Bone tissue has the capability to regenerate itself; however, defects of a critical size prevent the bone from regenerating and require additional support. To aid regeneration, bone scaffolds created out of autologous or allograft bone can be used, yet these produce problems such as fast degradation rates, reduced bioactivity, donor site morbidity or the risk of pathogen transmission. The development of bone tissue engineering has been used to create functional alternatives to regenerate bone. This can be achieved by producing bone tissue scaffolds that induce osteoconduction and integration, provide mechanical stability, and either integrate into the bone structure or degrade and are excreted by the body. A range of different biomaterials have been used to this end, each with their own advantages and disadvantages. This review will introduce the requirements of bone tissue engineering, beginning with the regeneration process of bone before exploring the requirements of bone tissue scaffolds. Aspects covered include the manufacturing process as well as the different materials used and the incorporation of bioactive molecules, growth factors and cells.
LiuYLuoDWangT.Hierarchical structures of bone and bioinspired bone tissue engineering. Small2016; 12(34): 4611–4632.
2.
PiaiaLSalmoriaGVHotzaD.Additive manufacturing of nanostructured bone scaffolds. In: SouzaJCMHotzaDHenriquesB., et al. (eds) Nanostructured biomaterials for Cranio-maxillofacial and oral applications. Amsterdam: Elsevier Inc, 2018, pp. 181–210.
3.
WubnehATsekouraEAyranciC, et al. Current state of fabrication technologies and materials for bone tissue engineering. Acta Biomater2018; 80: 1–30.
4.
SchemitschEH.Size matters: defining critical in bone defect size!J Orthop Trauma2017; 31: S20–S22.
5.
SheikhZBrooksPBarzilayO, et al. Macrophages, foreign body giant cells and their response to implantable biomaterials. Materials2015; 8(9): 5671–5701.
6.
HeskethMSahinKBWestZE, et al. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci2017; 18(7): 1545–1510.
7.
GhanaatiSUngerREWebberMJ, et al. Scaffold vascularization in vivo driven by primary human osteoblasts in concert with host inflammatory cells. Biomaterials2011; 32(32): 8150–8160.
8.
BarbeckMDardMKokkinopoulouM, et al. Small-sized granules of biphasic bone substitutes support fast implant bed vascularization. Biomatter2015; 5: e1056943.
9.
JensenSSGruberRBuserD, et al. Osteoclast-like cells on deproteinized bovine bone mineral and biphasic calcium phosphate: light and transmission electron microscopical observations. Clin Oral Implants Res2015; 26(8): 859–864.
10.
PericKacarevicZKaveheiFHoushmandA, et al. Purification processes of xenogeneic bone substitutes and their impact on tissue reactions and regeneration. Int J Artif Organs2018; 41(11): 789–800.
11.
BarbeckMUngerREBoomsP, et al. Monocyte preseeding leads to an increased implant bed vascularization of biphasic calcium phosphate bone substitutes via vessel maturation. J Biomed Mater Res A2016; 104(12): 2928–2935.
12.
LiBWangHQiuG, et al. Synergistic effects of vascular endothelial growth factor on bone morphogenetic proteins induced bone formation in vivo: influencing factors and future research directions. Biomed Res Int2016; 2016: 2869572.
13.
HanYYouXXingW, et al. Paracrine and endocrine actions of bone – the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res2018; 6: 16–11.
14.
CharoenlarpPRajendranAKIsekiS.Role of fibroblast growth factors in bone regeneration. Inflamm Regen2017; 37: 10–17.
15.
CuiXBreitenkampKLotzM, et al. Synergistic action of fibroblast growth factor-2 and transforming growth factor-beta1 enhances bioprinted human neocartilage formation. Biotechnol Bioeng2012; 109(9): 2357–2368.
16.
RiderPKacarevicZPAlkildaniS, et al. Additive manufacturing for guided bone regeneration: a perspective for alveolar ridge augmentation. Int J Mol Sci2018; 19(11): 3308–3335.
17.
BarradasAYuanHvan BlitterswijkCA, et al. Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. Eur Cell Mater2011; 21: 407–29; discussion 429.
