Table 2.

Ex Vivo Gene Therapy for Bone Regeneration

Vector and Gene	Cells	Target site	Main Results	Reference
Adenoviral BMP-2	Autologous bone marrow cells	Femur segmental defect in syngeneic rats	Superior bone properties to those treated BMP-2 protein alone	Lieberman et al., 1999 [37]
Adenoviral BMP-2	Human bone marrow MSCs	Subcutaneously implantation and radius bone segmental defect in nude mice	Bone formation in ectopic sites, and radius bone regeneration. Similar results were obtained with hMSCs isolated from a patient suffering from osteoporosis	Turgeman et al. 2001 [70]
Adenoviral BMP-2	Rabbit bone marrow MSCs	Subcutaneously implantation in nude mice	Robust ectopic bone formation after 4 weeks	Han et al., 2008 [73]
Adenoviral BMP-2	Human bone marrow vs. adipose tissue–derived MSCs	Athymic rat spinal fusion	No difference in bone formation was noted	Miyazaki et al., 2008 [74]
Adenoviral BMP-2	Human bone marrow MSCs	Mandible bone defect regeneration in NOD/SCID mice	Complete defect regeneration achieved	Steinhardt et al., 2008 [75]
Adenoviral BMP-2	Porcine bone marrow MSCs	Large-scale skull defect in a porcine model	Defects were completely repaired after 6 months. The bone formed was significantly thicker and stiffer.	Chang et al., 2009 [76]
Adenoviral/retroviral/ cationic lipid, human BMP-2	Rat bone marrow MSCs	Ectopic (subcutaneous) bone formation or orthotopic critical-size defect in a rat cranium	adBMP-2 MSCs showed statistically significant increase in bone formation relative to the other vectors	Blum et al., 2003 [78]
Lentiviral BMP-4	Rat bone marrow MSCs	Segmental defect in rat calvaria	Complete defect healing	Gysin et al., 2002 [79]
Retroviral osterix	Mouse bone marrow MSCs	Calvaria bone defects in a mouse model	MSCs induced 85% healing	Tu et al., 2007 [80]
Lentiviral BMP-2	Rat bone marrow buffy-coat cells	“Same-day” implantation in a rat femoral defect	Radiographic evidence of bone healing and higher bone volume	Virk et al., 2011 [36]
Plasmid DNA, BMP-4 and VEGF	Human bone marrow MSCs	Implanted subcutaneously in NOD/SCID mice	Significant increase in the quantity of bone formed	Huang et al., 2005 [81]
Plasmid DNA, BMP-2	Rat bone marrow MSCs	Culture in a perfusion bioreactor and then implanted subcutaneously in a rat model	Homogeneous bone formation was histologically observed	Hosseinkhani et al., 2006 [82]
Liposome-mediated and adenoviral, BMP-2	Rat bone marrow MSCs	Healing of critical size defects in the rat mandible.	Defects were healed at 6 weeks after gene transfer when liposomes were used, and within 4 weeks when adBMP-2 was used	Park et al., 2003 [89]
Liposome mediated, bFGF	Rabbit periosteum MSCs	Critical-size segmental bone defect in the rabbit radius	Elevation in bone formation and capillary regeneration	Guo et al., 2006 [90]
Liposome mediated, BMP-7	Rat bone marrow MSCs	Mandible distraction osteogenesis site in rat model	Higher bone formation and earlier mineralization in the distracted callus	Hu et al., 2007 [91]
Liposome mediated, osterix	Rabbit bone marrow MSCs	Rabbit model of mandibular lengthening	Higher bone mineral density, thickness of new trabeculae, and volume of the newly formed bone in the distraction zones	Lai et al., 2011 [92].
Nucleofection, BMP-2 or BMP-9	Human bone marrow MSCs	Implantation to ectopic (intramuscular)site s in NOD/SCID mice	Bone formation was induced 4 weeks after cell implantation	Aslan et al., 2006 [93]
Nucleofection, BMP-6	Porcine adipose tissue–deriv ed MSCs.	Posterior spinal fusion in a immunodeficient mouse model	Large bone mass was formed adjacent to the lumbar area.	Sheyn et al., 2008 [94]
Nucleofection, BMP-6	Porcine adipose tissue–derived MSCs	Repair of vertebral bone defects in a rat model	The rate of bone formation was two times faster than that in the no cells treated group	Sheyn et al., 2011 [95]
Nucleofection, BMP2/Runx2	Human adipose SCs	Dorsal Subcutaneous implantation to BALB/c-nu mice	Superior bone formation compared with cells nucleofected with BMP-2 alone	Lee et al., 2010 [96]