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

项目总结/摘要 在了解抗生素局部给药对预防和治疗结核病的作用方面存在根本性的差距， 治疗假体周围关节感染，这是一种真正的病态和昂贵的并发症，威胁超过100万人 每年接受关节置换术的患者。目前还没有完全承载的医疗设备， 也可用于抗生素的控制释放以治疗假体周围关节感染（PJI）。当前 治疗标准（没有预防）涉及两个阶段的修订，在此期间，患者 不动超过3个月。可用的治疗方法只有大约40-80%的时间有效， 复发极大地增加了发病率、死亡率和成本。非常需要改善结果， 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，以实现和周到地控制当地释放的 用于治疗骨科病症的治疗剂。本申请的总体目标是设计一种抗生素- 洗脱和承载关节种植平台技术及其实施策略，以提高 PJI的治疗我们的中心假设是，通过操纵掺入药物的协同作用， 药物/聚合物相互作用和药物掺入方法，一种高分子量聚乙烯 可以设计具有最佳抗菌效率和安全性的超高分子量聚乙烯植入物。的理由 拟议的研究是，通过使用一种新发现的抗生素协同作用之间的地方PJI抗生素和 常用的镇痛药，我们可以优化药物洗脱曲线，最大限度地有效防止 可变风险的临床相关感染的增长。这种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局的范例。具体目标是：（1）识别 工程UHMWPE协同抗菌释放的因素和（2）临床前风险的形成- 分层测试，用于实施抗渗透洗脱UHMWPE。开发一个坚韧的， 完全承载和耐磨表面，同时将药物掺入聚合物中， 策略：引入高度偏心的药物簇，使得能够降低药物载量并在空间上限制药物浓度。 载药区域到植入物的低承载区域。这种方法是创新的，因为它 不同于目前依赖于抗生素从暂时的非承重骨洗脱的方法 骨水泥装置经常在手术室组装，其次是因为止痛药，这可以改善 抗生素的功效可以使用该装置以预定的速率同时输送。的 预期的结果是一个平台轴承表面技术和实施战略， 感染微生物。这些策略利用了团队在开发临床使用的 基于抗氧化稳定、交联和形态学创新的UHMWPE植入物 操纵我们提出了强有力的初步数据显示我们的想法，包括纳入可行性 UHMWPE中万古霉素在临床前炎症和生物膜感染模型中安全有效释放 以及镇痛药酮咯酸和布比卡因与庆大霉素之间的协同作用。拟议 研究意义重大，因为它有望提供一种新的、安全有效的植入物来对抗PJI， 它可以消除昂贵和繁琐的黄金标准的两个阶段的修订与临时 固定化。

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.