18.
O’BrienFJ.Biomaterials & scaffolds for tissue engineering. Mater Today2011; 14(3): 88–95.
19.
Polo-CorralesLLatorre-EstevesMRamirez-VickJE.Scaffold design for bone regeneration. J Nanosci Nanotech;2014; 14(1): 15–56.
20.
WangWYeungKWK. Bone grafts and biomaterials substitutes for bone defect repair: a review. Bioact Mater2017; 2(4): 224–247.
21.
KlossFROffermannsVKloss-BrandstätterA.Com-parison of allogeneic and autogenous bone grafts for augmentation of alveolar ridge defects-A 12-month retrospective radiographic evaluation. Clin Oral Implants Res2018; 29(11): 1163–1175. DOI: 10.1111/clr.13380.
22.
SchnettlerRFrankeJRimashevskiyD, et al. Allogeneic bone grafting materials – update of the current scientific status. Travmatol Ortop Ross2017; 23(4): 92–100.
23.
JelusicDZirkMLFienitzT, et al. Monophasic ß-TCP vs. biphasic HA/ß-TCP in two-stage sinus floor augmentation procedures – a prospective randomized clinical trial. Clin Oral Implants Res2016; 28(10): e175–e183.
24.
AlbrektssonTJohanssonC.Osteoinduction, osteoconduction and osseointegration. Eur Spine J2001; 10(Suppl. 2): S96–S101.
25.
CortizoMSBelluzoMS.Biodegradable polymers for bone tissue engineering. In: GoyanesSND’AccorsoNB (eds) Industrial applications of renewable biomass products. Cham: Springer International Publishing, 2017, pp. 47–74.
26.
Parenteau-BareilRGauvinRBerthodF.Collagen-based biomaterials for tissue engineering applications. Materials2010: 3: 1863–1887.
27.
PinaSOliveiraJMReisRL.Natural-based nanocomposites for bone tissue engineering and regenerative medicine: a review. Adv Mater2015; 27(7): 1143–1169.
28.
PabstAMLehmannK-MWalterC, et al. Influence of porcine-derived collagen matrix on endothelial progenitor cells: an in vitro study. Odontology2014; 104(1): 19–26.
29.
LinSGuL.Influence of crosslink density and stiffness on mechanical properties of type I collagen gel. Materials2015; 8(2): 551–560.
30.
GentilePMcColgan-BannonKGianoneNC, et al. Biosynthetic PCL-graft-collagen bulk material for tissue engineering applications. Materials2017; 10(7): E693.
31.
TebyanianHNorahanMHEyniH, et al. Effects of collagen/β-tricalcium phosphate bone graft to regenerate bone in critically sized rabbit calvarial defects. J Appl Biomater Funct Mater2019; 17(1): 2280800018820490.
32.
OmenettoFGKaplanDL.New opportunities for an ancient material. Science2010; 329(5991): 528–531.
33.
FarokhiMMottaghitalabFSamaniS, et al. Silk fibroin/hydroxyapatite composites for bone tissue engineering. Biotechnol Adv2018; 36(1): 68–91.
34.
KunduBRajkhowaRKunduSC, et al. Silk fibroin biomaterials for tissue regenerations. Adv Drug Deliv Rev2013; 65(4): 457–470.
35.
VepariCKaplanDL.Silk as a biomaterial. Prog Polym Sci2007; 32(8–9): 991–1007.
36.
KimSHYeonYKLeeJM, et al. Precisely printable and biocompatible silk fibroin bioink for digital light processing 3D printing. Nature Communications2018; 9: 1620.
37.
RiderPBrookISmithPJ, et al. Reactive inkjet printing of regenerated silk fibroin films for use as dental barrier membranes. Micromachines2018; 9(2): 46.
38.
RiderPBrookIMSmithPJ, et al. Reactive inkjet printing of silk barrier membranes for dental applications. In: SmithPJMorrinA (eds) Reactive inkjet printing. Cambridge: Royal Society of Chemistry, 2017, pp. 147–168.
39.
