OSTEOCLAST REGULATION & OSSEOINTEGRATION OF BIOIMPLANTS

破骨细胞调节

• 批准号: 6516572
• 负责人: Peter V Hauschka
• 金额: $ 24.73万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516572
• 关键词: bioengineering /biomedical engineering; biomaterial development /preparation; biomimetics; bone morphogenetic proteins; bone sialoprotein; cell adhesion molecules; cell differentiation; cell growth regulation; chemotaxis; colony stimulating factor; fibroblast growth factor; hydroxyapatites; immunocytochemistry; implant; in situ hybridization; inflammation; laboratory mouse; laboratory rat; medical implant science; osteocalcin; osteoclasts; osteogenesis; osteopontin; polymerase chain reaction; tissue engineering; vitronectin; western blottings

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.

该项目将利用新发现的蛋白质调节剂来局部控制宿主破骨细胞的活性，作为优化颅面骨架内嵌体和种植体的骨整合速度和程度的策略。在HAD组织植入材料的生物工程设计中，一个重要的目标是在患者体内实现快速的机械愈合和稳定的骨结合。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，对于使用颗粒状羟基磷灰石、处理骨粉和矿化硬质植入物(如：孔间、Bio-Oss、身体骨)修复大型、临界大小的缺损，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，种植体界面上强烈的伤口愈合反应是由丰富的种植体表面混合物引起的。然而，这些“生物植入物”在其整个过程中经常保持贫瘠和未骨化，导致长期的吸收损失和失败的问题。该项目以一个中心假设为指导：通过两种并行机制--1)耦合内皮细胞内长入提供新血管，以及2)耦合成骨细胞形成新骨--可使植入物中受调控的非炎症性破骨细胞吸收在促进其骨整合方面发挥关键作用。该项目将测试新发现的调节破骨细胞招募、分化和活性的蛋白质因素在促进实验大鼠和小鼠颅面部部位的骨整合反应中的作用。第一个目标是将纯基质和调节蛋白整合到矿化植入物和相关的可控释放聚合物涂层中，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黏附和激活因子(玻璃连素、骨涎蛋白、骨桥蛋白、骨钙素)、分化因子(M-CSF、RANK-L)和抑制物(护骨素)。第二个目标建立在第一个目标的基础上，通过在植入物中加入内皮生长因子(BFGF)，以定量地将成骨和新生血管的程度与常驻破骨细胞的数量相关联。硬质、矿化的骨替代物对于避免颅面和脊柱手术患者的并发症具有重要的临床意义。控制破骨细胞活性的新策略将促进生物的骨整合和长期的生物力学功能，并可能适用于目前和未来的各种生物材料。

项目成果

VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin.

• DOI: 10.1016/j.matbio.2008.06.005
• 发表时间: 2008-09
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Quanli Yang;K. Mchugh;S. Patntirapong;Xuesong Gu;Lívius Wunderlich;P. Hauschka