Smart scaffolds in bone tissue engineering: A systematic review of literature

Table 1 Description of included studies which modified the scaffolds by addition of growth factors

Ref.	Scaffold	Fabrication	Type of modification	Cell type	Tests and results
Yang et al[33], 2005	GTG + BMP-4	-	Surface modification	NRCOCs	ALP activity: ALP levels in GTG + BMP-4 samples higher than GTG samples H and E staining: Greater numbers of attached cells and richer matrix deposits in the GTG + BMP-4 samples VK staining: Larger mineralizing nodules, in greater numbers
Turhani et al[34], 2007	TCP + rhBMP-2	-	Surface coating	SaOS-2Cs	Cell viability and ALP activity: TCP + BMP-2 > TCP (control) OC secretion: TCP + BMP-2 = TCP
Abarrategi et al[29], 2008	β-TCP + rhBMP-2	Homogenized + demineralized + heterogeneous deacetylation	Surface coating	C2C12Cs	No alteration in biocompatibility In vivo: New bone formation 3 wk after surgery, much shorter time than control β-TCP ceramics
Fei et al[35], 2008	PLGA/CPC + rhBMP-2	Solvent-extraction technique	Surface coating	BMMSCs	ELISA: OC: PLGA/CPC + rhBMP-2: 1.2 ng/mL rhBMP-2/CPC: 0.4 ng/mL ALP activity: PLGA/CPC + rhBMP-2: 0.12 μg/h rhBMP-2/CPC: 0.06 μg/h
Yilgor et al[36], 2010	PCL + BMP-2/BMP-7	Plotting procedure Bioplotter’s CAD/CAM software + wet spinning	Scaffold architecture + surface coating	BMMSCs	ALP activity: BMP-2/BMP-7 + PCL: 1.2 nmol/min
Zhang et al[37], 2010	PCL + BMP-2	Crosslinking conjugation method	Surface coating	BMMSCs	RT-PCR: (relative) p-smad: PCL + BMP-2 conjugated five times higher than adsorption and control Col 1: PCL + BMP-2 conjugated: 3 PCL + BMP-2 adsorption: 1.5 Control (PCL): 1 ALP activity: 2 times higher than adsorption and control
Mitchell et al[38], 2010	Tol-OPN-ST+BMP2	-	Spatial and conformational display + surface coating	BMMSCs	Cell attachment: Tol-OPN-ST + BMP2: 175 mm3 Tol-OPN-ST: 60 mm3 Luciferase activity: Tol-OPN-ST + BMP2: 8000 ability unit Tol-BMP-ST: 6000 ability unit
Huh et al[39], 2011	Bio-Oss® + rhBMP-2 + iH	Deep and dry methods	Surface coating	MG63Cs	Cytotoxicity and proliferation: No difference compared to control (Bio-Oss®) ALP activity: 0.2 μmol/min per μg higher than control
Dai et al[40], 2011	CMMS + rhBMP-2	Polymeric sponge method	New composition + surface coating	BMMSCs	MTT assay: More viable cells on CMMS + rhBMP-2 compared to CMMS RT-PCR: (relative) RunX2: CMMS + rhBMP-2: 32 Control (CMMS): 4 OPN: CMMS + rhBMP-2: 38 Control: 3 In vivo: Induced the ectopic bone formation in the thigh muscle pouches of mice
Lu et al[41], 2012	Col/PLGA + CBD-BMP4	Forming collagen microsponges	Surface coating	BMMSCs	ALP activity: No differences compared to control group Scaffold supports cell adhesion and proliferation
Li et al[42], 2013	SWNTs-COOH/SWNTs-CH3 + BMP-2	Organic phase/aqueous phase replacement approach + sonication	Surface coating	C2C12Cs	ALP activity: (relative) SWNTs-ch3 + BMP-2: 150% SWNTs-cooh + BMP-2: 120%

TCP: Tricalcium phosphate; PCL: Poly(e-caprolactone); CMMS: Calcium/magnesium-doped mesoporous silica; CPC: Calcium phosphate cement; GTG: Glutaraldehydecrosslinked gelatin; PLGA: Poly(lactic-co-glycolic acid); col: Collagen; SWNTs-COOH and SWNTs-CH3: Hydrophilic COOH- and hydrophobic CH3-terminated single-walled carbon nanotubes; Tol-OPN-ST: TolAIII fusion-osteopontin-switch tag; rh: Recombinant human; BMP: Bone morphogenetic protein; CBD: Collagen-binding domain; BMMSCs: Bone marrow mesenchymal stem cells; NRCOCs: Neonatal rat calvaria osteoblast cells; MG63Cs: Human osteosarcoma cells; SaOS-2 Cs: Sarcoma osteogenic cells; C2C12C: Immortalized mouse myoblast cells; ALP: Alkaline phosphatase; H and E: Hematoxylin and eosin; VK: Von Kossa; RT-PCR: Real time polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay; MTT: 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide; XTT: Sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt; RunX2: Runt-related transcription factor 2; OPN: Osteopontin.