HaYYParkYWKweonHY, et al. Comparison of the physical properties and in vivo bioactivities of silkworm-cocoon-derived silk membrane, collagen membrane, and polytetrafluoroethylene membrane for guided bone regeneration. Macromol Res2014; 22: 1018–1023.
40.
SinghBNPandaNNPramanikK.A novel electrospinning approach to fabricate high strength aqueous silk fibroin nanofibers. Int J Biol Macromol2016; 87: 201–207.
41.
PanilaitisBAltmanGHChenJ, et al. Macrophage responses to silk. Biomaterials2003; 24: 3079–3085.
42.
AramwitPKanokpanontSDe-EknamkulW, et al. Monitoring of inflammatory mediators induced by silk sericin. J Biosci Bioeng2009; 107(5): 556–561.
43.
CroisierFJérômeC.Chitosan-based biomaterials for tissue engineering. European Polymer Journal2013; 49(4): 780–792.
44.
GadgeyKKSharmaGS.Investigation of mechanical properties of Chitosan based films: a review. Int J Adv Res Eng Technol2017; 8(6): 93–102.
45.
AbrahamASolomanPARejiniVO.Preparation of Chitosan-Polyvinyl alcohol blends and studies on thermal and mechanical properties. Procedia Technol2016; 24: 741–748.
46.
LeeJLeeKY.Local and sustained vascular endothelial growth factor delivery for angiogenesis using an injectable system. Pharm Res2009; 26(7): 1739–1744.
47.
LeeKYMooneyDJ.Alginate: properties and biomedical applications. Prog Polym Sci2012; 37(1): 106–126.
48.
JeonOBouhadirKHMansourJM, et al. Photocrosslinked alginate hydrogels with tunable biodegradation rates and mechanical properties. Biomaterials2009; 30(14): 2724–2734.
49.
BaoLinGMaPX.Synthetic biodegradable functional polymers for tissue engineering: a brief review. Sci China Chem2014; 57(4): 490–500.
50.
NairLSLaurencinCT.Biodegradable polymers as biomaterials. Prog Polym Sci2007; 32(8–9): 762–798.
51.
LiuFHuangBHindujaS, et al. Biofabrication techniques for ceramics and composite bone scaffolds. In: AntoniacI (ed.) Bioceramics and biocomposites: from research to clinical practice. Hoboken, NJ: John Wiley, 2019, pp. 17–37.
52.
WuY-HChiuY-CLinY-H, et al. 3D-printed bioactive calcium silicate/poly-ε-caprolactone bioscaffolds modified with biomimetic extracellular matrices for bone regeneration. Int J Mol Sci2019; 20(4): 942–919.
53.
FarahSAndersonDGLangerR.Physical and mechanical properties of PLA, and their functions in widespread applications – a comprehensive review. Adv Drug Deliv Rev2016; 107: 367–392.
54.
GremareAGuduricVBareilleR, et al. Characterization of printed PLA scaffolds for bone tissue engineering. J Biomed Mater Res A2018; 106(4): 887–894.
LiTPengMYangZ, et al. 3D-printed IFN-γ-loading calcium silicate-β-tricalcium phosphate scaffold sequentially activates M1 and M2 polarization of macrophages to promote vascularization of tissue engineering bone. Acta Biomater2018; 71: 96–107.
57.
TanodekaewSChannasanonSUppananP.Preparation and degradation study of photocurable oligolactide-HA composite: a potential resin for stereolithography application. J Biomed Mater Res B Appl Biomater2014; 102(3): 604–611.
58.
GinebraM-PEspanolMMaazouzY, et al. Bioceramics and bone healing. EFORT Open Reviews2018; 3(5): 173–183.
59.
KeavenyTMMorganEFYehOC.Bone mechanics. In: MyerK (ed) Standard handbook of biomedical engineering and design, New York: McGraw-Hill, 2004, pp. 8.1–8.23.
60.
MarkovicSVeselinovicLLukicMJ, et al. Synthetical bone-like and biological hydroxyapatites: a comparative study of crystal structure and morphology. Biomed Mater2011; 6(4): 045005.
61.
