Drug-eluting joint implants with synergistic antimicrobial release and risk stratified models of preclinical efficacy testing

项目摘要/摘要 在理解当地使用抗生素预防和预防癌症的效果方面存在着根本的差距。 假体周围关节感染的治疗，一种真正病态和昂贵的并发症威胁&100万 每年接受关节置换术的患者。目前还没有完全负重的医疗设备 也可用于抗生素的控制释放，以治疗假体周围关节感染(PJI)。海流 治疗标准(没有预防的标准)包括两个阶段的修订，在此期间患者 固定3个月以上。现有的治疗方法只有大约40%-80%的时间是有效的 复发极大地增加了发病率、死亡率和成本。有很大的需要改善结果， 提高患者的生活质量，降低成本。 我们的长期目标是开发材料和方法，使之能够并周到地控制当地的释放 治疗骨科疾病的治疗学。这项应用的总体目标是设计一种抗生素- 洗脱承重关节植入平台技术及其实施策略 PJI的治疗。我们的中心假设是，通过操纵合并药物的协同作用， 超高相对分子质量聚乙烯的药物/聚合物相互作用及药物掺入方法 可以设计出具有最佳抗生素效率和安全性的(UHMWPE)植入物。该计划的基本原理 拟议的研究是通过使用一种新发现的抗生素协同作用，在当地的PJI抗生素和 通常使用的镇痛剂，我们可以优化药物洗脱曲线，以最大限度地防止 风险可变的临床相关感染的增长。这一策略有可能改变治疗方法。 在不给患者带来任何额外风险的情况下改善结果的范例。具体目标是(1)确定 设计抗菌协同释放的UHMWPE的因素和(2)开发临床前风险- 实施抗生素洗脱UHMWPE的分层测试。开发一种艰难的、 在聚合物中加入药物的同时完全承载和耐磨的表面将被两个方面所克服 战略：引入高度偏心的药物集群，使药物负载量更低，并在空间上限制 药物负荷区到种植体的低负荷区。这种方法是创新的，首先是因为它 与目前依赖抗生素从临时的、非负重的骨骼中洗脱的方法不同 水泥器械经常装配在手术室里，其次是因为镇痛剂，这可以提高 抗生素的药效，可以使用这种设备以预定的速度同时提供。这个 预期成果是平台承重面技术和针对 感染微生物。这些策略利用了团队在临床使用的开发方面的专业知识 基于抗氧化剂稳定性、交联性和形态创新的UHMWPE植入物 操纵。我们提供了强有力的初步数据，表明了我们的想法的可行性，包括将 万古霉素在UHMWPE中的临床前浮游和生物被膜感染模型中安全有效的释放 以及止痛药酮咯酸和布比卡因与庆大霉素的协同作用。建议数 这项研究意义重大，因为它有望为抗击PJI提供一种新的、安全和有效的植入物， 它可以消除昂贵而繁重的两阶段修订的黄金标准 动弹不得。

Project Summary/Abstract There is a fundamental gap in understanding the effect of local delivery of antibiotics for the prevention and treatment of peri-prosthetic joint infections, a truly morbid and costly complication threatening >1 million patients undergoing joint arthroplasty each year. There is currently no fully load-bearing medical device which can also be used for the controlled release of antibiotics to treat peri-prosthetic joint infection (PJI). The current standard of treatment (there is none for prevention) involves a two-stage revision during which patients are immobilized for more than 3 months. Available treatments are effective only about 40-80% of the time with recurrence increasing morbidity, mortality and cost tremendously. There is a great need to improve outcomes, patients’ quality of life and to reduce cost. Our long-term goal is to develop materials and methods to enable and thoughtfully control the local release of therapeutics to treat orthopaedic conditions. The overall objective of this application is to devise an antibiotic- eluting and load-bearing joint implant platform technology and its implementation strategy to improve the treatment of PJI. Our central hypothesis is that by manipulating the synergy of incorporated drugs, drug/polymer interactions and drug incorporation methods, an ultrahigh molecular weight polyethylene (UHMWPE) implant with optimal antibiotic efficiency and safety can be designed. The rationale for the proposed research is that by using a newly discovered antibiotic synergy between local PJI antibiotics and commonly used analgesics, we can optimize drug elution profiles with maximum efficacy in preventing the growth of clinically relevant infections of variable risk. This strategy has the potential of changing the treatment paradigms for improved outcomes without any additional risks to patients. The specific aims are (1) identifying the factors in engineering UHMWPE with synergistic antibacterial release and (2) developing preclinical risk- stratification tests for the implementation of antibiotic-eluting UHMWPE. The challenge of developing a tough, fully load-bearing and wear resistant surface while incorporating drugs in the polymer will be overcome by two strategies: introducing highly eccentric drug clusters that enable lower drug loading and spatially limiting the drug-loaded regions to low load bearing regions of the implant. The approach is innovative firstly because it departs from the current methods of depending on antibiotic elution from temporary, non-weight bearing bone cement devices often assembled in the operating room and secondly because analgesics, which can improve the efficacy of antibiotics, can be delivered concurrently at a predetermined rate using this device. The expected outcome is a platform bearing surface technology and an implementation strategy tailored to the infecting microorganism. The strategies capitalize on the team’s expertise in the development of clinically used UHMWPE implants based on innovations in antioxidant stabilization, cross-linking and morphology manipulation. We present strong preliminary data showing the feasibility of our ideas including incorporating vancomycin in UHMWPE with safe and efficient release in pre-clinical planktonic and biofilm infection models and the synergy between the analgesic drugs ketorolac and bupivacaine with gentamicin. The proposed research is significant, because it is expected to provide a new, safe and efficient implant for combating PJI, which can eliminate the costly and burdensome gold standard of two-stage revision with temporary immobilization.