Biomedical Materials Research Part A, 2006, 77A(4): 747–762

[159] Rechendorff K, Hovgaard M B, Foss M, . Enhancement of protein adsorption induced by surface roughness. Langmuir, 2006, 22(26): 10885–10888

[160] Smith I O, Liu X H, Smith L A, . Nanostructured polymer scaffolds for tissue engineering and regenerative medicine. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechno-logy, 2009, 1(2): 226–236

[161] Liu X, Ma P X. Polymeric scaffolds for bone tissue engineering. Annals of Biomedical Engineering, 2004, 32(3): 477–486

[162] Li S, De Wijn J R, Li J, . Macroporous biphasic calcium phosphate scaffold with high permeability/porosity ratio. Tissue Engineering, 2003, 9(3): 535–548

[163] Li Y, Yang S T. Effects of three-dimensional scaffolds on cell organization and tissue development. Biotechnology and Bioprocess Engineering; BBE, 2001, 6(5): 311–325

[164] Perez R A, Kim J H, Buitrago J O, . Novel therapeutic core–shell hydrogel scaffolds with sequential delivery of cobalt and bone morphogenetic protein-2 for synergistic bone regeneration. Acta Biomaterialia, 2015, 23: 295–308

[165] Perez R A, Seo S J, Won J E, . Therapeutically relevant aspects in bone repair and regeneration. Materials Today, 2015, 18(10): 573–589

[166] Oliviero O, Ventre M, Netti P A. Functional porous hydrogels to study angiogenesis under the effect of controlled release of vascular endothelial growth factor. Acta Biomaterialia, 2012, 8(9): 3294–3301

[167] Artel A, Mehdizadeh H, Chiu Y C, . An agent-based model for the investigation of neovascularization within porous scaffolds. Tissue Engineering Part A, 2011, 17(17–18): 2133–2141

[168] Kuboki Y, Jin Q M, Takita H. Geometry of carriers controlling phenotypic expression in BMP-induced osteogenesis and chondrogenesis. Journal of Bone and Joint Surgery: American Volume, 2001, 83A(Suppl 1): S105–S115

[169] Feng B, Jinkang Z, Zhen W, . The effect of pore size on tissue ingrowth and neovascularization in porous bioceramics of controlled architecture in vivo. Biomedical Materials, 2011, 6(1): 015007

[170] Mouriño V, Cattalini J P, Boccaccini A R. Metallic ions as therapeutic agents in tissue engineering scaffolds: An overview of their biological applications and strategies for new developments. Journal of the Royal Society: Interface, 2012, 9(68): 401–419

[171] Yamasaki H, Sakai H. Osteogenic response to porous hydroxyapatite ceramics under the skin of dogs. Biomaterials, 1992, 13(5): 308–312

[172] Klein C, de Groot K, Chen W, . Osseous substance formation induced in porous calcium phosphate ceramics in soft tissues. Biomaterials, 1994, 15(1): 31–34

[173] Ripamonti U. Bone induction in nonhuman primates. An experimental study on the baboon. Clinical Orthopaedics and Related Research, 1991, (269): 284–294

[174] Wang L, Zhang B, Bao C, . Ectopic osteoid and bone formation by three calcium-phosphate ceramics in rats, rabbits and dogs. PLoS One, 2014, 9(9): e107044

[175] LeGeros R Z. Calcium phosphate-based osteoinductive materials. Chemical Reviews, 2008, 108(11): 4742–4753

[176] Lutolf M P, Hubbell J A. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nature Biotechnology, 2005, 23(1): 47–55

[177] Wei G, Ma P X. Partially nanofibrous architecture of 3D tissue engineering scaffolds. Biomaterials, 2009, 30(32): 6426–6434

[178] Yuan H, Fernandes H, Habibovic P, . Osteoinductive ceramics as a synthetic alternative to autologous bone grafting. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(31): 13614–13619

[179] Ripamonti U. The morphogenesis of bone in replicas of porous hydroxyapatite obtained from conversion of calcium carbonate exoskeletons of coral. The Journal of Bone and Joint Surgery: American Volume, 1991, 73(5): 692–703

[180] Espanol M, Perez R A, Montufar E B, . Intrinsic porosity of calcium phosphate cements and its significance for drug delivery and tissue engineering applications. Acta Biomaterialia, 2009, 5(7): 2752–2762

[181] Barradas A M C, Yuan H, van Blitterswijk C A, . Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. European Cells & Materials, 2011, 21: 407–429, discussion 429

[182] Hoppe A, Güldal N S, Boccaccini A R. A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics. Biomaterials, 2011, 32(11): 2757–2774

[183] Wang P Y, Clements L R, Thissen H, . High-throughput characterisation of osteogenic differentiation of human mesenchymal stem cells using pore size gradients on porous alumina. Biomaterials Science, 2013, 1(9): 924–932

[184] Papadimitropoulos A, Riboldi S A, Tonnarelli B, . A collagen network phase improves cell seeding of open-pore structure scaffolds under perfusion. Journal of Tissue Engineering and Regenerative Medicine, 2013, 7(3): 183–191

[185] Bohner M, Baumgart F. Theoretical model to determine the effects of geometrical factors on the resorption of calcium phosphate bone substitutes. Biomaterials, 2004, 25(17): 3569–3582

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