Table 2.
The characteristics of included studies.
| Ref | Animal | Type | Scaffold | Control | Type of VEGF | Release | Dosage | TOE | Results | BV/TV | Quality score |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Amirian 2015 [25] | Rat | Cranial defect model | Pectin-biphasic calcium phosphate | Empty defect | rhVEGF | Gelatin hydrogel scaffolds | Total concentration VEGF: Unknown 75% released in 15 days |
2 weeks/4 weeks | MicroCT: VEGF significantly better than control No mentioned P-values. |
MicroCT: Control: 2w/4w 2.3%/3.3% VEGF: 2w/4w 6.4%/6.5% Histomorphometry: Control: 2w/4w 2.13%/3.75% VEGF: 2w/4w 6.74%/8.95% |
4 |
| Keeney 2010 [34] | Mice | Intra-femoral defect | Collagen/calcium phosphate | Only scaffold | Therapeutic plasmid VEGF165 | Plasmid DNA | 0.35ug/mm3 | 30 days | Significant more bone in scaffold + VEGF165 | Histomorphometry: Control: 9.8% VEGF (non-complexed): 24.2% VEGF (complexed): 17.1% |
3 |
| Lohse 2015 [26] | Rat | Mandible | calcium carbonate granules |
Scaffold and empty defect | rhVEGF165 | poly-dl-lactic acid (PDLLA) | 0.24ug/1.5ug /6ug. ≈50% release first 3 days, low constant release till 5 weeka. |
4 weeks/13 weeks | Only significantly better with 1.5ug after 4 weeks. NS other timepoint and dosages |
Histomorphometry: 4 weeks: 4.4%–7.3% 13 weeks: 2.7%–4.6% Blank scaffold and empty defect, 4 or 13 weeks: 0.6–1.8% |
3 |
| Çakır-Özkan 2017 [36] | Rabbit | Mandible | PLLA-PEG | Only scaffold | rhVEGF165 | Gelatin | 750ng/scaffold Release 60% first 2 days, constant release for more than 14 days. |
4 weeks/8 weeks | Significantly better than control. | Histomorphometry: Newly formed bone Control: 4w/8w 34%/17% VEGF: 4w/8w 53%/31% |
4 |
| L Zhang 2014 [44] | Beagle | Femoral neck fracture model | Cannulated (titanium) screws | Cannulated screw fibrin glue | VEGF | PLGA/Fibrin glue | Unknown total VEGF in fibrin glue. 21.5% released after 3 days. Steady with 1.71% till 42 days with 88% cumulative release. |
4 weeks/8 weeks/12 weeks | VEGF had significant better results in week 8 and week 12 (p < 0.01) | 4 weeks: Control 5.7% VEGF 8.0% 8 weeks: Control: 19.5% VEGF: 29.0% 12 weeks: Control: 32.3% VEGF 41.3% |
6 |
| Lv 2015 [37] | Rabbit | Femoral condyle defect model | Titanium scaffold or empty defect | Empty titanium scaffold | rhVEGF165 | Fibrin glue | 0.5ug VEGF. Steady 100% release in 96 h 0.6%/hour steadily from 12 to 96 h |
4 weeks | Significantly better than control | New bone: Control: 7.8–8.3% VEGF: 17.4% |
4 |
| Khojasteh 2017 [45] | Dog (mongrel) | Mandible defect | B-TCP | Scaffold only | VEGF | PLGA microspheres | Release: Burst 60 ng/ml 8h. Steady 14 days release total 200 ng/ml. |
8 weeks | No significant difference to control | Histomorphometry_ Control: 7.2% VEGF: 20% |
4 |
| Moser 2018 [27] | Rat | Ectopic | PDLLA/CaCO3 composite granules | Scaffold + granules | rhVEGF165 | PDLLA/CaCO3 | 25ug VEGF/g polymer Total dose: 1.5ug VEGF Burst release: 3 days 5.5%/6% total release in 29 days 100ug/g polymer /6ug VEGF Burst release: 3 days 6% total release in 29 days 10.5% |
4 seeks/13 weeks | No significant difference to control | Histomorphometry: 4 weeks: Control: 0–1% VEGF: 0–1% 13 weeks: Control: 0–1% VEGF: 0–1% |
