Surface modified metal implants using doped hydroxyapatite

描述（由申请人提供）：伴有骨缺陷的肌肉骨骼疾病以及髋关节和膝关节问题等疾病是当今常见的重要人类健康状况。在这些情况下，重建通常伴随着必须与周围骨整合的人造金属植入物。该资助申请的目的是在钛（Ti）基质上使用选定的掺杂剂和小分子进行羟基磷灰石（HA）涂层，以提高生物活性，增强组织材料相互作用。本研究的长期目标是通过为年轻患者和髋关节、肩关节或膝关节植入物的翻修手术设计成分分级的小分子/离子掺杂纳米级涂层，开发新型HA涂层金属植入物，由于骨整合增强，体内寿命延长。我们的设计目标是：1）通过控制化学和微观结构增强界面机械性能，2）改善HA涂层金属植入物的生物活性并引入骨诱导性。我们的初步数据表明，激光和RF感应等离子体处理的HA和磷酸三钙（TCP，另一种常用的磷酸钙相）涂层在钛可以消除离散和薄弱的金属-陶瓷界面，以提高涂层的界面强度。我们假设优化的激光和等离子体处理参数沿着掺杂剂化学可以产生具有强界面的成分分级的HA涂层，以改善金属植入物中涂层的体内机械稳定性。在目标1中，我们将研究它们的梯度组织、物理和机械性能。我们将对我们的植入物与Biomet Inc.的市售涂层植入物进行测试和比较，请参阅随附的支持信。基于我们的初步数据，我们表明，选定的掺杂剂可以促进早期骨组织整合大鼠和控制人成骨细胞（OB）和破骨细胞（OC）的活动在体外。由于Si可以诱导血管生成，Sr和Mg降低OC活性，Mg和Zn增强OB活性，因此我们假设掺杂剂的存在将调节体外生物相容性以及体内骨组织整合。在目标2中，我们将评估掺杂HA涂层钛样本，根据现行ASTM标准，界面机械强度>15 MPa，在大鼠和家兔模型中股骨远端形成髓内缺损。我们的初步数据表明，HA和TCP可以用于负载和释放小分子药物和蛋白质，例如阿仑膦酸钠（AD，双膦酸盐，BP，药物）/模型蛋白牛血清白蛋白（BSA），并且AD的存在可以增加局部骨密度。我们的假设是，掺杂剂将改善早期骨细胞附着和体内组织与涂层的整合，而小分子药物，例如阿仑膦酸盐，将局部增加骨细胞的粘附。 植入后的骨密度，特别是在翻修手术中。在目标3中，我们将在体外确定生物活性、掺杂剂/药物释放动力学，然后进行体内研究，以使用大鼠股骨远端髓内缺损评价这些涂层的骨组织整合。该项目的科学理解将改善非骨水泥型关节置换和其他金属植入物的长期固定。

DESCRIPTION (provided by applicant): Musculoskeletal disorders with bone deficiencies, and conditions such as hip and knee problems are common important human health conditions that exist today. In these situations, reconstruction is often accompanied by an artificial metallic implant that must integrate with the surrounding bone. The objective of this grant application is focused on hydroxyapatite (HA) coating with selected dopants and small molecules on Titanium (Ti) substrates to improve bioactivity with enhanced tissue material interactions. The long-term goal of this research is to develop novel HA-coated metal implants by designing compositionally graded, small molecule / ionically doped nanoscale coatings for younger patients and revision surgeries in hip, shoulder or knee implants, with improved in vivo lifetime due to enhanced osseointegration. Our design goals are to: 1) enhanced interfacial mechanical properties via controlled chemistry and microstructure and 2) improve bioactivity and introduce osteoinductivity in HA-coated metal implants. Our preliminary data show that laser and RF induction plasma processed HA and tricalcium phosphate (TCP, another commonly used calcium phosphate phase) coating on Ti can eliminate discrete and weak metal- ceramic interface to improve interfacial strength of coatings. We hypothesize that optimized laser and plasma processing parameters along with dopant chemistry can produce a compositionally graded HA coating with strong interface to improve mechanical stability of coatings in vivo in metal implants. In Aim 1, we will study their gradient microstructure, physical and mechanical properties. We will test and compare our implants with commercially available coated implants from Biomet Inc., please see the attached support letter. Based on our preliminary data, we show that selected dopants can promote early-stage bone tissue integration in rat and control human osteoblast (OB) and osteoclast (OC) activities in vitro. Since Si can induce angiogenesis, Sr and Mg reduce OC activities, Mg and Zn enhance OB activities, we hypothesize that the presence of dopants will regulate in vitro biocompatibility as well as in vivo bone tissue integration. In Aim 2, we will evaluate doped HA coated Ti samples, with interfacial mechanical strength >15 MPa per current ASTM standard, creating an intramedullary defect in the distal femur in rat and rabbit models. Our preliminary data shows that HA and TCP can be used in loading and releasing small molecule drug and protein, e.g. alendronate (AD, a bisphosphonate, BP, drug) / model protein bovine serum albumin (BSA) and presence of AD can increase local bone density. Our hypothesis is that the dopants will improve early stage bone cell attachment and in vivo tissue integration with the coating while the small molecule drug, e.g. Alendronate, will locally increase bone density after implantation, especially in revision surgeries. In Aim 3, we will determine the bioactivity, dopant / drug release kinetics in vitro, followed by in vivo studies to evaluate bone tissue integration of these coatings using intramedullary defects in rat distal femurs. The scientific understanding from this program will lead to improved long-term fixation of cementless joint replacements and other metal implants.