ZhouMGengY-MLiS-Y, et al. Nanocrystalline hydroxyapatite-based scaffold adsorbs and gives sustained release of osteoinductive growth factor and facilitates bone regeneration in mice ectopic model. J Nanomater2019; 2019(1): 1–10.
62.
KamitakaharaMOhtsukiCMiyazakiT.Review paper: behavior of ceramic biomaterials derived from tricalcium phosphate in physiological condition. J Biomater Appl2008; 23(3): 197–212.
63.
BarrereFvan BlitterswijkCAdeGrootK.Bone regeneration: molecular and cellular interactions with calcium phosphate ceramics. Int J Nanomed2006; 1(3): 317–332.
64.
GerhardtL-CBoccacciniAR.Bioactive glass and glass-ceramic scaffolds for bone tissue engineering. Materials2010; 3(7): 3867–3910.
65.
HenchLL.The story of Bioglass®. J Mater Sci Mater Med2006; 17(11): 967–978.
66.
FuQSaizERahamanMN, et al. Bioactive glass scaffolds for bone tissue engineering: state of the art and future perspectives. Mater Sci Eng C Mater Biol Appl2011; 31(7): 1245–1256.
67.
JonesJR.Review of bioactive glass: from Hench to hybrids. Acta Biomater2013; 9(1): 4457–4486.
68.
GhoshDSinghaPSSFWRJ.Biometals in health and disease: a review. World J Pharm Res2016; 5(12): 390–399.
69.
GlenskeKDonkiewiczPKowitschA, et al. Applications of metals for bone regeneration. Int J Mol Sci2018; 19(3): 826.
70.
ZhengYFGuXNWitteF.Biodegradable metals. Mater Sci Eng, R: Reports2014; 77: 1–34.
71.
BornapourMCelikinMCerrutiM, et al. Magnesium implant alloy with low levels of strontium and calcium: the third element effect and phase selection improve bio-corrosion resistance and mechanical performance. Mater Sci Eng, C: Mater Biol Appl2014; 35: 267–282.
72.
ChengM-QWahafuTJiangG-F, et al. A novel open-porous magnesium scaffold with controllable microstructures and properties for bone regeneration. Sci Rep2016; 6: 24134–24114.
73.
PrasadASankarMRKatiyarV.State of art on solvent casting particulate leaching method for orthopedic scaffolds fabrication. Mater Today: Proc2017; 4(Part A): 898–907.
74.
HutmacherDW.Scaffolds in tissue engineering bone and cartilage. Biomaterials2006; 21: 2529–2878.
75.
CaoHKuboyamaN.A biodegradable porous composite scaffold of PGA/β-TCP for bone tissue engineering. Bone2010; 46(2): 386–395.
76.
KhangGParkCSRheeJM, et al. Preparation and characterization of demineralized bone particle impregnated poly(l-lactide) scaffolds. Korea Polym J/한국고분자학회2001; 9(5): 267–276.
77.
WeiJChenFShinJ-W, et al. Preparation and characterization of bioactive mesoporous wollastonite – polycaprolactone composite scaffold. Biomaterials2009; 30(6): 1080–1088.
78.
FereshtehZ.Freeze-drying technologies for 3D scaffold engineering. In: YingDJordanK (eds) Functional 3D tissue engineering scaffolds. Cambridge: Woodhead Publishing, 2017, p. 24.
79.
LiXZhangSZhangX, et al. Biocompatibility and physicochemical characteristics of poly(Ɛ-caprolactone)/poly(lactide-co-glycolide)/nano-hydroxyapatite composite scaffolds for bone tissue engineering. Mater Des2017; 114: 149–160.
80.
SangkertSKamonmattayakulSLinCW, et al. A biofunctional-modified silk fibroin scaffold with mimic reconstructed extracellular matrix of decellularized pulp/collagen/fibronectin for bone tissue engineering in alveolar bone resorption. Mater Lett2015; 166: 30–34.
81.
MenonAHSoundaryaSPSanjayV, et al. Sustained release of chrysin from chitosan-based scaffolds promotes mesenchymal stem cell proliferation and osteoblast differentiation. Carbohydr Polym2018; 195: 356–367.
82.