7 |
| W Zhang 2014 [38] | Rabbit | Skull defect | Silk scaffold | Silk scaffold with water | VEGF | Silk scaffold + water absorption | 6ug/scaffold | 12 weeks | No significant difference to control | uCT BV/TV control: 4.12 VEGF: 10.14 Histomorphometry: Control: ~28% VEGF ~44% |
3 |
| W Zhang 2011 [39] | Rabbit | Sinus floor elevation surgery | Silk hydrogel | Silk gel alone | rhVEGF165 | Silk hydrogel | 1000ug/ml ∗ 0.200 ml = 4 ug per scaffold No burst release. At least 24 days release |
4 weeks/12 weeks | No signficant difference between VEGF and control | Histomorphometry 4 weeks: Control: 1.8% VEGF: 5.6% 12 weeks: Control 8.7% VEGF: 18.5% |
4 |
| Quinlan 2017 [28] | Rat | Calvarial defect model | Collagen-Hydroxyapatite scaffold | Empty defect and only scaffold | rhVEGF165 | Alginate microparticles | 1ug/mg (1.6 ug/scaffold) Burst release till day 7. Steady release till 8 weeks. |
8 weeks | Significantly better than empty defect. NS against scaffold alone. Significant more new bone in VEGF group |
uCT: Empty defect: 0.4% Empty scaffold: 1.8% VEGF: 3.2% Histomorphometry: (um2, 10ˆ5) Empty defect: 0.9 um2 x 10ˆ5 Empty scaffold: 1.9 um2 x 10ˆ5 VEGF: 5.4 um2 x 10ˆ5 |
7 |
| Schliephake 2015 [29] | Rat | Tibia head placement | Titanium implant | Empty implants Empty implants with empty DNA nucleotide surface |
rhVEGF165 | DNA oligonucleotide | 750ng/screw 53% released within week 1. |
1 week/4 weeks/13 weeks | Significant lower bone formation in week 4. NS in week 1 and 13. | Histomorphometry: 1 week: Empty control: 4.0% Surface control: 4.3% VEGF: 5.9% 4 weeks Empty control: 17.6% Surface control: 20.3% VEGF: 5.9% 13 weeks No values mentioned |
7 |
| Behr 2011 [35] | Mouse | Calvarial model | Collagen sponge | PBS soaked collagen sponges | VEGFA | Collagen sponge | 200ng/mouse | 2 weeks/4 weeks/8 weeks/12 weeks | VEGF significantly better than control. | uCT 2 weeks: Control:1.2% VEGF:81.0% 4 weeks: Control:0–2% VEGF: ~95% 8 weeks: Control:~12% VEGF: ~90% 12 weeks: Control: 18.3% VEGF: 95.1% Histomorphometry: 3 weeks: Control: ~2% VEGF: ~55% 12 weeks: Control: ~11% VEGF: ~65% |
6 |
| Geuze 2012 [46] | Beagle | Ectopic | BCP scaffold | Calcium phosphate BCP scaffold mixed with microparticles or hydrogel without growth factors | rhVEGF165 | Sustained release: PLGA microparticles. Fast release: Hydrogel (gelatin) |
0.4ug per ectopic implant | 9 weeks | No significant difference to control. | Histomorphometry: PLGA release: Control:0–1% VEGF:0–1% Hydrogel release: Control: 0-% VEGF: 3–4% |
8 |
| Hernandez 2012 [40] | Rabbit | Bone defect condyle femur | PLGA pororus scaffold | Empty defect and empty scaffold | rhVEGF165 | PLGA microspheres | 4 mg (0.35ug)/20 mg (1.75ug) 50% release after 4 days. Around 90% in 2 weeks (fig says 2 weeks, text 3 weeks fig. 3a) |
2 weeks/4 weeks/8 weeks/12 weeks | 2 weeks: VEGF (1.75) significantly better than all groups 4 weeks: significantly better in VEGF group. 8 weeks: no difference from week 4. Data not shown. 12 weeks: no difference in control and VEGF. |
4 weeks Control: 10% VEGF: 20% 12 weeks Control: 10–15% VEGF: 18–20% |
4 |
