OSTEOCLAST REGULATION & OSSEOINTEGRATION OF BIOIMPLANTS

该项目将利用新发现的蛋白质调节剂局部控制宿主破骨细胞的活性，作为优化颅面骨骼中骨高嵌体和植入物骨整合速率和程度的策略。生物工程设计had组织植入材料的一个基本目标是实现快速机械愈合和与患者骨表面的稳定骨整合。纯钛或涂层钛种植体的真正骨整合在文献中得到了很好的证实。然而，对于用颗粒羟基磷灰石、处理过的骨粉和矿化的刚性植入物（例如，Interpore、Bio-Oss、尸体骨），典型的结果是在与宿主骨的界面处有限的骨整合（通过骨诱导和/或骨传导）。最初，植入物界面处的强烈伤口愈合反应是由植入物表面的丰富混合物引起的。然而，这些“生物植入物”通常在其整个体积中保持贫瘠和未骨化，导致吸收损失和失败的长期问题。该项目由一个中心假设指导：骨植入物内受调节的非炎性骨吸收可通过两种平行机制-- 1）偶联内皮细胞向内生长提供新血管，2）偶联成骨细胞形成新骨--在促进骨整合中发挥关键作用。该项目将测试新发现的调节破骨细胞募集、分化和活性的蛋白质因子在实验大鼠和小鼠颅面部位促进骨整合反应中的作用。第一个目标是将纯基质和调节蛋白掺入矿化植入物和相关的控释聚合物涂层中，以建立高、中、低破骨细胞活性的可靠设定点。这些因子包括特异性破骨细胞附着和活化因子（玻连蛋白、骨唾液蛋白、骨桥蛋白、骨钙素）、分化因子（M-CSF、RANK-L）和抑制剂（骨保护素）。第二个目标建立在第一个基础上，通过将内皮生长因子（bFGF）纳入植入物中，以定量地将骨生成和新血管形成的程度与常驻破骨细胞的数量相关联。刚性矿化骨替代物在临床上对于避免颅面和脊柱手术中的患者发病率非常重要。控制骨生物植入物中破骨细胞活性的新策略应促进生物骨整合和长期生物力学功能，并可适用于广泛的当前和未来生物材料。

This Project will utilize newly discovered protein regulators to locally control the activity of host osteoclasts as a strategy for optimizing the rate and extent of osseointegration of bone onlays and implants in the craniofacial skeleton. An essential goal in the bioengineering design of had tissue implant materials is to achieve rapid mechanical union and stable osseointegration with bone surfaces in the patient. True osseointegration of pure or coated titanium implants is well established in the literature. However, for the repair of large, critical-size defects with particulate hydroxyapatite, treated bone powders, and mineralized rigid implant (eg., Interpore, Bio-Oss, cadaver bone) the typical result is a limited osseointegration (by osteoinduction and/or osteoconduction) at the interface with host bone. Initially, the robust wound-healing reaction reaction at the implant interface is caused by the rich mixture of implant surfaces. Yet these "bioimplants" often remain barren and unossified throughout their bulk, causing long-term problems of resorptive loss and failure. The Project is guided by a central Hypothesis: regulated, non- Inflammatory osteoclastic resorption within a bone implant can be made to play a key role in facilitating its osseointegration through two parallel mechanism-- 1) coupled endothelial cell ingrowth providing new blood vessels, and 2) coupled osteoblastic formation of new bone. The Project will test the role of newly discovered protein factors which regulate osteoclast recruitment, differentiation, and activity in promoting the osseointegration reaction in craniofacial sites in experimental rats and mice. The first aim is to incorporate pure matrix and regulatory proteins into mineralized implants and associated controlled-release polymer coating to Establish reliable set points for high, intermediate, and low osteoclast activity. These factors include specific osteoclast attachment and activating factors (vitronectin, bone sialoprotein, osteopontin, osteocalcin), differentiation factors (M-CSF, RANK-L) and inhibitors (osteoprotegerin). The second aim builds on the first by incorporating an endothelial growth factor (bFGF) into the implant in order to quantitatively correlate the extent of osteogenesis and neovascularization with the number of resident osteoclasts. Rigid, mineralized bone substitutes are clinically important to avoid patient morbidity in craniofacial and spinal surgery. New strategies for controlling osteoclast activity in osseous bioimplans shoulld facilitate biological osseointegration and long-term biomechanical functionality, and my be applicable to a wide range of current and future biomaterials.