ZengWYanYZhangF, et al. Chrysin promotes osteogenic differentiation via ERK/MAPK activation. Protein Cell2013; 4(7): 539–547.
83.
AkbarzadehRYousefiA-M.Effects of processing parameters in thermally induced phase separation technique on porous architecture of scaffolds for bone tissue engineering. J Biomed Mater Res B Appl Biomater2014; 102(6): 1304–1315.
84.
Carfi PaviaFConoscentiGGrecoS, et al. Preparation, characterization and in vitro test of composites poly-lactic acid/hydroxyapatite scaffolds for bone tissue engineering. Int J Biol Macromol2018; 119: 945–953.
85.
ChenSZhaoXDuC.Macroporous poly (L-lactic acid)/chitosan nanofibrous scaffolds through cloud point thermally induced phase separation for enhanced bone regeneration. European Polym J2018; 109: 303–316.
86.
HuangY-CMooneyDJ.Gas foaming to fabricate polymer scaffolds in tissue engineering. In: PeterX MJenniferE (eds) Scaffolds in tissue engineering. Florida: Taylor and Francis Group. CRC Press, 2006, pp. 155–167.
87.
Preethi SoundaryaSHaritha MenonAViji ChandranS, et al. Bone tissue engineering: scaffold preparation using chitosan and other biomaterials with different design and fabrication techniques. Int J Biol Macromol2018; 119: 1228–1239.
88.
DuarteRMCorreia-PintoJReisRL, et al. Subcritical carbon dioxide foaming of polycaprolactone for bone tissue regeneration. J Supercrit Fluid2018; 140: 1–10.
89.
CatanzanoOSorienteALa GattaA, et al. Macroporous alginate foams crosslinked with strontium for bone tissue engineering. Carbohydr Polym2018; 202: 72–83.
90.
TurnbullGClarkeJPicardF, et al. 3D bioactive composite scaffolds for bone tissue engineering. Bioactive Materials2017; 3: 278–314.
91.
SharifiFAtyabiSMNorouzianD, et al. Polycaprolactone/carboxymethyl chitosan nanofibrous scaffolds for bone tissue engineering application. Int J Biol Macromol2018; 115: 243–248.
92.
QinX. Coaxial electrospinning of nanofibers. In:AfshariM (ed.) Electrospun nanofibers (Woodhead Publishing Series in Textiles). Duxford: Woodhead Publishing, 2017, pp. 41–71.
93.
ChengGMaXLiJ, et al. Incorporating platelet-rich plasma into coaxial electrospun nanofibers for bone tissue engineering. Int J Pharm2018; 547(1–2): 656–666.
94.
AoCNiuYZhangX, et al. Fabrication and characterization of electrospun cellulose/nano-hydroxyapatite nanofibers for bone tissue engineering. Int J Biol Macromol2017; 97: 568–573.
95.
RamachandranKGoumaP-I.Electrospinning for bone tissue engineering. Recent Pat Nanotechnol2008; 2(1): 1–7.
96.
GeZWangLHengBC, et al. Proliferation and differentiation of human osteoblasts within 3D printed poly-lactic-co-glycolic acid scaffolds. J Biomater Appl2009; 23(6): 533–547.
97.
KacarevicZPRiderPMAlkildaniS, et al. An introduction to 3D bioprinting: possibilities, challenges and future aspects. Materials2018; 11(11): 1–21.
98.
BogaJCMiguelSPde Melo-DiogoD, et al. In vitro characterization of 3D printed scaffolds aimed at bone tissue regeneration. Colloids Surf B Biointerfaces2018; 165: 207–218.
99.
Roohani-EsfahaniS-INewmanPZreiqatH.Design and fabrication of 3D printed Scaffolds with a mechanical strength comparable to cortical bone to repair large bone defects. Sci Rep2016; 6: 19468.
100.
VozziGCoralloCDaraioC.Pressure-activated microsyringe composite scaffold of poly(L-lactic acid) and carbon nanotubes for bone tissue engineering. J Appl Polym Sci2012; 129(2): 528–536.
101.