| Kempen 2009 [30] | Rat | Critical sized femur shaft model, subcutaneous model | Empty defects (only orthotopic) and empty scaffold | VEGF | Gelatine Hydrogel | 2.0ug/scaffold 58% release during first 3.5 days. Total release after 2 weeks |
8 weeks | Subcutaneous: No significant difference between control and VEGF. Orthotopic: No significant difference between VEGF and empty scaffold or empty defect. |
Subcutaneous: Empty scaffold: 0% VEGF: 0% Orthotopic¢: uCT new bone; Empty defect: 28mm3 Empty scaffold: 28mm3 VEGF: 30mm3 |
4 | |
| Casap 2008 [41] | Rabbit | Mandible distraction | Injections | No injection | rVEGF165 | — | After 14 days 5ug/uL for 4 days. | 60 days | No significant difference to control (p = 0.057) | MicroCT BV/TV: Control: 2.5% VEGF: 13% |
6 |
| Patel 2008 [55] | rat | Cranial defect | Gelatin microspheres in porous PPF scaffold | Blank Gelatin microspheres or empty defect | VEGF | Gelatin | 0.24ug/mm3 | 4 weeks/12 weeks | No significant difference to control | Histomorphometry scoring: Control 4 weeks: 0.5 12 weeks: 1 VEGF 4 weeks: 0.5 12 weeks: 1 MicroCT Empty defect: 4w: 7% 12w: 16% Control 4 weeks: 4% 12 weeks: 8% VEGF 4 weeks: 2% 12 weeks: 6% |
6 |
| Yang 2010 [42] | Rabbit | Radial diaphysis | BTCP coated with fibrin sealant | Scaffold and untreated | rhVEGF165 | Absorption fibrinogen | 2.6ug VEGF/scaffold 90% release after 7 days. |
4 weeks, 8 weeks, 12 weeks | Significant difference to control | microCT new bone/TV 4 weeks: Control: 18% VEGF:33% 8 weeks: Control:34% VEGF: 63% 12 weeks: Control: 55% VEGF: 18% |
5 |
| Yonamine 2010 [32] | Rat | calvaria | PLGA microspheres | Empty defect/sham surgery | VEGF165 | PLGA microspheres | 1ug per 500ul No release from day 0–7. Full release till day 21. |
12 weeks | No significant difference to control | X-ray: Control: 20% VEGF:27–28% |
3 |
| Wu 2012 [43] | rabbit | Mandibular distraction | Plasmid pIRES injection | pIRES and normal saline | hVEGF165 | Plasmid | 2ug | 2 weeks/4 weeks/8 weeks | Significant difference to control in both bone types. | Histomorphometry: Cortical 2 weeks: Saline:33% pIRES: 35% VEGF: 39% 4 weeks: Saline:81% pIRES: 84% VEGF: 93% 8 weeks: Control:91% pIRES: 93% VEGF: 96% Trabecular 2 weeks: Saline: 23% pIRES: 23% VEGF: 25% 4 weeks: Saline: 41% pIRES: 43% VEGF: 47% 8 weeks: Control:43% pIRES:46% VEGF: 53% |
7 |
| Schmitt 2013 [48] | pigs | Calvaria defect or vertical augmentation | Bio-oss | Bio-oss collagen carriers (empty scaffold) | rhVEGF165 | Fibrin glue | 8ug/ml, 3 ml total | 30 days/60 days | No significant difference to control | X-ray Critical size defect: 30 days: Control: 17% VEGF: 19% Vertical augmentation: 30 days: Control: 6% VEGF 4% 60 days Control: 10% VEGF: 11% |
5 |
| Du 2015 [47] | Beagle | Mandible defect | Nano-hydroxyapatite coral blocks | Only scaffold | rhVEGF165 | Absorption to scaffold | 3ug per scaffold block | 3 weeks/8 weeks | No significant difference to control | Histomorphometry 3 weeks: Control: 22% VEGF: 27% 8 weeks: Control: 33% VEGF: 39% |
7 |
| Das 2016 [33] | Rats | Mandible | PLGA microsphere | Empty defect | rhVEGF | PLGA microsphere | 200 ng steady release 3 weeks. | 12 weeks | No significant difference to control | Histomorphometry 12 weeks: Control: 1% VEGF 5% |
5 |