The Role of Three-Dimensional Scaffolds in Treating Long Bone Defects: Evidence from Preclinical and Clinical Literature—A Systematic Review

Table 2

Complete details of 39 preclinical papers identified in this systematic review focusing on the usefulness of scaffolds with augmentation in treating long bone defects.

	Authors	Biomaterials	Animal model	Cells/Gfs type and dose	Analysis	Scaffold results
Cells	Grundel et al., 1999 (Clin. Orthop. Relat. Res) [31]	(1) Untreated; (2) HA-TCP-Granular-BMCs; (3) HA-TCP-Block-BMC; (4) ABG	Dog ulna defect (2.5 cm)	BMCs	X-ray: +; Hist: +; Mech: +	+; (For HA-TCP-Block BMC)
	Johnson et al., 1996; (J. Orth. Res) [32]	(1) TCP; (2) TCP-BMCs; (3) HA-COL; (4) HA-COL-BMCs; (5) ABG	Dog radial defect (2.5 cm)	BMCs	X-ray: +; Hist: +; Mech: +	+; (For TCP-BMCs)
	Bruder et al., 1998; (J. Bone & Joint Surg) [33]	(1) Untreated; (2) HA-TCP; (3) HA-TCP-BMSCs	Dog femoral defect (2.1 cm)	BMSCs	X-ray: +; Hist: +	+
	Kon et al., 1999; (J. Biomed. Mat. Res) [34]	(1) HA; (2) HA-BMSCs	Sheep tibial defect (3.5 cm)	BMSCs	X-ray: +; Hist: +; SEM: +; Mech: +	+
	Arinzeh et al., 2003; (J. Bone & Joint Surg) [35]	(1) Untreated; (2) HA-TCP; (3) HA-TCP-allogenic BMSCs	Dog femoral defect (2.1 cm)	BMSCs	X-ray: +; Hist: +	+
	Bensaïd et al., 2005; (J. Tiss. Eng. A) [36]	(1) Untreated; (2) CHA; (3) CHA-BMSCs; (4) ABG	Sheep metatarsus defect (2.5 cm)	BMSCs	X-ray: +; Hist: +	+
	Mastrogiacomo et al., 2005; (Orthod. Craniofac. Res) [37]	(1) HA-TCP-BMSCs	Sheep tibial defect (5 cm)	BMSCs; –	X-ray: +; Hist: +; µCT: +	+
	Viateau et al., 2006; (J. Orth. Res) [38]	(1) Untreated; (2) Coral; (3) Coral-BMSCs	Sheep metatarsus defect (2.5 cm)	BMSCs	X-ray: +; Hist: +	+
	Zhu et al., 2006; (J. Tiss. Eng) [39]	(1) Coral; (2) Coral-BMSCs	Goat femoral defect (2.5 cm)	BMSCs	X-ray: +; Hist: +; Mech: +	+
	Mastrogiacomo et al., 2007; (J. Biomat) [40]	(1) Si-TCP; (2) Si-TCP-BMSCs	Sheep tibial defect (4 cm)	BMSCs; –	Micro-diffraction: +; µCT: +	+
	Liu et al., 2008; (J. Mat Sci: Mat Med) [41]	(1) Untreated; (2) β-TCP; (3) β-TCP-BMSCs	Goat tibia defect (2.6 cm)	BMSCs	X-ray: +; Hist: +; µCT: +; SEM: +	+
	Giannoni et al., 2008; (J. Tiss. Eng. Regen. Med) [42]	(1) ABG; (2) HA-Si-TCP; (3) HA-Si-TCP-BMSCs	Sheep tibial defect (4.5 cm)	BMSCs; –	X-ray: +; Hist: +	+
	Nair et al., 2008; (J. Biomed. Mater. Res. A) [43]	(1) HASi; (2) HASi + BMSCs	Goat femoral defect (2 cm)	BMSCs	X-ray: +; Hist: +; µCT: +; SEM: +	+
	Niemeyer et al., 2010; (J. Tiss. Eng. A) [44]	(1) Untreated; (2) HA-COL-BMSCs (allogenic); (3) HA-COL-BMSCs (xenogenic)	Sheep tibial defect (3 cm)	BMSCs	X-ray: +; Hist: +	+; (For allogenic BMSCs)
	Cai et al., 2011; (J. Biomat) [45]	(1) CHA; (2) CHA-BMSCs (vascularized); (3) CHA (vascularized); (4) CHA-BMSCs	Dog fibula defect (1 cm)	BMSCs	Hist: +; µCT: +; Hist: +	+; (For CHA-BMSCs vascularized)
	Manassero et al., 2013; (J. Tiss. Eng. A) [46]	(1) Coral; (2) Coral-BMSCs	Sheep metatarsus defect (2.5 cm)	BMSCs	X-ray: +; Hist: +; µCT: +	+
