Antimicrobial-releasing gels for preventing infection in total joint arthroplasty

描述（由申请人提供）：骨科手术部位感染（SSI），包括人工关节感染（PJIs），是一个极其昂贵的医疗保健问题，如 在美国，每年治疗超过20，000例髋关节和膝关节置换术感染的平均总成本为70，000 - 114，000美元。当人工关节在关节成形术后感染时，生物体在假体上形成生物膜，并且全身递送的抗生素或免疫细胞无法接近。目前还没有一种方法可以将抗菌剂输送到假体关节的整个表面上，而大多数植入物都是直接压配到骨植入部位的。这种技术将为患者提供真实的益处，并且可以将目前治疗这些感染的费用每年减少约20亿美元。 预防关节置换术后感染的一种有希望的方法是使用可再吸收的原位形成凝胶，用于缓释 抗微生物药物这些新型凝胶具有以下优点，可改善人工关节感染的预防：1）有效和持续的抗生素释放; 2）柔软而有粘性的物理结构，可完全覆盖表面，防止孤立裂隙中生物膜的形成; 3）快速降解，可实现正常骨愈合，将植入物固定到位。 拟议工作的目标是生成关键的体内安全性和有效性数据，以支持未来对这些新的、合成的和完全可吸收的抗菌剂释放凝胶的临床前和临床试验的投资。为此，原位形成水凝胶 将评价其安全性和两个临床相关结果-通过凝胶部位的骨愈合质量和骨修复凝胶在预防压配金属植入物感染中的有效性。将在兔松质骨压配植入物模型中通过组织学和载荷框架测试评价通过凝胶部位的骨愈合。将通过压配毛面金属植入物进行S.金黄色葡萄球菌注入预先填充有抗菌剂凝胶的松质骨的空隙中。成功完成拟定工作将提供有关这些水凝胶安全性和有效性的临床相关原理验证数据，特别是其在骨科植入物表面的使用。这些数据将立即用于与FDA进行IND前会议，并将吸引未来对该新药商业化的投资。

DESCRIPTION (provided by applicant): Orthopaedic Surgical Site Infections (SSIs), including Prosthetic Joint Infections (PJIs), are an extremely costly health care problem, illustrated by the $70,000-$114,000 average total cost per case to treat more than 20,000 hip and knee replacement infections in the US each year. When a prosthetic joint becomes infected following arthroplasty, organisms form a biofilm on the prosthesis and become inaccessible to systemically delivered antibiotics or immune cells. There is no available option for antimicrobial delivery over the entire surface of a prosthetic joint that is press-fit directly into a bony implantation site, as the vast majority of implants are. Such a technology would provide a real benefit to patients and could decrease the current costs of treating these infections by approximately $2,000,000,000 per year. A promising approach for preventing infections following joint replacement is to use reasorbable in situ forming gels for the sustained release of antimicrobial drugs. These new gels offer the following advantages for improved prevention of prosthetic joint infections: 1) efficient and sustained antibiotic release; 2) soft yet cohesive physical structure allowing for complete surface coverage and preventing the development of biofilm in isolated crevasses, and 3) rapid degradability allowing for normal bone healing, fixing the implant in place. The goal of the proposed work is to generate critical in vivo safety and efficacy data to support future investment in pre-clinical and clinical trials on these new, synthetic, and fully resorbable antimicrobial-releasing gels. To do this, in situ forming hydrogels will be evaluated with respect to their safety and two clinically relevant outcomes-the quality of bone healing through the gel site and the efficacy of antibiotic-loaded gels in preventing infection on press-fit metal implants. Bone healing through the gel site will be evaluated by histology and load frame testing in a rabbit cancellous bone press-fit implant model. The efficacy in preventing infection will be evaluated by press-fitting textured metal implants subjected to S. aureus into a void in cancellous bone pre-filled with antimicrobial- loaded gels. Successful completion of the proposed work will provide clinically relevant proof-of- principle data regarding the safety and efficacy of these hydrogels and in particular their use on the surface of orthopaedic implants. This data will immediately be used to lead to a pre-IND meeting with the FDA and will attract future investment for the commercialization of this new drug product.