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Primary versus secondary reconstruction of mandibular critical size defects using recombinant human bone morphogenetic protein 2: an experimental study in dogsVery often, delayed reconstruction becomes the setting of choice in the reconstruction of large segmental defects in the mandible. Our hypothesis is that rhBMP2 delivery would elicit endogenous expression of BMP2 and VEGF in the soft tissue bed of the defect. Such response is expected to be more pronounced in the immediate than the delayed reconstruction, which will correlate with the quantity and quality of bone formation in the two settings. We also hypothesized that vascular endothelial cells (ECs) of the surrounding soft tissue contribute to the endogenous production of BMP2. In this study we used a mandibular canine segmental defect model (35 mm), periosteum was excised and also the delayed reconstruction group was included in this study in addition to the control group. We investigated the effect of different reconstruction settings on the quantity and quality of bony regenerates; on the production of endogenous BMP2 from the soft tissue bed of the defects and finally we tried to explore the source of this rhBMP2- induced endogenous BMP2 production both in vivo and in vitro. This study demonstrated that rhBMP2 delivery is more effective in immediate reconstruction of large mandibular segmental defects. Immediate delivery of rhBMP2 yielded more adequate reconstruction of the defect after 12 weeks, evident by the quantity and quality of the bone regenerate. Only in the immediate reconstruction group, the advantageous bone parameters were associated with significant up-regulation of BMP2 mRNA and protein in the soft tissue bed of the defect. This suggests that endogenous-BMP2 is important in maintaining the short-acting effect of the delivered rhBMP2. Regarding the source of the endogenous-BMP2, protein co-localization with ECs marker suggested that these cells could be the source for the endogenous BMP2 secretion in response to rhBMP2 treatment. This was confirmed by the in-vitro results on both the mRNA and protein levels. The gradual increase in expression of BMP2 mRNA and the significant upregulation of secreted BMP2 protein upon stimulation of human umbilical vein endothelial cells with 100-ng/ml rhBMP2 recognized a new mechanism of positive feed back response of ECs in response to BMP2 treatment.
Sustained Release Formulation for Vascular Endothelial Growth FactorNecrosis of tissue due to trauma or a surgical procedure is a complication of wound healing. This necrosis, or tissue death, occurs when the vasculature is unable to perfuse involved tissue with the oxygen and nutrients necessary to maintain viability. To provide adequate access, reflecting a flap of tissue is often necessary in a variety of surgical procedures, including periodontal surgeries. The success of these procedures is limited by the development of tissue flap necrosis. The survival of these tissue flaps is dependent upon adequate perfusion by the blood vessel supply at the base of the flap, followed by the growth of new vascular channels from the recipient site. However, if angiogenesis does not promptly reach the distal extent of the flap, this portion becomes ischemic, leading to necrosis. Loss of the protective flap delays healing and increases the risk of scarring and infection. Necrosis of this distal region of a tissue flap begins as early as 24 hours following the surgical procedure and progresses rapidly until day 3 when the unaffected tissue begins to stabilize.1 A variety of pharmacological strategies to enhance tissue flap perfusion have been tested in an attempt to prevent necrosis. One such strategy is the administration of angiogenic growth factors such as vascular endothelial growth factor (VEGF). VEGF is known to stimulate the proliferation of endothelial cells from existing vasculature to create new blood vessels, thus enhancing 8 tissue survival.2-7 In addition, VEGF contributes to other aspects of wound healing, including inflammation, granulation tissue formation, reepithelialization, matrix formation, and remodeling.2 Administration of VEGF to wound healing models has shown promising results by increasing vascular formation, leading to enhanced tissue perfusion. However, its short duration of action and rapid dissipation from the target site reduces its effectiveness.8 Maintaining therapeutic concentrations of VEGF at the target site to maximize new vessel growth and reduce necrosis, either multiple applications or an extended-release delivery system is required. An ideal system would provide ease of use and delivery kinetics for sustained therapeutic dosing of VEGF to the wound environment for the duration of healing, thereby minimizing tissue necrosis. A variety of application methods and delivery systems are under investigation in the search to develop one that provides utility as well as improved clinical outcome.