Table 2.
Growth factors and other agents used for local activation and/or mobilization of stem cells in craniofacial and bone regeneration.
| Agent | Evidence(s) | Reference(s) |
|---|---|---|
| Bone Morphogenetic Proteins (BMPs) | Activation of mesenchymal stem cells and osteogenic differentiation. Mechanisms of action and effects vary between the 15 isoforms of BMPs. The most osteoinductive are BMP-2, -6, -9, -4, -7. | Bae et al., 2001; Zhao, 2003; Luu et al., 2007 |
| BMP-2 | Knockout mice are lethal; haploinsufficiency causes orofacial clefting in humans. Use suggested for mandible, cleft, and cranial vault reconstruction. | Zhang and Bradley, 1996; Schliephake et al., 2008; Sahoo et al., 2011; Chenard et al., 2012 |
| BMP-4 | Knockout mice are lethal; heterozygous null mice exhibit skeletal defects such as craniofacial malformations and polydactyly. Enhances bone healing when co-expressed with VEGF by genetically manipulated stem cells. May be detrimental in osseointegration of oral implants coated with collagen. | Peng et al., 2002; Zhao, 2003; Stadlinger et al., 2008 |
| BMP-7 | Knockout mice are postnatal lethal and show skeletal patterning defects in skull, hindlimbs, and ribcage. Stimulates periodontal wound healing in an animal model. | Luo et al., 1995; Giannobile et al., 1998; Springer et al., 2005a |
| BMP-6 | Some evidences show this isoform to be one of the most osteogenic in animal models. | Solloway et al., 1998; Kang et al., 2004 |
| Vascular Endothelial Growth Factor (VEGF) | Delivered with PLGA or collagen scaffolds enhances bone regeneration in cranium, calvarial and mandibular defects. Sustained release (up to 5 weeks) can be obtained by pre-encapsulation of VEGF in PLGA, alginate, or gelatin microspheres or, alternatively, by VEGF co-precipitation onto BCP (Basic Calcium Phosphate). | Murphy et al., 2004; Kleinheinz et al., 2005; Patel et al., 2008; De la Riva et al., 2009, 2010; Wernike et al., 2010; Behr et al., 2012; Farokhi et al., 2013, 2014 |
| VEGF + BMP2 | A combination of these two factors showed an increased vascular density during bone regeneration but no detectable enhancement in bone formation compared to BMP2 alone in animal models of cranial and mandibular defects. This combination is also capable of facilitating bone marrow stem cells (BMSCs) homing and differentiation. | Young et al., 2009; Zhang et al., 2011; Ramazanoglu et al., 2013; Zhang et al., 2014 |
| Platelet-Derived Growth Factor (PDGF) | Local administration of PDGF in a critical-size calvarial defect has been shown to increase bone mineralization similarly to VEGF, but less than BMP-2. Use approved for periodontal repair by FDA. Chemoattractant for Mesenchymal stem cells (MSCs) | Fiedler et al., 2004; Pellegrini et al., 2009; Phipps et al., 2012; Jin and Giannobile, 2014 |
| SDF-1 | Induces extravasation and homing of mesenchymal cells through the CXCR4 receptor. SDF-1-loaded scaffolds have been studied in fracture healing models and in calvarial defects with excellent results. Capable of inducing migration, proliferation and activation of human periodontal ligament stem cells (PLSCs). | Kitaori et al., 2009; Fujio et al., 2011; Li D. et al., 2011; Du et al., 2012; Ji et al., 2013; Liu et al., 2014 |
| SDF-1 + BMP2 | The combination of SDF-1 + BMP2 increases bone volume in a calvarial defect model compared to SDF-1 alone | Jin and Giannobile, 2014 |
| Platelet-rich Plasma (PRP) | PRP is a concentrate of blood platelets that upon activation releases various growth factors, including PDGF and VEGF. It can be used to enhance tissue healing, especially in case of concomitant cell transplantation. Potential use of PRP as a stem cell activator has been suggested in the case of periodontal regeneration. | Anitua et al., 2008; Chen et al., 2010; Del Corso et al., 2012; Fekete et al., 2012 |
| Platelet-rich Fibrin (PRF) | PRF is a polymeric (fibrin-based) scaffold loaded with PRP that has shown good results in promoting craniofacial bone regeneration both in preclinical and in clinical setting | Simonpieri et al., 2012; Li et al., 2014 |