Early Detection and Intervention of Orthopedic Implant Loosening using Polymer Th

使用聚合物 Th 早期检测和干预骨科植入物松动

基本信息

批准号：
8627117
负责人：
Dong Wang
金额：
$ 34.21万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627117
关键词：
Acids Animals Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Autopsy Biodistribution Biological Blood Vessels Bone Resorption Bone Tissue Calvaria Cell Culture System Cell Separation Cells Clinical Data Detection Development Dexamethasone Diagnosis Diagnostic Disease Drug Delivery Systems Drug Kinetics Dyes Early Diagnosis Early Intervention Early identification Elements Event Extravasation Failure Flow Cytometry Future Goals Hematoxylin and Eosin Staining Method Histology Image Imaging Techniques Immunohistochemistry Implant In Vitro Inflammation Inflammatory Intervention Kinetics Label Lymphatic Magnetic Resonance Imaging Malignant Neoplasms Maps Mediating Mesenchymal Modeling Molecular Weight Mus Myelogenous Myeloid Cells Organ Orthopedics Osteolysis Outcome Patients Pharmaceutical Preparations Polymer Chemistry Polymers Property Protocols documentation Quality of life Replacement Arthroplasty Resolution Safety Second Look Surgery Series Signaling Molecule Site Societies Solid Neoplasm Staging Symptoms System Therapeutic Uses Time Tissues Toxic effect Treatment Efficacy Water Work base bioimaging bone bone loss bone quality copolymer design effective therapy imaging modality improved in vivo in vivo imaging interdisciplinary approach lymph nodes macromolecule methacrylamide mouse model novel novel strategies particle peri-implant osteolysis prevent public health relevance sample fixation single photon emission computed tomography theranostics tool uptake

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel theranostic tool for early diagnosis and effective treatment of peri-implant orthopedic wear particle-induced osteolysis. Orthopedic wear particle-induced inflammation is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement. Ou previous work has identified two critical elements of macromolecular passive targeting to sites of inflammation: 1) specific extravasation through enhanced vascular leakage associated with inflammation and 2) inflammatory cell-mediated sequestration of the macromolecules. To further exploit this novel mechanism for targeting inflammatory disease, we will optimize the structural parameters of the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer system in order to develop a highly sensitive and efficacious theranostic for early peri-implant osteolysi detection and treatment. Specifically, we will first systematically modify the structural and functional properties of the polymer theranostics to optimize cellular uptake, retention and drug cleavage kinetics. The factors governing polymer theranostics' extravasation/lymphatic clearance at the site of inflammation will then be investigated. Based on the findings of these two steps, we will then develop an optimized polymer theranostic system for highly sensitive detection of wear particle-induced peri-implant osteolysis using an intraosseous femoral implant model. To develop a HPMA copolymer-based drug delivery system with an optimal in vivo efficacy and safety profile, we will then perform a pharmacokinetic/biodistribution study to identify the optimal structural parameters of HPMA copolymer-dexamethasone conjugates (P-Dex) that maximize protection of the peri-implant bone quality while minimizing the well characterized off-target toxicities associated with Dex. The macromolecular theranostic approach that we have developed represents a major shift of the current orthopedic implant management paradigm and can be adapted in the future to the development of novel approaches for imaging disease activity and progression in other inflammatory diseases. Importantly, this system may also be exploited for targeting additional intracellular signaling molecules involved in inflammatory and autoimmune disorders.

描述（由申请人提供）：该项目的总体目标是开发一种新型的疗法工具，用于早期诊断和有效治疗植入物周围的骨科磨损颗粒诱导的骨溶解。骨科磨损颗粒引起的炎症被认为是无菌植入物松动和总关节置换后临床失败的主要原因。 OU先前的工作已经确定了大分子被动靶向炎症部位的两个关键要素：1）通过增强与炎症相关的血管泄漏和2）大分子炎症细胞介导的隔离大分子的炎症。为了进一步利用这种靶向炎性疾病的新机制，我们将优化水溶性N-（2-羟基丙基）甲基丙烯酰胺（HPMA）共聚物系统的结构参数，以便为早期的植皮性植物植物学检测和治疗而开发高度敏感有效的治疗疗法。具体而言，我们将首先系统地修改聚合物疗法学的结构和功能特性，以优化细胞摄取，保留和药物裂解动力学。然后将研究控制聚合物疗法学的外部渗出/淋巴清除炎症部位的因素。基于这两个步骤的发现，我们将开发一种优化的聚合物疗法系统，用于使用骨内股骨内植入物模型高度敏感地检测磨损颗粒诱导的植入物周围的骨溶解。为了开发具有最佳体内功效和安全性最佳的基于HPMA共聚物的药物输送系统，然后我们将执行一项药代动力学/生物分布研究，以确定HPMA共聚合物 - 塞米斯米松共轭物（P-DEX）（P-DEX）的最佳结构参数（P-DEX），从而最大程度地将e-eplant bone bone质量的保护效率与explant extion Chiptical alligation alsimize a de-aximize a velys进行了描述。我们开发的大分子疗法方法代表了当前骨科植入物管理范式的重大转变，并且将来可以改编成对其他炎症性疾病的成像疾病活性和进展的新方法的发展。重要的是，该系统还可以利用用于靶向涉及炎症和自身免疫性疾病的其他细胞内信号分子。