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针对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物产品，该产品将抑制抗菌剂以抑制感染。所有开放性伤口的48 - 68%和严重开放性损伤的100%存在围手术期细菌污染。在美国，每年约有123，000例开放性胫骨骨折受到污染，需要增加29，000美元的患者治疗成本。额外的间接成本（工人赔偿、工资损失、生产力等）数量巨大却难以量化目前的护理标准涉及全身抗生素、早期清创以及通过浸渍的聚（甲基丙烯酸甲酯）（PMMA）珠粒的局部抗生素递送的标签外预防性使用，这些珠粒具有未知的释放动力学并且必须在骨复位手术之前从缺损处移除。临床医生需要一种产品，可以增强骨修复，并通过局部抗生素输送控制感染。Carmell认为，将抗菌剂输送与其基于血浆的生物材料（PBM）（在再生因子降解时吸收再生因子）相结合，有可能满足这一需求。第一阶段的假设是，该产品，修复加"骨腻子，可以局部提供抗菌剂，以控制感染。为了检验假设，将抗菌剂掺入PBM中，并使用基于纸片扩散的体外试验验证其释放和活性。然后使用代谢试验和电子显微镜在体外确定产品的生物活性和生物相容性。该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将使用3D荧光染色和细胞培养技术在体外证明。最后，对S.将在使用大鼠胫骨模型的初步可行性研究中建立体内金黄色葡萄球菌感染，其中添加细菌 将用产品挑战骨缺损，以确定产品在14天内清除细菌的能力。在第一阶段证明可行性之后，第二阶段将建立在感染控制数据的基础上，以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，所有这些都是为首次人体临床研究做准备。Carmell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、现成且易于使用的产品，可以改善患者结局并减少治疗并发症和成本，对于治疗开放性胫骨骨折和其他开放性骨折应用具有巨大的市场潜力。