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

具有协同抗菌释放功能的药物洗脱关节植入物和临床前疗效测试的风险分层模型

• 批准号: 10593923
• 负责人: Ebru Oral
• 金额: $ 36.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593923
• 关键词: Amputation; Analgesics; Anti-Bacterial Agents; Antibiotics; Antioxidants; Arthrodesis; Attention; Bacterial Infections; Biomedical Engineering; Biometry; Bone Cements; Bupivacaine; Caring; Clinical; Communicable Diseases; Complication; Data; Devices; Economic Burden; Engineering; Excision; Failure; Formulation; Gentamicins; Goals; Growth; Health; Healthcare; Immobilization; Implant; In Vitro; Infection; Inflammatory; Joints; Ketorolac; Knowledge; Life; Link; Mechanics; Medical Device; Methods; Microbial Biofilms; Mission; Modality; Modeling; Morbidity - disease rate; Morphology; Nature; Non-Steroidal Anti-Inflammatory Agents; Operating Rooms; Operative Surgical Procedures; Oral; Organ Transplantation; Organism; Orthopedic Surgery; Orthopedics; Outcome; Patients; Periprosthetic joint infection; Pharmaceutical Preparations; Polymers; Pre-Clinical Model; Prevention; Probability; Procedures; Property; Public Health; Quality of life; Rattus; Recurrence; Replacement Arthroplasty; Research; Resistance; Risk; Risk Assessment; Safety; Staphylococcal Infections; Staphylococcus aureus; Surface; System; Technology; Testing; Therapeutic; Time; Treatment Cost; Treatment Failure; United States National Institutes of Health; Vancomycin; Weight-Bearing state; Work; alternative treatment; antimicrobial; antimicrobial drug; care burden; chemotherapy; clinical development; clinically relevant; controlled release; cost; crosslink; design; disability; efficacy testing; immunological status; implant material; implantation; implementation strategy; improved; improved outcome; in vivo; innovation; joint infection; mechanical properties; microorganism; mortality; novel; pharmacodynamic model; pre-clinical; prevent; recurrent infection; risk stratification; sample fixation; standard care; synergism; technology platform; treatment duration; treatment risk; ultra-high molecular weight polyethylene

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.

项目摘要/摘要 理解局部输送抗生素对预防和预防的影响有根本的差距 治疗围场围场关节感染，一种真正的病态且昂贵的并发症> 100万 每年进行关节关节置换术的患者。目前没有承重的医疗设备 也可以用于控制抗生素的控制释放以治疗螺旋围关节感染（PJI）。电流 治疗标准（没有用于预防）涉及两阶段的修订，在此期间 固定超过3个月。可用的治疗仅在约40-80％的时间内生效 复发增加了发病率，死亡率和成本。非常需要改善结果， 患者的生活质量并降低成本。 我们的长期目标是开发材料和方法，以实现和周到的本地发布 治疗骨科疾病的治疗剂。该应用的总体目的是设计一种抗生素 - 洗脱和承重的关节植入物平台技术及其实施策略，以改善 PJI的处理。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，一种超高分子量聚乙烯 可以设计具有最佳抗生素效率和安全性的植入物（UHMWPE）。理由 拟议的研究是，通过使用新发现的局部PJI抗生素和新发现的抗生素协同作用 常用的镇痛药，我们可以优化具有最大效率的药物洗脱剖面 可变风险的临床相关感染的增长。该策略有可能改变治疗 改善预后的范例，没有任何其他风险。具体目的是（1）确定 具有协同抗菌释放和（2）临床前风险的工程UHMWPE的因素 - 分层测试实施抗生素洗脱的UHMWPE。发展艰难的挑战 在聚合物中掺入药物的同时，充满负荷和耐磨表面将被两个 策略：引入高度古怪的药物簇，使药物载荷较低并在空间上限制 植入物的低负载轴承区域的药物负载区域。这种方法是创新的，首先是因为它 偏离当前取决于临时，无重量骨骼的抗生素洗脱的方法 水泥设备通常在手术室组装，其次是因为镇痛药可以改善 抗生素的效率可以使用该设备同时以预定的速度同时传递。 预期的结果是一种轴承表面技术的平台，并且是针对该平台的实施策略 感染微生物。这些策略利用了团队在临床开发方面的专业知识 根据抗氧化剂稳定，交联和形态的创新，UHMWPE落下 操纵。我们提供了强大的初步数据，显示了我们想法的可行性，包括合并 UHMWPE中的万古霉素，在临床前浮游生物和生物膜感染模型中具有安全有效的释放 以及与庆大霉素的镇痛药和布比卡因之间的协同作用。提议 研究很重要，因为预计它将为打击PJI提供一种新的，安全和有效的植入物， 可以消除临时修订的两阶段修订的昂贵和朴实的金标准 固定。