MondscheinRJKanitkarAWilliamsCB, et al. Polymer structure-property requirements for stereolithographic 3D printing of soft tissue engineering scaffolds. Biomaterials2017; 140: 170–188.
102.
Mironi-HarpazIWangDYVenkatramanS, et al. Photopolymerization of cell-encapsulating hydrogels: crosslinking efficiency versus cytotoxicity. Acta Biomater2012; 8(5): 1838–1848.
103.
WangZAbdullaRParkerB, et al. A simple and high-resolution stereolithography-based 3D bioprinting system using visible light crosslinkable bioinks. Biofabrication2015; 7(4): 045009.
104.
FairbanksBDSchwartzMPBowmanCN, et al. Photoinitiated polymerization of PEG-diacrylate with lithium phenyl-2,4,6-trimethylbenzoylphosphinate: polymerization rate and cytocompatibility. Biomaterials2009; 30(35): 6702–6707.
105.
LanPXLeeJWSeolY-J, et al. Development of 3D PPF/DEF scaffolds using micro-stereolithography and surface modification. J Mater Sci Mater Med2008; 20(1): 271–279.
106.
LeeJWKangKSLeeSH, et al. Bone regeneration using a microstereolithography-produced customized poly(propylene fumarate)/diethyl fumarate photopolymer 3D scaffold incorporating BMP-2 loaded PLGA microspheres. Biomaterials2011; 32(3): 744–752.
107.
RoncaAAmbrosioLGrijpmaDW.Design of porous three-dimensional PDLLA/nano-hap composite scaffolds using stereolithography. J Appl Biomater Funct Mater2012; 10(3): 249–258.
108.
ShanjaniYPanCCElomaaL, et al. A novel bioprinting method and system for forming hybrid tissue engineering constructs. Biofabrication2015; 7(4): 045008.
109.
MazzoliA.Selective laser sintering in biomedical engineering. Med Biol Eng Comput2012; 51(3): 245–256.
110.
FengPWeiPShuaiC, et al. Characterization of mechanical and biological properties of 3-D scaffolds reinforced with zinc oxide for bone tissue engineering. PLoS ONE2014; 9(1): e87755.
111.
LaurentiMCaudaV.ZnO nanostructures for tissue engineering applications. Nanomaterials2017; 7(11): 374–334.
112.
DengJLiPGaoC, et al. Bioactivity improvement of forsterite-based scaffolds with nano-58S bioactive glass. Mater Manuf Process2014; 29(7): 877–884.
113.
XiaYXuSZhouP, et al. Selective laser sintering fabrication of nano-hydroxyapatite/poly-ε-caprolactone scaffolds for bone tissue engineering applications. Int J Nanomedicine2013; 8: 4197–4213.
114.
LiaoH-TLeeM-YTsaiW-W, et al. Osteogenesis of adipose-derived stem cells on polycaprolactone-β-tricalcium phosphate scaffold fabricated via selective laser sintering and surface coating with collagen type I. J Tissue Eng Regen Med2013; 10: E337–E353.
115.
RiderPKačarevićŽPAlkildaniS, et al. Bioprinting of tissue engineering scaffolds. J Tissue Eng2018; 9: 2041731418802090.
LimKSSchonBSMekhileriNV, et al. New visible-light photoinitiating system for improved print fidelity in gelatin-based bioinks. ACS Biomater Sci Eng2016; 2(10): 1752–1762.
118.
TzengJ-JHsiaoY-TWuY-C, et al. Synthesis, characterization, and visible light curing capacity of polycaprolactone acrylate. Biomed Res Int2018; 2018: 8719624.
119.
ChristensenKXuCChaiW, et al. Freeform inkjet printing of cellular structures with bifurcations. Biotechnol Bioeng2015; 112(5): 1047–1055.
120.
XuTBinderKWAlbannaMZ, et al. Hybrid printing of mechanically and biologically improved constructs for cartilage tissue engineering applications. Biofabrication2013; 5(1): 015001.
121.
O’ConnellCDDi BellaCThompsonF, et al. Development of the Biopen: a handheld device for surgical printing of adipose stem cells at a chondral wound site. Biofabrication2016; 8(1): 015019.
