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: 10372936
• 负责人: Ebru Oral
• 金额: $ 36.38万
• 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/10372936
• 关键词: Amputation; Analgesics; Anti-Bacterial Agents; Antibiotics; Antioxidants; Arthrodesis; Attention; Bacterial Infections; Biomedical Engineering; Biometry; Bupivacaine; Caring; Clinical; Communicable Diseases; Complication; Data; Devices; Economic Burden; Engineering; Excision; Failure; Formulation; Gentamicins; Goals; Gold; Growth; Health; Healthcare; Immobilization; Implant; In Vitro; Infection; Inflammatory; Joint Prosthesis; Joints; Ketorolac; Knowledge; Life; Link; Mechanics; Medical Device; Methods; Microbial Biofilms; Mission; Modality; Modeling; Molecular Weight; Morbidity - disease rate; Morphology; Nature; Non-Steroidal Anti-Inflammatory Agents; Operating Rooms; Operative Surgical Procedures; Oral; Organ Transplantation; Organism; Orthopedic Surgery; Orthopedics; Outcome; Patients; Pharmaceutical Preparations; Polyethylenes; Polymers; Pre-Clinical Model; Prevention; Probability; Procedures; Property; Prosthesis; 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; base; bone; 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 validation; treatment duration; treatment risk

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.

项目概要/摘要 对于局部施用抗生素对于预防和治疗的效果的理解存在根本差距。 治疗假体周围关节感染，这是一种真正病态且昂贵的并发症，威胁超过 100 万患者 每年都有接受关节置换术的患者。目前尚无完全承重的医疗器械 也可用于抗生素的控释，以治疗假体周围感染（PJI）。目前的 治疗标准（没有预防措施）涉及两个阶段的修订，在此期间患者 固定不动超过3个月。现有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、死亡率和费用。非常需要改善结果， 患者的生活质量并降低费用。 我们的长期目标是开发材料和方法，以实现并深思熟虑地控制本地释放 治疗骨科疾病的疗法。本申请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， 药物/聚合物相互作用和药物掺入方法，超高分子量聚乙烯 可以设计出具有最佳抗生素效率和安全性的（UHMWPE）植入物。理由如下： 拟议的研究是通过使用本地 PJI 抗生素和新发现的抗生素之间的协同作用 常用的镇痛药，我们可以优化药物洗脱曲线，以最大功效预防 不同风险的临床相关感染的增长。该策略有可能改变治疗方法 改善结果的范例，而不会给患者带来任何额外的风险。具体目标是 (1) 确定 工程 UHMWPE 具有协同抗菌释放的因素和 (2) 开发临床前风险 实施抗生素洗脱 UHMWPE 的分层测试。培养坚韧、 完全承重和耐磨的表面，同时将药物掺入聚合物中将克服两个问题 策略：引入高度偏心的药物簇，以降低药物负载量并在空间上限制 植入物的载药区域到低承载区域。这种方法之所以具有创新性，首先是因为它 不同于目前依赖抗生素从临时、非承重骨中洗脱的方法 水泥装置经常在手术室组装，其次是因为镇痛剂，这可以改善 使用该装置可以以预定的速率同时输送抗生素的功效。这 预期成果是一个承载表面技术的平台和一个适合的实施策略 感染微生物。这些策略利用了团队在临床使用开发方面的专业知识 基于抗氧化稳定性、交联和形态创新的 UHMWPE 植入物 操纵。我们提供了强有力的初步数据，显示了我们的想法的可行性，包括合并 UHMWPE 中的万古霉素在临床前浮游和生物膜感染模型中安全有效地释放 以及镇痛药物酮咯酸和布比卡因与庆大霉素之间的协同作用。拟议的 研究意义重大，因为它有望提供一种新的、安全且高效的植入物来对抗 PJI， 这可以消除成本高昂且繁重的临时两阶段修订黄金标准 固定化。