	Berner et al., 2013; (Acta. Biomater) [47]	(1) mPCL-TCP; (2) mPCL-TCP-BMSCs (Autologous); (3) mPCL-TCP-BMSCs (allogenic); (4) ABG	Sheep tibial defect (3 cm)	BMSCs	X-ray: +; Hist: +; µCT: =; Mech: =	+; (Similarly for both autologous and allogenic cells)
	Fan et al., 2014; (J. Biomat) [48]	(1) Untreated; (2) TCP-β; (3) TCP-β-BMSCs; (4) TCP-β-BMSCs-saphenous vascular; (5) TCP-β-BMSCs-fascia flap	Monkey tibial defect (2 cm)	BMSCs	X-ray: +; Hist: +; SPECT: +; MRI: +	+; (For TCP-β-BMSCs-saphenous vascular)
	Yoon et al., 2015; (J Vet Sci) [49]	(1) Untreated; (2) ASA; (3) ASA-AdMSCs; (4) ASA-β-TCP; (5) ASA-β-TCP-AdMSCs	Dog ulna defect (1.5 cm)	ADMSCs	X-ray: +; Hist: +	+; (For ASA-Ad-MSCs)
	Berner et al., 2015; (Stem cells Trans Med) [50]	(1) PCL-HA; (2) PCL-HA-allogenic BMSCs; (3) ABG	Sheep tibial defect (3 cm)	BMSCs	X-ray: +; Hist: +; µCT: +; SEM: +; Mech: +	+
	Masaoka et al., 2016; (The Open Biomed Eng J) [51]	(1) β-TCP; (2) β-TCP-BMSCs	Monkey femur defect (5 cm)	BMSCs; –	X-ray: +; Hist: +	+
	Smith et al., 2017 (J Tiss Eng Reg Med) [52]	(1) Untreated; (2) PLLA-PCL; (3) PLLA-PCL-BMSCc	Sheep tibial defect (3.5 cm)	BMSCs	Hist: +; µCT: +; Mech: +	+
GFs	Kirker-Head et al., 1995 (Clin. Orthop. Relat. Res) [53]	(1) 2 mg BMP-2-PLGA-blood; (2) 4 mg BMP-2-PLGA-blood; (3) PLGA-blood	Sheep femoral defect (2.5 cm)	BMP-2; (2 mg and 4 mg)	X-ray: +; Hist: +	+; (For both concentrations of BMP-2
	Sciadini et al., 1997; (J. Orth. Res) [54]	(1) Coral; (2) Coral-BMP; (3) ABG	Dog radial defect (2.5 cm)	BMP extract; (3 mg/implant)	X-ray: +; Hist: +; Mech: +	+
	Gao et al., 1997; (Int. Ortho) [55]	(1) Coral; (2) Coral-BMP	Sheep tibial defect (1.6 cm)	BMP extract; (100 mg/implant)	X-ray: +; Hist: +; Mech: +	++)
	Tuominen et al., 2001; (Ann Chir Gynaecol) [56]	(1) HA; (2) HA-BMP; (3) ABG	Dog ulna defect (2 cm)	BMP extract	X-ray: −; Hist: −; Mech: −	−; (With or without BMPs but inferior to ABG)
	Hu et al., 2003; (J. Biomed. Mater. Res. A) [57]	(1) Untreated; (2) HA-COL-PLA; (3) HA-COL-PLA-BMP	Dog radial defect (2 cm)	BMP extract; (30 mg/implant)	X-ray: +; Hist: +; DEXA: +	+
	Cook et al., 2005; (J. Biomed. Mat. Res) [58]	(1) 3.5 mg BMP-7; (2) 3.5 mg BMP-7-CMC; (3) 1.75 mg BMP-7; (4) 1.75 mg BMP-7-CMC	Dog ulna defect (2.5 cm)	BMP-7; (3.5 mg/implant and 1.75 mg/implant)	X-ray: =; Hist: =; Mechanical: =	=
	Maissen et al., 2006; (J. Orth. Res) [59]	(1) Untreated; (2) PLA; (3) PLA-rhTGFβ-3; (4) ABG	Sheep tibial defect (1.8 cm)	rhTGFβ-3; (269.4 µg/implant)	µCT: −; X-ray: −; Mech: −	−; (Inferior to ABG)
	Cipitria et al., 2015; (Act Biomat) [60]	(1) mPCL-TCP; (2) mPCL-TCP+BMP-7	Sheep tibial defect (3 cm)	BMP-7; (3.5 mg/implant)	Hist: +; µCT: +; BSE: +; SAXS: +; Mech: +
Comparisons	Petite et al., 2000; (Nat Biotech) [61]	(1) Coral-BMSCs; (2) Coral-BMCs; (3) Coral	Sheep metatarsus defect (2.5 cm)	BMSCs; cells/ml); BMCs	X-ray: +; Hist: +	+; (For BMSCs)
	den Boer et al., 2003; (J Orth Res) [62]	(1) Untreated; (2) ABG; (3) HA; (4) HA-BMP-7; (5) HA-BMCs	Sheep tibial defect (3 cm)	BMP-7; (2.5 mg/implant); BMCs	X-ray: +; Hist: =; Mech: +	+; (For both HA + BMP-7 and HA + BMCs)
