OSTEOCLAST REGULATION & OSSEOINTEGRATION OF BIOIMPLANTS

本项目将利用新发现的蛋白质调节因子局部控制宿主破骨细胞的活性，作为优化颅面骨骼中骨嵌体和植入物的骨整合速度和程度的策略。骨组织植入材料生物工程设计的一个重要目标是实现快速的机械愈合和与患者骨表面稳定的骨整合。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，对于用羟基磷灰石颗粒修复大的、临界尺寸的缺陷，处理过的骨粉和矿化的刚性种植体(例如。（Interpore, Bio-Oss，尸体骨），典型的结果是在宿主骨界面处有限的骨整合（通过骨诱导和/或骨传导）。最初，强大的伤口愈合反应是由种植体表面丰富的混合物引起的。然而，这些“生物植入物”通常在其整体中保持贫瘠和未石化，造成长期的吸收损失和失败问题。该项目以一个中心假设为指导：骨植入物内受调节的非炎症性破骨细胞吸收可以通过两种平行机制在促进其骨整合中发挥关键作用- 1)内皮细胞向内生长提供新血管，2)耦合成骨细胞形成新骨。该项目将在实验大鼠和小鼠中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促进颅面部位骨整合反应中的作用。第一个目标是将纯基质和调节蛋白结合到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值。这些因子包括特异性破骨细胞附着和激活因子（玻璃体连接蛋白、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目标的基础上，将内皮生长因子（bFGF）纳入植入物中，以便定量地将成骨和新生血管的程度与常驻破骨细胞的数量联系起来。坚硬的矿化骨替代物对于避免颅面和脊柱手术患者的发病率具有重要的临床意义。控制骨生物计划中破骨细胞活性的新策略应该促进生物骨整合和长期生物力学功能，并且可能适用于广泛的当前和未来的生物材料。

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.