An antimicrobial-eluting bioresorbable bone filler for orthopaedic application

用于骨科应用的抗菌洗脱生物可吸收骨填充剂

• 批准号: 8712646
• 负责人: JASON D SMITH
• 金额: $ 15.66万
• 依托单位: CARMELL THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712646
• 关键词: Address; Adjuvant; Animals; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Bacteria; Bacterial Infections; Biocompatible Materials; Biological Assay; Biological Products; Blood Platelets; Bone Growth; Bone Regeneration; Cell Culture Techniques; Clinical; Clinical Research; Data; Debridement; Defect; Deoxyribonuclease I; Development; Diffusion; Documentation; Electron Microscopy; Excision; Facilities and Administrative Costs; Feasibility Studies; Filler; Fluorescence; Fracture; Fracture Healing; Gentamicins; Goals; Growth Factor; Human; In Vitro; Infection; Infection Control; Injury; Kinetics; Knowledge; Label; Lead; Licensing; Limb structure; Marketing; Metabolic; Microbial Biofilms; Modeling; Open Fractures; Operative Surgical Procedures; Orthopedics; Osteoblasts; Osteomyelitis; Outcome; Patients; Phase; Plasma; Polymethyl Methacrylate; Prevalence; Price; Procedures; Productivity; Proteins; Pseudomonas aeruginosa; Rattus; Recruitment Activity; Risk; Safety; Side; Site; Small Business Innovation Research Grant; Staging; Staining method; Stains; Staphylococcus aureus; Technology; Testing; Therapeutic; Time; Treatment Cost; Validation; Wages; Work; Workers' Compensation; antimicrobial; antimicrobial drug; bacterial resistance; base; biodegradable product; biomaterial compatibility; bone; bone healing; cold temperature; cost; cost effective; cytotoxic; design; drug resistant bacteria; improved; in vitro Assay; in vitro activity; in vivo; man; manufacturing process; meetings; open wound; prophylactic; public health relevance; regenerative; repaired; standard of care; technological innovation; tibia; tissue repair

DESCRIPTION (provided by applicant): The long-term goal of Carmell Therapeutics for this proposal is to develop a blood plasma-based biomaterial bone filler product that will elute antimicrobials to inhibit infection. Bacterial contamination is present perioperatively in 48-68% o all open wounds and 100% of severe open injuries. Per year in the U.S. ~ 123,000 open tibia fractures are contaminated, requiring an added patient treatment cost of $29,000. Additional indirect costs (Worker's Compensation, lost wages, productivity, etc.) are enormous but harder to quantify. Current standard of care involves systemic antibiotics, early debridement, and the off-label, prophylactic use of local antibiotic delivery via impregnated poly(methyl methacrylate) (PMMA) beads, which have unknown release kinetics and must be removed from the defect prior to bone reduction procedures. Clinicians need a product that enhances bone repair as well as controls infection through local antibiotic delivery. Carmell believes that combining antimicrobial delivery with its blood plasma-based biomaterials (PBMs) (which elute regenerative factors as they degrade) have the potential to meet this need. The Phase I hypothesis is that the product, the REPAIR Plus" Bone Putty, can locally deliver antimicrobials to control infection. To test the hypothesis antimicrobials will be incorporated into PBMs and their release and activity will be verified using disk diffusion-based in vitro assays. The products biological activity and biocompatibility will then be established in vitro using a metabolic assay and electron microscopy. The product's antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus and their biofilms will be demonstrated in vitro using 3D fluorescence staining and cell culture techniques. Finally, clearance of S. aureus infection in vivo in a pilot feasibility study using a rat tibia model will be established, where bacteria added to a bone defect will be challenged with the product to determine the product's ability to clear the bacteria over 14 days. Following the demonstration of feasibility in Phase I, Phase II will build on the infection control data to examine enhanced bone repair (with infection control) in vivo as well as conduct regulatory-focused studies to demonstrate biocompatibility and safety, all to prepare for a first-in-man clinical study. Carmell will additionally recruit an antibiotic supplier as a partner for supply and regulatory documentation as well as for potential licensing opportunities. Overall, an effective, off-the-shelf, and easy to use product that could improve patient outcome and reduce treatment complications as well as costs will have enormous marketing potential for the treatment of open tibia fractures and other open bone fracture applications.

描述（由申请人提供）：Carmell Therapeutics 该提案的长期目标是开发一种基于血浆的生物材料骨填充产品，该产品将洗脱抗菌剂以抑制感染。围手术期，48-68% 的开放性伤口和 100% 的严重开放性损伤存在细菌污染。在美国，每年约有 123,000 例开放性胫骨骨折受到污染，需要额外增加 29,000 美元的患者治疗费用。额外的间接成本（工人赔偿、工资损失、生产力等）是巨大的，但难以量化。目前的护理标准包括全身抗生素、早期清创以及标签外预防性使用通过浸渍聚甲基丙烯酸甲酯 (PMMA) 珠递送的局部抗生素，这些珠的释放动力学未知，必须在骨植入前从缺损处去除减少程序。临床医生需要一种能够增强骨修复并通过局部抗生素输送控制感染的产品。卡梅尔认为，将抗菌药物输送与其基于血浆的生物材料（PBM）（在降解时洗脱再生因子）相结合有可能满足这一需求。第一阶段的假设是，REPAIR Plus“骨泥”产品可以局部输送抗菌剂来控制感染。为了测试这一假设，抗菌剂将被纳入 PBM 中，并且将使用基于盘扩散的体外测定来验证其释放和活性然后将使用代谢测定和电子显微镜在体外确定产品的生物活性和生物相容性，并证明产品对铜绿假单胞菌和金黄色葡萄球菌及其生物膜的抗菌活性。最后，将使用大鼠胫骨模型进行体内金黄色葡萄球菌感染的清除试验，其中添加了细菌。 骨缺损患者将接受该产品的挑战，以确定该产品在 14 天内清除细菌的能力。继第一阶段的可行性论证之后，第二阶段将在感染控制数据的基础上检查体内增强的骨修复（感染控制），并进行以监管为重点的研究以证明生物相容性和安全性，所有这些都是为了为首次临床试验做好准备。 -人体临床研究。卡梅尔还将招募一家抗生素供应商作为供应和监管文件以及潜在许可机会的合作伙伴。总体而言，一种有效的、现成的、易于使用的产品，可以改善患者的治疗效果并减少治疗并发症和成本，对于开放性胫骨骨折和其他开放性骨折应用的治疗将具有巨大的市场潜力。