	Filardo et al., 2014; (J Tiss Eng A) [63]	(1) BioSiC(HA-COL); (2) BioSiC(HACOL) + PRP; (3) BioSiC(HA-COL) + BMSCs	Sheep metatarsus defect (2 cm)	BMSCs	X-ray: =; Hist: +	+; (For BMSCs)
	Berner et al., 2015; (J. Tiss. Eng. Reg. Med) [64]	(1) mPCL-TCP-PRP; (2) mPCL-TCP-allogenic-MPC; (3) mPCL-TCP-allogenic-mOB; (4) mPCL-TCP-allogenic-tOB	Sheep tibial defect (3 cm)	MPCs, mOB, tOB; cells)	X-ray: +; Hist: +; µCT: +; Mech: +	+; (For mPCL-TCP-allogenic MPC)
Combinations	Nair et al., 2009; (Acta. Biomat) [65]	(1) HASi; (2) HASi + BMSCs; (3) HASi + BMSCs + PRP	Goat femoral defect (2 cm)	BMSCs	X-ray: +; Hist: +	+; (For HASi + BMSCs + PRP)
	Zhu et al., 2009; (J Orth Res) [66]	(1) Coral-BMSCs; (2) Coral-AdBMP-7-; BMSCs	Goat femoral defect (2.5 cm)	BMSCs	X-ray: +; Hist: +; Mech: +	+; (For Coral-AdBMP-7-BMSCs)
	Reichert et al., 2012; (Sci Trans Med) [67]	(1) Untreated; (2) mPCL-TCP; (3) mPCL-TCP-BMSCs +; PRP; (4) mPCL-TCP-BMP-7; (5) ABG	Sheep tibial defect (3 cm)	BMSCs; cells/ 250 µl); BMP-7; (3.5 mg/implant)	X-ray: +; Hist: +; µCT: +; Mech: +	+; (For mPCL-TCP-BMP-7)
	Li et al., 2014; (Orthop) [68]	(1) TCP-β-OCs-ECs; (2) TCP-β-ECs	Sheep femoral defect (3 cm)	OCs and ECs	X-ray: +; Hist: +	+; (For TCP-β OCs-ECs)
	Ronca et al., 2014; (J Biomat Appl) [69]	(1) HYAFF11®; (2) HYAFF11 + PRP +; BMSCs; (3) HYAFF11 + BMP-7	Sheep metatarsus defect (2 cm)	BMSCs; BMP-7; (0.4 µl/ml)	Hist: +	+; (For HYAFF11 + BMP-7)

HA: hydroxyapatite, HA-TCP: hydroxyapatite-tricalcium phosphate, HA-COL: hydroxyapatite-collagen, TCP: tricalcium phosphate, ABG: autologous bone graft, PLGA: poly(D,L-(lactide-co-glycolide)), HA-COL-PLA: hydroxyapatite-collagen-poly(L-lactic acid), CMC: carboxyl methyl cellulose, CHA: coral hydroxyapatite, PLA: poly(L/DL/lactide), Si-TCP: silicon stabilized tricalcium phosphate, β-TCP: beta tricalcium phosphate, HA-Si-TCP: hydroxyapatite silicon stabilized tricalcium phosphate, HASi: calcium silicate, tricalcium phosphate, hydroxyapatite, mPCL-TCP: medical grade polycaprolactone-tricalcium phosphate, BioSic(HA-COL): biomorphic silicon carbide hydroxyapatite-collagen, HYAFF11: poly-ε-caprolactone-poly-L-lactic acid with hyaluronan derivatives, PLLA-PCL: poly(L-lactic acid)-poly(ε-caprolactone), ASA: autologous serum albumin, PCL-HA: polycaprolactone-hydroxyapatite, AdBMP-7: adenovirus mediated bone morphogenetic protein 7, ADMSCs: adipose derived mesenchymal stem cell, BMCs: bone marrow concentrates, MPCs: mesenchymal progenitor cells, tOBs: axial skeleton osteoblasts, mOBs: orofacial skeleton osteoblasts, BMP: bone morphogenetic protein, BMP-2: bone morphogenetic protein-2, BMP-7: bone morphogenetic protein-7, BMSCs: bone marrow derived mesenchymal stem cell, rhTGF-β3: recombinant transforming growth factor beta 3, PRP: platelet rich plasma, OCs: osteoblast cells, ECs: endothelial cells, SEM: scanning electron microscopy, SAXS: small angle X-ray scattering, DEXA: dual-energy X-ray absorptiometry, Hist: histological analysis, µCT: microcomputed tomography, Mech: mechanical analysis, X-ray: radiological analysis, +: positive effects, −: negative effects, and =: no significant difference.